Transgene SA (TNG) Earnings Call Transcript & Summary

Hello, everyone. Thanks - Thank you very much for being here, either in person via webcast or in the replay. It's a great pleasure to have you here with you today with our management team and our leading clinicians from around the world who will share their enthusiasm on our development. Today, we have the honor to be hosting Jean-Pierre Delord, MD-PhD, General Manager of IUCT Oncopole of Toulouse; Adel Samson, MD-PhD, Clinical Associate Professor, CAI U.K., Clinician Scientist and Honorary Medical Oncologist for the University of Leeds; and Pedro Romero, MD Chief Editor of the JITC and Deputy Scientific Imaging Director of the Lausanne branch of the Ludwig Institute for Cancer Research, who are here with us in person. Also, Christian Ottensmeier, MD-PhD, FRCP, Professor of Immuno-oncology at the University of Liverpool, The Clatterbridge Cancer Center, NHS Foundation Trust; and Matthew Block, MD-PhD, Medical Oncologist at the Mayo Clinic, who will participate remotely. Having their support today gives us a lot of confidence on the products that we are developing. I would like also to thank a lot of the organization team and our support companies who helped us make this a reality. And special thanks to Lucy, great job like always. Today, we are going to discuss the latest progress that we have made on our clinical trials, and you will see that the data that we are generating in patients can really be game-changing in oncology. Maud and our [indiscernible] colleagues will walk you through the very promising data that we have generated. Also, science is at the core of who we are and what we do at Transgene. We are 160 employees, all committed to pushing the boundaries of innovation to better treat cancer patients. What you will see today is also the result of the hard work and daily commitments, thanks to all of them. Today, we will take the time to deep dive into the way we design our candidates and showcase the highly innovative content. Eric will discuss our highly innovative platforms, [indiscernible], that could be created, thanks to our years of expertise in viral vectors. Our uniqueness also comes from our capability to partner with best-in-class innovators. Our collaboration on artificial intelligence with NEC precisely falls into this category. When it comes to developing a product such as individualized vaccines, we biologists have ventured into the wild world of artificial intelligence. I believe it takes humility to go and partner with specialists. But by doing this, I'm certain that we have integrated one of the best, if not the best artificial intelligence tool for antigen selection on earth. Combined with our vision, with a powerful vector and with an adequate clinical positioning and with the commitment of our employees and clinicians present today, it could be very well translate to landscape changing opportunity for patients. Our uniqueness also relies on our condition that the intravenous routes could be the next big things for oncolytic viruses. With TG6002, we have demonstrated in the clinic that this route of administration is feasible. This is important for TG6002. It is important for the Invir.IO platform, and this is important for the partners such as AstraZeneca that will help us go beyond what we thought could be the limitations of our technologies. There are also a few topics that are of great importance that we will not have time to cover today. For instance, manufacturing. This is key in our industry. For both our platform, on oncolytic viruses and therapeutic vaccine and even more for individualized treatment. So as you know, we have 2 technology platforms, therapeutic vaccines and oncolytic viruses for products in the clinics, and a lot of ideas and new ideas that will be communicated today. I now would like to welcome Maud, who will be hosting the session on therapeutic vaccines. Thank you, Maud.

Thank you, Hedi. So I am very glad to introduce and to share this session on cancer vaccine in the treatment of patients with solid tumor. As you all know, immunotherapy has become the fourth pillar of cancer treatment besides surgery, radiotherapy and chemotherapy. This has been possible, thanks to years of intensive work and strong confidence in the potency of immune system to destroy cancer cells. This has led to the advent of checkpoint blockers. And we know that checkpoint blocker have demonstrated the efficacy in many solid tumor types. Having said that, the response rate to checkpoint blocker remain in the range of 20% to 30%. It means that for a significant proportion of patients, they are not responding. They have primary resistance to immunotherapy. In addition, among patients who respond, unfortunately, responders' relapse and develop secondary resistance. So obviously, there is a need for a new therapeutic option to overcome primary and secondary resistance. There is you know many, many developments in that field, but we believe that vaccine cancer -- virus-based cancer vaccine can be a potential game changer. So the concept of cancer vaccine is very attractive. So you inject vaccine at the distant site of the tumor, where the immune system is functional. And this vaccine will promote de novo in specific immune cell response and also amplify existing T-cell response. Very attractive concept, but you know very well that clinical data coming from the past clinical trial has been disappointing so far. So obviously, we need new technology to make cancer vaccine a success. So the first key element for success of vaccine is a choice of the antigens. In the past years, the focus has been on oncofetal antigen or antigen, which are expressed by tumor cells. But those antigens are poorly specific because they are also expressed by normal sales, and they are poorly immunogenic. So that's the reason why Transgene focused is R&D development on 2 categories of antigen. The first 1 is OncoVille and more specifically, TG4001, which is targeting HPV. You know that HPV is a strong -- HPV-16, specifically, is a strong oncogenic driver and is associated with a number of tumor like head and neck cancer, and anogenital cancer. The other category of antigen where our focus has been made is, are neoantigens. Neoantigens are specific of each patient's tumor. So it's a personalized vaccine approach. And obviously, neoantigen produced very strong and potent specific immune response. The other key element for the success of the cancer vaccine is the choice of the platform. Antigens by themselves are sufficient to promote a strong stimulation of the immune system that need to be adjuvanted. There is several platforms which are used, and some of them are illustrated here, like donating pulse vaccine, DNA, Erni, peptides and viral vectors. And obviously, what we have seen is that viral vector induce a strong and durable stimulation of the innate and adaptive immunity. So having said that, it is important to show you and to convince you of what I am saying. And I will leave the floor to Eric, who will provide us with the demonstration of the potency of viral vector and more specifically, MVA. So the floor is yours, Eric.

Thank you, Maud, and hello to everyone. So next slide. So I'm Eric Quemeneur, I'm the Chief Scientific Officer of the company. And I will, as Maud said, give you some details on the value of viral vectors compared to other available technologies for the design of cancer vaccines, and share with you what we think are strong points in favor of MVA compared to other possible viral vectors. So brightly, Maud also recall that designing a successful vaccine is a heart of combining the choice of right antigens from neoantigens to oncoviral antigens. It's also a question of selecting the most suitable target populations. And you'll see in our presentations that we take a lot of care in analyzing and phenotyping our patients during and after treatment. And the third pillar in this successful design is the selection of the good vector. We have chosen viral vectors for the reason I will detail here. The first one is, of course, to rely on their strong biological properties. Viral vectors are intrinsic immunological devices on new machines build to interact with the immune system. We know that most of the vectors would be able to stimulate B-cell response as well as T-cell response. And pox viruses are well documented to induce long-lasting T-cell memory response. Second aspect of that is the ability to have a potent antigen display. And we also know that among the viral vectors, pox viruses are strong infecting antigen-presenting cells, and this is in the periphery, but also in the tumor surrounding. The second criteria of choice is, of course, the easiness for clinical development. Viral vectors as pox viruses have been used for decades in the frame for small-pox vaccination. So there is a well-documented track record of safety. Furthermore, the flexibility and ability to design a large diversity of viral vectors based on MVA has been also documented over the years, and we take that as an asset for our technological development. And third, at least the industrial development point of view is important. And this experience we have built over the years with MVA is also very instrumental in our development, in particular for the private neoantigen vaccine. That depends on our ability to be fast, and inefficient in designing a product for every single patient. Among the various technologies, of course, there have been a lot of competition. And most of the community has been informed on the merit of mRNA-based technologies that is nowadays a direct competitor to us. But you might remember that before COVID, we also had to face against plasmid approach or DC-loaded systems. We still believe that even after the COVID period, viral vectors have some differentiation point. What we learned from the mRNA development is that they are very good at raising B response, still discuss whether they are good at raising long-lasting memory response. And despite major investment made by our competitors, we know that there are still bottlenecks in being able to design a product for a single patient. Viral vectors, of course, present a lot of advantages in terms of mode of action and manufacturability. Of course, there are always drawbacks, but our experience with MVA make those, I would say, limitations, something that we don't consider that much, considering our experience with the vaccine. If I move to the kinetics of the immune response, what is specifically strong with viral vectors is that they act very early on by stimulating innate response. And that's very important. Most of the technology around peptides or mRNA needs some adjuvant component in vaccine for boosting the innate response. We know that we have strong factors in the MVA to, early on in the game, stimulate NK cells innate immunity at large. It will be priming the secondary engagement of helper T cells and effector T cells. So this kind of a long-lasting activity is also, for me, a key component of the value of the viral vectors compared to other technologies. So many, many lessons have been acquired during the development for almost 20, 30 years with MVA over the years. So the first one is that the vector has proven to be usable in several routes of administrations, from intravenous to intramuscular, intra-tumoral, even intraperitoneal, so many experience and the way we could better stimulate all components needed for a strong antigen response. The second, of course, is obviously the ability for large reengineering of the vector. What is noticeable is the large cargo capacity with the capacity documented to be up to 2025 KB that allows us to embark either very large antigen sequences plus stimulating components like cytokines or antibody that can be built in director. The one important point is also the ability to really nicely interact with several steps in the process of mounting long-lasting immune response, especially the ability to engage intrinsic adjuvant properties of the vector, especially manipulating the TLR3 pathways, plus the ability to also favor the TH1 skewing in a T-cell response. There are 2 examples of recent products we have developed. The first one is TG4001 for a [indiscernible] we present the recent data. Please notice in this design that we have made the choice of encoding the entire E67 protein sequence. So to present to the immune system, the largest set of T- and B-cell epitopes that one can imagine. They are all available for presentation. And we know also by antigen processing that we are not restricted in terms of HLA typing. So any kind of patient appetite could manage a presentation of the vaccine. We are not restricted in that sense. For TG4050, which is the product expressing private new antigens, the -- our expertise in protein engineering allowed us to make this design, presented here with 3 different promoters, including 3 polyeptopic assets, each expressing 10 new antigens linked all together by a small linker peptide that was optimized for optimal antigen display. So these are 2 examples of what could be achieved. And of course, much more to come in terms of medical engineering. If I come to the clinical experience, these are again 3 examples of recent developments. Some of you might consider that they were not success. But what is clear is that all trials demonstrated the superiority of the MVRM compared to the reference group. And we had very, very significant response rates and benefit in the survival in those advanced patients where most of the immunotherapy approaches failed. As Hedi said, research is very active in our field, and internal research has been focused on optimizing the way we design our product. That's key for the TG4050 program because you might know and that will be recalled by Christian, that a fast responsiveness through the vector design is needed. In a matter of months, you have to design from the tumor sequencing, a customized product in less than 3 months, if possible. And so we have developed the very specific techniques to be fast in that cloning and characterization of the vaccines. We also optimized the way we design our polytopic assets. We have an internal software that is called Vac Designer that help us make the better prediction of the way we should organize the new peptides in the vaccine design to be sure that we have a patient for every single one. The curves would highlight the progress made over the last 2 years in the rate of success for antigen design. And today, we are close to 90% of the patients that could be successfully treated and propose a vaccine, when the end of the trial. The box on the right is an example of a brand-new discovered pox virus that is not yet in the clinic, but for which we are working at positioning. It's a PCPV, another pox virus, different from MVA and other related vaccines in the sense, it can induce a very large amount of internal alpha at the site of administrations. So boosting dramatically, the innate engagement. So these are examples of the progress that have to be done in parallel to the clinical designs. So in summary, I think we -- I hope that I convinced you that viral vectors are very differentiating carrier system for vaccine presentation. MVA, among the viral vectors, is well suited for T-cell response and very different from other type of immune response generated by other small viruses, enabling the presentation of very large antigen sequences. And what is also important is that the experience gain over the years makes us very reactive and able to design efficient clinical trials. So next presentation will be Jean-Pierre, and maybe a few words from Maud.

So thank you so much, Eric, for this convincing demonstration on the capacity of NVH to stimulate the immune system. And so now we will have the presentation from Jean-Pierre Delord, who is the General Manager of IUCT Oncopole of Toulouse, on the updated clinical data we have on the TG4001 HPV-16 therapeutic vaccine.

Thank you, Maud, and thank you to all my colleagues from Transgene. We work for -- with Transgene for more than, I guess, more than 10 years because we are at the beginning of the story of the MVA proof-of-concept studies. I can't remember exactly when it was. I guess, more than 10 years ago. So it's always a pleasure to meet my colleagues and to work with them every day. So I'm a medical oncologist by background. And I'm happy to present to you, some of the first results we have with proof-of-concept study, the first in human and the beginning of Phase II trials with the TG4001, which is a therapeutic vaccine, currently in Phase I. So I can -- let's see. So I'm the current general merger of a new big cancer comprehensive center in Toulouse in France. So it's a pleasure to work with all the teams, especially those who are implicated in clinical research. We have a terrific Phase I team and also, at the transactional level with Professor Ayub, who is one of the key opinion leader in the field of immunology and especially, the T lymphocyte specific of antigens and especially tumor antigens. So next slide. So this is a team involved in the head-and-neck program. You can see all my colleagues involved in the recruitment and the care of all the patients we have recruited in the trial. And this is one of the key images. The slide has been, I guess, asked by my Director of Communications. I'm just happy to say that last year, we published close to 700 papers, including the clinic and the fundamental research. So it means that we published 2 papers a day, except on Sunday afternoon. So the team can have some rest. There's no big issue with people. So as you probably perfectly know, HPV's worldwide health concern. If you read the paper published by the World Health Organization, each year, more than 700,000 people could be facing HPV-induced cancer in the Western countries. So we consider that more than 25,000 patients a year have diagnosis of cancer induced by HPV, mostly euro fungal, prerenal and of course, as you perfectly know, cervical cancer. So in France, a number of new patients a year is between 5,000 and 6,000 a year. So next slide. So this is a slide describing what are today, the standards of care. So I must say that treating patients with HPV cancer is unfortunately, is still a prehistoric story because we're treating these patients with only surgery sometimes, but mostly radiotherapy and even if the radiotherapy has made, in the recent years, a lot of technical progress, it's still a treatment, with provide to patients, a lot of poor condition after cancer. And we usually use with that radiotherapy, all the real chemotherapy drug called cisplatinum. And cisplatinum is also 1 of the most dirty chemotherapy drug we have in the daily practice. Very efficient to radiosensitize the cancer cells, but still very tricky to use in the daily practice. So that's why, once a patient relapsed with an HPV-induced cancer, the options to treat that patient are very limited, and the prognosis of metastatic HPV-induced cancer, it's very poor. And the other targeted drugs or chemotherapy compounds doesn't provide any good option for treatment and to modify the overall survival of disease. So that's why immunotherapy, first-generation immunotherapy, like PD-1 antibodies has been tested in the clinic. And the results are not so good, but it is also a sort of proof of concept considering that some patients will benefit from the treatment. So if you pull all the data trying to see what's going on with HPV-induced cancer patients when the disease become a metastatic disease. This kind of treatment works between 10% and 20% of cases. So it's not enough to modify their overall natural history of that cancer. But we have some case in the daily practice of patient who benefit from the drug with a partial or complete response. So it means that reactivating their immune system can be an option for patients with cancer when it becomes a metastatic disease. So that's why we have designed with the support of Transgene, a clinical trial with the TG4001. So as it was mentioned by Eric a few minutes ago, so this is a DNA construction with 2 major epitopes of HPV, E6 and E7, and also the integration of a boost by IL-2, so Interleukin-2, which is 1 of the major cytokine in inducing T-cell response against many antigen, including viral antigen. So all the construction is done on Cara-modified virus and injected subcutaneously to patients in the trial. So again, I guess that what you see on the left panel, that has already been presented, but I would just like to focus on the results concerning intraepithelial carcinoma of cervical cancers due to HPV. So it was the first time in the literature where we could observe in the paper, published by my colleague, that complete disappearance in between 1/3 and 40% of patients with a tumor, what we call an intraepithelial tumor. It's just before the cancer becomes an invasive form of cancer. So all the patient was treated after the vaccination by surgery. But you can see that the response rate, which was a complete histologic response rate in that subgroup of patients with an infection, due to HPV-16 was observed. And again, it was really a strong signal showing that the therapeutic vaccination could do something directly against transform cancer cells. So this is the characteristic of the patient included in the Phase I part of the first-in-human trial with TG4001 plus PD-L1 antibody. So we directly do the Phase I trial with a PD-L1 antibody. And as you can see, I'm not going to go deeply in the details. But as you can see, the patient were what we call AV pretreated patient. So it means that the number of organs involved by the metastatic disease was superior to different sites, and the number of previous lines of treatment was between 2 and 3. So as you can see, the patient, of course, was patient of first-in-human trials, they were still in good standing, but they had been previously easily pretreated with other anticancer drugs. So the scale of injection was what is the following one. So there is an injection phase when we vaccine the patient once a week during 2 months. And then we do form a new injection every 2 weeks. And of course, the treatment with the PD-L1 antibody was used all the time, and the tumor assessment was done every 2 months. So this is a very conventional classical schedule for assessing the safety in Phase I trial, but also the efficacy like we do in, again, classical Phase II trial. So we have already observed that TG4001 Plus Avelumab as definitively an antitumor activity in the overall patient population. So we have more than 40 patients of patients with the disease control. I'm going to go more in the details concerning the level of disease control we did observe. And response rate, it means tumor shrinkage. So just to let you know what we call a partial response in oncology is that we have the volume of metastasis that decrease of more than 50%. So it means that we can see with the classical CT scan or MRI, a clear tumor shrinkage that is reproducible at least 2x after the first CT scan compared to baseline. So what is also very enthusiastic for the people in the clinic was that we observed 1 complete response with the patients that are still doing well. And this was a patient with an anal cancer and with metastasis on the peritoneum surface. So this is something in oncology, when that kind of cancer is reaching the peritoneal surface usually, the chemotherapy doesn't work at roll. And the prognosis of that kind of tumor invasion is very poor. Usually, the patients are passing away after only a few weeks of humans, whatever you do using conventional chemotherapy. So the question we ask what -- it's the way we're doing first-in-human trials in oncology. So we usually include first, patients that have been already treated with a large number of drugs already registered in that indication. But what we have observed is that the patient with very large number of metastasis, especially those with liver metastasis at a very poor prognosis. And for many reasons, I don't want to go back to a scientific background concerning liver metastasis. But we all know in the clinic that liver meta have a special prognosis in oncology. And we did observe that those patients were -- has no benefits under treatment. So excluding the patient with that special clinical presentation of metastatic disease, we upsell that the overall response rate was observed in 1/3 of patients. And the overall survival was more than 1 year. Meaning again, that the proof of concept to whether adding a therapeutic vaccine and monoclonal PD-L1 antibody, was probably doing something that was very -- it was at least a very good signal in that very special subgroup of patients. So this is another way to show you the results. So it's something we call a spider plot. So it's a longitudinal reports of the size of the tumor from 1 patient to -- compared to the other. So as you can see here, as an example. So the size of the metastatic disease is increasing very quickly in that subgroup of patients. But for a large part of the patients, the size of the metastatic is decreasing very largely with a size of metastasis of less than 50% of them. One patient with a complete response very, very quickly. And all the patients with what we call a long-term effect of the vaccination and the stimulation of the immune system with a follow-up, and we're waiting for the next follow-up in the next few months, I guess we will get it very, very quickly. So there is some patients with a very long-term benefit with no sign of any progression of their cancer. So it means again that without chemotherapy, without radiotherapy, you can control or probably do more than a simple control of the disease, but obtaining a clear remission of the disease in 1/3 of patients again. Next slide. So this is the first result of the monitoring of what we observed in each patient. So on that panel, this is a level of response against E6 and E7 at baseline before receiving any injection in the trial. So as you can see, there was no patient with any cytotoxic T cell-specific cells in PBMC that has been assessed by Edispot. And after the vaccination period, there were 7 patients with very clear and so we observed that a peripheral level. So it means that probably the very good signal we observed in -- during this Phase I trial was clearly due to the induction of T-cell response specific on the -- of the antigens of the HPV virus. So this is what has been observed at the tissue level within the metastases of patients. We have made a sequential biopsy program in order to see what's going on. And the most important result is probably on the medium panel where you can see that CD8 per cell, it means the cells that contains T cell -- the memory T cells that are in cancer, the tumor cell memory, but also those who are the effector of the cytotoxic effect were increasing numbers within the tumor. It means that all the T cells were probably acting close to the cancer cells and the tumor shrinkage were linked to the cytotoxic effect of the combination of the vaccine and the PD-L1 antibody. So there is a current comparative randomized Phase II trial. We have decided in -- after discussion with all the investigators and our colleagues from Transgene, to exclude from the Phase II part of the current trial, the patient with liver met. I mentioned before, we do believe that these patients do not have a clear benefit from the combo. So we are currently including patients with recurrent metastatic and of course, have not been previously exposed to cancer immunotherapy and whatever the level of expression of target of PD-L1 antibody. So it's a randomized trial where we compare directly to the standard of care, which is PD-1 or PD-L1 treatment, the combo of TG4001 and PD-L1 antibody. So the primary endpoint is a mix between tumor shrinkage and long-term benefit. We call a progress on free survival, and we are expecting the results very soon because the recruitment of patients in that trial is good and a little bit superior to the recruitment that was expected at the beginning of the trial. So I guess between, I don't know, but between the end of this year and early next year, we will get all the clinical results concerning that comparative Phase II trial. Thank you for your attention. Okay. Sounds good. No. The most important information is that we -- the interim analysis are expected in the next 3 months before Christmas.

Thank you so much, Jean-Pierre, for this excellent presentation. And truly, Jean-Pierre has shown the evidence that the combination of TG4001 -- and avelumab is active in advanced HPV associated cancer. And this led us to implement this randomized Phase II trial, which is actually the first Phase II randomized trial in anogenital cancer. And as previously mentioned, we are expecting very soon the result of the interim analysis before the end of the year. So we are going now to move to the other categories of antigen I mentioned in the introduction, meaning new antigen. So here, we are speaking about a personalized approach, meaning that a batch of vaccine is prepared for each individual patient. Here, the clinical positioning is different. We are testing this personalized vaccine in early stage of the disease as a single agent. And again, it is direct towards the tumor specific new antigen of the patients. So what do we mean by early stage of the disease? You know that when a patient is diagnosed with cancer, usually, the tumor is surgically removed. But importantly, for some patients and from some tumor types, the diagnosis is made at an advanced stage of the disease, which means that the risk of relapse is quite high. So even though the patients in the apparent clinical remission based on standard imaging procedures, there remain some micro beta status, which needed to relapse, that we call minimal residual disease. And this MRD offers a very good opportunity to test a personalized vaccine as a single agent. The goal, of course, being to delay as much as possible, the relapse and even, if possible, to prevent relapse. So we have 2 ongoing Phase I trial, and we have selected 2 indications to test our personal vaccine, TG4050. One is ovarian cancer and the other one is the head-and-neck cancer. So patients who are selected in our Phase I trial are patients in clinical remission. So meaning in -- with minimal residual disease. We know that in those 2 indications, checkpoint blockers have limited or no efficacy. They had even been shown recently at the last ESMO Congress in head-and-neck with pembrolizumab, a negative Phase III trial in the adjuvanted. The immune system of those patients is functional because they received a limited number of produce line of therapy. And those 2 cancers have low to medium tumor mutational burden, which means that it makes -- is there for us to identify the new antigen, the immunogenic new antigen that will be included in the vaccine. So maybe a few words by -- on neoantigen. What do we mean by neoantigen? So neoantigen, antigen specific of each patient's tumor. So they are supposed to induce a very, very strong immune response. They are 100% tumor specific, have not been subject to central tolerance. And they are more immunogenic. Obviously, that the so-called classical [indiscernible] antigens. We are able, in our vaccine, to introduce up to 30 new antigen. And for doing that, obviously, we need good tools. And one important tools for this identification is obviously the use of artificial intelligence. And we will have now a presentation by Kaidre Bendjama, who is the scientific leader of the new antigen program on the use of artificial intelligence, in general and more specifically, in clinics.

So thank you, Maud. Good afternoon, everyone. So just during this afternoon, I step aside to speak about this term of artificial intelligence. You will all be hearing it more and more. You've been hearing it over the last the last few years, and many of you are watching it with some wise skepticism. So the first thing I'd like to point out is that what we call artificial intelligence encompasses a large array of technologies, a large number of approaches that are already widely implemented in our daily lives. There are many users of so-called artificial intelligence system. Some very trivial, in your phone, in many applications of your phones; and some in more regulated environment, in banking. A lot of use for artificial intelligence have been emerging in those last year or even in some critical application, highly regulated environment like in air transport, and you'll find a lot of artificial intelligence in some airlines, particularly those made in Toulouse close to the city. Health care is no exception to that. Today, there is more than -- or at least there is -- at least 100 different devices that are registered by the FDA that use some sort of artificial intelligence or some sort of machine learning to make decision about the care of patients. This is in various medical specialties. It's essentially in the U.S., it's in oncology, but also in critical care or in some other applications. And some of those decisions are critical for the patients, for instance, to get system for the 3 years of patient intensive care, you get eligibility for some critical therapy procedures. So those systems have reached a level of maturity to allow them to be robust enough to have a regulator review them and approve them for use, which is critical for the patient. So this evolution is not something that happened from one day to the other. It's actually an evolution that have taken decades. It started very early when you look in the late '50s or early '60s, they already had what they call the intelligent machine, and it started with diagnostics. And those machines were used to automatically generate data from -- for the patients and mainly there were some very early markers for -- used in critical care. And by quantum leaps, artificial intelligence technology have evolved from intelligent machine. We went to a learning or to call machine learning, which are like traditional approaches of artificial intelligence to move toward deep learning and what we call our foundation models. Foundation models are the most advanced models. They are not very much used in health care now, but they have some other use essentially in language or translation, for instance. Today, with TG4050, we're really making use of what we call deep learning, and I'll come to that later. In parallel to those evolution and those progress in machine learning technologies, oncology had like a parallel track of complexification and sophistication a long time. Of course, the care of cancer patients have improved a lot over time, over the last decades, but this came with a trade-off of complexity because we started from 1 indication, 1 recommended treatment, very easy, very simple guideline to apply as long as you have the diagnostic for the patients and we moved them to a more characterized -- more molecularly characterized disease. We targeted therapy. That's what I call here oncology 2.0. And we went to more and more data intense process of characterization of the patient and therapeutic decision-making. So with TG4050, we are at a convergence point basically. We're at an edge where the data you get for every single patient, which is a whole-exome sequencing and full transcriptomic of the tumor and the patients, where this amount of data becomes too high to comprehend for the human brain and the single physician. And that's where artificial intelligence is really of help. And this help comes only because the performance of this technology have increased a lot. So I've spoken about deep neural network. I will explain on the work letter, but deep networks are the AI technology, the machine learning technologies that allowed those approaches to have a much higher performance over the last decades. Why? Because those approach can comprehend and take into account a lot of data, a lot of input data without necessarily deciding which part of the data is important. It just takes all the data during the learning process, have this data used to learn -- to teach the system and come out with a conclusion or come out with an information. Unlike other approaches, there is no human -- I would say, prejudice or human hypothesis, on which part of the data is important. It's not this gene or this gene. All the data gets in and the system itself will select what is relevant or not, for the final outcome. This has driven a lot of performance. And for instance, there is this famous example of computer vision in a given task where machine learning has a 26% error rate in 2011. Today, we are less at 3%, which is basically turning the table phase to the human contender, which is around 5%. So those approaches have -- had allowed a tremendous increase in performance. So I've spoken about neural network. I'm not going to get into the details about the mathematical way neural network works. But what you have to keep in mind, it's basically a compression of information. You start from a complex information. And here, the complex information is a picture. A picture is a complex thing. There is a background, there is, what is on the picture. It varies from 1 angle to the other. There's a lot of complexity, basically, in the input data. And you go through this process, and you come up with the information you want, which is the animals that is on the picture. Is it a cat? Or is it a dog? And this is a very simple information that goes into only 3 letters. You don't need all the information that is in the picture. So basically, a neural network is a way to start with a lot of information, many of it relevant, many of it irrelevant, and come down to the very single information you want. It's transforming a lot of data into relevant information. So how it does that? It does that because it's organized as unit of calculus that are like neurons, that are organized in layer. For instance, the first layer is going to take each one a small part of the picture. The second layer is trying, I don't know, to look for whiskers, for instance. And the third layer is to say, "Oh, I see many neurons of the second layer have picked up whiskers and the organism metrically around the mouth, then it's a cat," and then you come up with the information. So it's a way to lose the complexity of the information, gain the relevance and compress the information. And when you think about it, I started with this cat and this dog, but then you apply it to cancer. Cancer is actually a data mix in terms of genomic because you get variability across patients, of course. And as we all know, everyone is different. You get variability across the diseases. Many people with the same disease, but these diseases will have a lot of different molecular feature and within the same patient should get viability across space, meaning in different position in the tumor into different metastasis, but also a long time. Because when you treat these patients or the way you let the disease evolve, it has also changes into its complexity and its genome. So a lot of variability, highly heterogenous, highly parametric. And the point with the immune system is that you get all this mutation in a tumor, but only a very small fraction of those mutations are going to be relevant to make a vaccine. Actually, if you look at all the mutation, one of the numbers of relevant mutation for the immune system would be between 1% and 5%. It varies, but it's only a minor fraction. So when you want to do a vaccine based on those mutations, you better have a system that helps you to select what are the relevant mutations. So that's what we do. And we use deep neural network-based technology or a flavor of this approach that was developed by a Japanese company called NEC, that was mentioned before. So NEC has been working on 2 aspects. The first aspect is the mathematical basis and the technology of machine learning, and they've been 1 of the driver in this field with some of the top machine learning scientists working in the research laboratory on one side. And on the other side, they've been working on the learning of this system by generating data, of course, public data, but also perforatory data to feed the system to learn, to have the system learn how to recognize the good antigens. And this is something that happened throughout the last decade. They've been doing that for almost 10 years now, and that's the system that we have built in into our 4050 process, to design the vaccine. So this vaccine is now into its first phase of study. A lot of people wonder whether this is going to be a value, so-called validated system, whether it's going to be efficient. It's too early to answer now, but we do have some data that are very encouraging. First, the colleagues at NEC, when they have -- when they wanted to implement that in the clinic, they did some exercise to see whether this system has the capacity to detect what are relevant mutation. So they've started with existing data on T-cell therapy that were established by the Rosenberg's lab. So you know what he's doing, Steven Rosenberg is that he's taking patients, looking at the mutations, and testing mutation by mutation, which one is actually leading to an immune response that is beneficial for the patients. So across 7 clinical trials, he did that with more than 700 mutations and he identified 23 clinically relevant mutations. So what we did here in this exercise is that we take the system we use into our trial, we feed the system, the 700 mutation, and we ask among the 700-plus mutation, can you tell me which one are actually relevant for the patient. And we see whether this system is able to find back the 23 that Rosenberg shown as being beneficial for the patient. So it depends, of course, a question of threshold and so on. And those familiar with the performance of diagnostic we'll see that we get an IRR under the AUROC curve which is more than 90 -- 0.9, 90%, which is an excellent performance for such system. If we were to use classical approach based on expression and binding, like netMHCpan, we would have much less performance. So this is obviously a retrospective exercise and it's not a data from our studies what I've just shown. But now when we look at our patients and our Phase I that we are running, we have data -- at the time we had data for 6 patients, we did this little theoretical exercise. So for the 6 patients, we have more than 2,000 mutations that were expressed and somehow binding in terms of CA mentioned in those 6 patients in total. And the total for those 6 patients, we generated, of course, 6 different vaccines, and we used 115 different targets suggested by the AI. Among this 115 target, 36 turned out to be immunogenic in the patient. So you look at 36 positive by [indiscernible] spot out of 115, is it a lot? Is it not enough? We don't know, but still, if we were to select them randomly just looking at binding and looking at expression, we would have less than 1 chance out of 118 billion to achieve a similar performance. So I can tell you today that the AI system we'll do a decent job a sufficiently good job to treat the patient and deliver to the promise. But what I can tell you is that it's doing much better than having like a very classical I look at what is expressed and what's binding and I select it. 1 chance out of 118 billion is not a lot, and you have much more chance to win at the national lottery than achieve this type of performance. So this is antigen design, vaccine design, we have other use of AI because basically, we start from the same data. We generate a lot of data of each patient, and we try to create value out of this data beyond having the vaccine. And one of the first things that comes into mind is to use this data to characterize the immune contexture and characterize the patients to better understand which are the patients that are actually responding to the vaccine, which are that are benefiting from such approach and which one that probably benefits less and that we probably should not treat. So using this type of system, we can characterize each one of our patients and compare it to the disease population globally. So we can see how our patients compare to the global disease population, whether they are rather hard to treat, whether they were more like good prognosis patients. That's something that we can do, and we can classify them from human desert to which we remunerate and so on and the classical immunological characterization as well as patient by patients using AI. For each individual patient, we can create a profile and see whether this patient would normally benefits from other existing therapies, whether we are actually having a patient benefiting from the vaccine, while this patient would normally, according to the existing letter, should have less chance to benefiting from existing therapy. So basically, it's a way to better understand our patient and better target our vaccine to the right population. And that's something that we do for exploratory purpose, but that we do on a routine basis on our operations. So in a nutshell, a massive amount of data, systems that are getting mature enough to achieve regulatory review. It's adaptive, it's learning from each time it works. It basically fed back with the data we're generating. So it's improving over time. And it's only at the start because today, it helps designing the vaccine. Tomorrow, it will also help target the patients and provide further information to the clinician that is probably our value beyond just providing the vaccine. So now I'll let the floor back to Maud and we'll get into more information about our clinical trial on our vaccines.

Thank you so much, Kaidre, of this very well documented presentation. So we have now in our hands and in clinic a very innovative vaccine based on this personalized approach. So we use the MVA vector, and we have seen with Eric, the capacity of these viral vectors to promote a very strong and durable stimulation of the immune system. We have also, in Transgene, the GMP manufacturing capacity. So we are able to produce for each patient the batch needed to treat him. And we have the technology which are needed to identify the immunogenic neoantigen based on the artificial intelligence, which support of NEC, which is also supporting 50% of the cost of our development. And we have also internally designed this vaccine design tool, which is able to optimize the selection of the cassette and the manufacturing capacity of -- for the vaccine. And last but not least, we have also skilled and very enthusiastic investigators. And thanks to them, we are able now to present to you clinical data, and I will leave the floor to Christian Ottensmeier who is Professor of Immuno-oncology University of Liverpool. So Christian, floor is yours.

Thank you so much for the very kind introduction. I can hear myself echo, so I'll try and do my best to only speak once to you. So I think the really extraordinary perspective here for us is that this trial suggests that this approach is safe. It's immunogenic, and it looks as though it does what it's supposed to do in the early suggestions, it seems to reduce the risk of recurrence for patients with head and neck cancer. And so my presentation, we'll look at some of the data that led us to this trial, review with you some of the early data that we have. And then I will offer you my personal prejudice on what we are learning. So cancer immunotherapy in a nutshell, it is an intriguing challenge. If cancer develops, the immune system must have failed. And so then for the clinicians and for the scientists among us, we need to try and work out can we reestablish immune control? What does that immune control look like? At the patient level, that's quite simple. The cancer disappears. But at a cellular level, what does this actually mean? And if we can understand what it means, how can we get there? So if we think that the immune system is able to attack cancer, then we need to have a look at the first examples of successful immunotherapy. And clearly, that is very well recognized in allergenic transplantation where giving a healthy immune system into someone who has cancer and who had failed effective treatment can restore the immune control of the cancer but at significant toxicity. Since 2011, the world has changed in solid tumor oncology also, and immunotherapy has become a standard of care treatment with really stunning clinical benefit in individual responses. And nonetheless, the outcome is that only about between 10% to 25% of patients currently benefit across the board in many solid tumors from immunotherapies with anti-PD-1 or anti-PD ligand 1 antibodies, and have listed the tumors on the right-hand side where such data are commonly recognized. When we look at the immunological underpinning features under the microscope, then it's relatively simple to count T cells that are in the tumor. And in the slide on the left -- in the left part of the slide, in the histopathology image, you can see a group of adenocarcinoma cells with a lumen in the middle, the nice pink rounded cells. But in between the darker dots are the immune cells, in this case, CD8 T cells that are trying to attack and to remove the tumor. So this simple quantifying the immune cells already gives us a really good sense for what might happen to the patient as a cohort, but not to the individual patients. So on the right-hand side, I picked out a reference data set from HPV, from head and neck cancers in blue, those tumors that are driven by human papillomavirus or HPV in black, the tumors of the type that we are vaccinating the patients against the HPV negative tumors. And you can see that if you have lots of T cells, and these are direct to the antivirus, many patients survive the top blue line in the survival curve, whereas if you have tumor cells that are not driven by human papillomavirus that are the standard alcohol-induced tumors and if you also have tumors that are low in these immune cells, the bottom -- the bottom line in the black lines, that more than 60% of the patients eventually die. And that's the group of patients that we're targeting here in our trial. So the sheer enumeration gives us so far, but what we need to understand is what do these T cells do and what do they recognize. And that's just putting the red arrow here to identify that, that's the group we are targeting in out trial. So over the last decade or so, we've learned much about the immune cells. And specifically, we found out that particular groups of immune cells that live in the tissue and do not recirculate are really important. So we found out that it's not just the number of immune cells but also the quality of the immune cells. And this is a data set of just short of 600 patients in this case, with lung cancer, where the stack bar chart on the left identify the type of immune cells in 3 categories. On the very left, few immune cells; on the right, many immune cells; and in the middle, an intermediate amount. The colors in this stack bar identify the cells that are of this tissue resident feature. And they are the pink ones, and that's then on the right-hand side on the survival graph identified what happens to patients whose tumors have lots of immune cells of the right kind, these tissue resident memory cells identified by a protein called CD103 which is essentially a molecule that makes the T cells stick in the tissue. It's the functional outcome of this tissue residency program. And you could see that if you have those, even if you have lung cancer, then you're likely to do quite well. But if you don't have these cells, then you do really badly. We can count these quite easily by immunohistochemistry. And the bottom hand panel identifies on the top row at high tumor with PD-1, CD8 and CD103 industry panels, and at the bottom of the same slide, a tumor that is low in these immune cells. So what we've learned and many groups have now confirmed that, that these are the tissue resident many cells are highly effective killers. They expand in the cancer tissue. They express unique and actionable targets. As I've shown you, they're easily quantified. And very importantly, they underpin tumor control in multi models very easily to model. And in humans and in mice, these cells are activated by anti-PD-1 antibodies, but you need to have enough of them for that to be the case. And then can be trained, expanded and activated by vaccination. And of course, that takes us to the areas that we want to talk about today. What is much less well understood is what these cells actually recognize. So we know that they are tumor reactive and that they -- that there are multiple possible antigens that can be recognized. And the slide -- the right-hand side of the slide, we've already seen before because it categorizes molecularly defined antigens according to how similar to our -- what is present in our healthy cells. So at the bottom left, the self epitodes, which are not very good at activating immune responses, shared antigens that many groups have targeted with some effect, including Transgene in the MEK1 study; the oncoviral antigen that we've heard about from Dr. Delord; and then the neoepitopes, which are really quite appealing because there is no central immunological tolerance, so an attempt of the human immune system to limited cells built in because these are very different. They are generated in the tumor. And immunologically, they therefore would appear to set a relatively low bar. And the key bit is that the immune cells that are recognizing epitopes generically and specifically no epitopes are presented to the -- are being presented with these epitopes on antigen-presenting cells. On the left-hand side at the top are the antigen-presenting cells in our case with tumors. And then we expressed a molecule called MHC Class I and Class II molecules. And in my head, I imagine this a little bit like a silver platter on which the cell presents its identity to the outside world. And the long term the T cell that [indiscernible] tumor market environment and if it recognizes something and latches on and that's what the bottom part says. And this is the T cell receptor that does the latching on and then because similar to molecules term that connection that latching on into biological function. And the point I'm trying to make here is that the T cell receptor is unique for each T cell type. And therefore, you can imagine it a little bit like a molecular signal for the T cell. And wherever that T cell is, whether in the blood or in the skin or in the tumor, it will have that same T cell receptor. So we can consider and then exploit the T cell receptor as a molecular bar code for a particular T cell type with a known or unknown reactivity. So in an ongoing program of systematic probing, which is in parallel to the work that the Transgene team is doing, we're collecting blood from the patient, we're stimulating the cells with antigens, in this case, tumor antigens, to find reactive cells; we identify the T cell receptor, i.e. the molecular barcode; and we can now say, well, a T cell that is reactive to a particularly in the neoepitope has this particular molecular barcode and, therefore, allows us to have a unique identifier for this type of cell. And so if you then do the same in the cancer and analyze all T cells, you can then work out which ones of the cells that you've identified in the blood are also present in the tumor and therefore allocate reactivity to the T cells in the tumor without having to do very sophisticated analysis and tumor cell rescue in the tumor microenvironment. So this kind of cure is now becoming readily available. We can apply that to any antigen of interest. For example, viral antigen, shared antigen, of course, neoepitope antigens. And the really neat bit is that you can do that now in any tissue starting in the blood, going into the cancer, and also looking at cytotoxicity. So this kind of platform technology begins to enable us to probe and to track antigen reactive T cells with no specificity throughout the patient. So the initial discussion now some years ago with the Transgene team, we wanted to know whether such tumor antigen-reactive T cells existed not just in tumors that have lots of T cells and not just in tumors that are responsive to anti-PD-1 therapies, but whether these could be present in tumors that are immune cold. And the comment for the investigation was a patient who was in trouble, a gentlemen with non-small cell lung cancer. And of course, he, in this case, represented a huge clinical need. This was a tumor with a relatively low patients, did not express PD-L1, and his cancer has progressed on chemotherapy and anti-PD-1 treatment and radiation treatment. And we were lucky enough to be allowed to collect a large quantity of blood from him, an apheresis product, and we're also able to access both the primary tumor as well as a metastatic deposit. Here's the methodology. So at the top are the T cell densities, which really shows not very much. But at the bottom panel, you can see that MHC Class 1 is expressed, bottom panel on the right; and that MHC Class 2 is also expressed. So in theory, this tumor should be visible to T cells. What we did then is to compare the number of T cells, in this case, using transcriptomics, and quantifying the markers for CD3, so the cell marker; CD4 and CD8; as well as marker parts of tissue residency, CD103, bottom left; PD-1 and PD ligand-1. And you can see that in each of these instances, our tumor sits at the rock bottom of the cohort. Each round circle is 1 patient. Each filled circle is a head and neck cancer patient. Each empty circle is a lung cancer patient. So we've contextualized the biology of the primary tumor in pink, and the metastases in turquoise in the context of a larger set. And you can see it's perhaps not surprising that immunotherapy is an anti-PD-1 antibody wouldn't work because there aren't very many T cells that could respond to being released. So we wondered whether we could identify the neoepitopes that might drive this. And we sequenced both the primary and the metastatic disease. We found about 1,000 or so single point mutations out of these -- of disease. And 1,000 mutations, 18 genes allowed us to predict neoepitopes. So in other words, the transcriptome allowed us to suggest that we might make it into protein. And so we made a construct with -- or we identified the peptide sequence. And then in collaboration with the Transgene team and the Transgene team that made the construct and assembled a personalized cancer vaccine to us. We were not very quick in this process. So by the time the vaccine was ready, the patient had progressed and then it was no longer able to receive the vaccine. So we were able to, however, test whether we could recover the reactivities in a surrogate model. So the patient had atrial a tumor-restricted genotype in this MHC molecule. And just by circumstance, there is a well-recognized mouse model, which also meets the same MHC Class 1 molecule. So we tested in the blood of the patient whether the neoepitopes that have predicted were able to stimulate T cells. And indeed, we're able to find T cell that match them interferon gamma in response to the peptides, not the non-mutated general and counterparts. And we were then able to look at the T cell receptors of the reacting cells. And to our surprise, we're able to track such T cell clones, both into the primary tumor as well as in the metastatic disease. So identifying that even in the tumor with a low tumor mutational burden, T cells exist that have a counterpart in the blood, that have a T cell counterpart in the tumor as well as in this 1 case, metastatic disease. We weren't sure though whether the vaccine would be able to activate immune cells. So we took this vaccine into a mouse model, and we're able to reproduce many of the T cell responses that we had recognized in the patient. Also, in the HLA restricted mouse model and CD8 responses to these epitopes could be recovered. And intriguingly, we're not able to find CD4 responses, but that's unsurprising because the human CD4 genotype was completely different to the gene restriction elements in the mouse. So the science really came together very nicely. So the question then is -- and that is what takes us to where we stand today. If we have enough of the right kind of T cells, anti-PD-1 treatment is really good, solves the cancer problem, but that's only in a small minority of patients, and we need to exceed the state-of-the-art by training more of the right T cells. And now we are right back to where we started with our vaccination program. So the aim of the TG4050 program is to translate this exemplar data into proper medicine and to establish the relevance of counter vaccines and demonstrate the power of new evident vaccines. We spent a lot of time and many, many discussions with Maud and Kaidre and the Transgene team about what the right setting might be for the initial study. We decided that the best part place would be a setting where the patient had completed their standard of care, had the smallest possible tumor load, but had a really high risk of recurrence. And we argued that this would be a setting in which there would be minimal immunosuppression because of treatment often, and the patient had small volume of cancer, but nonetheless, a very high unmet clinical need. And that's how we designed the trouble to assess whether we could prevent relapse in high-risk patients. And the real puzzle was how would we go about measuring effect if there was no cancer to assess. And I think it is really a testament to the collaborative group that, that seems to have been really successful. And we were going to compare immunogenicity in the proof of cancer -- to the proof of concept data, test feasibility and then clinical benefit, and that's what's currently ongoing. So the trial design is relatively straightforward. So at the time of definitive surgery, the cancer is removed. We take a little bit of the tissue and send it off to the team in Transgene. The patient then completes their adjuvant treatment. And in parallel, in this time, the Transgene team generates the mutations, or rather reads out the mutations and the [indiscernible] for vaccine in parallel that cause the opportunity to look at the T cell receptors of the immune cells that are already in the cancer. When the patient has undergone their resection and adjuvant chemoradiotherapy and remains disease-free clinically, we undertake a look at releases and then randomize the patients either to vaccination upfront or to vaccination at a later time point. So we have a short exclude period of weekly injections, the induction period and then a longer period of -- longer interval 3 week injections in which we are vaccinating the patients. And again, at day 64, take a second large blood sample to assess what has happened to the patient. And it's really quite a study. So the thing to hear at the bottom left on the stack bar chart identify evidence from, in this case, 2 patients in the ovarian study and Dr. [ Block ] talk to us about that in a minute. And on the right-hand side, from 2 head-neck cancer patients, and really quite intriguing that we not only expanded immune reactivities that were passed before, but that we also induced the significant numbers of the novel responses. So in other words, T cell reactivities that were not present at baseline. The median response is 10 reactivities out of [ 13, 14 ] into the vaccine, that's a really quite remarkable outcome because I think we also respect and recognize that the breadth of the reactivity will be important. For these dots here, each color identifies 1 patient. The top row identifies the baseline. The bottom row identifies the [ day 6 ] before. And you can see that by and large, there is a really nice elevation of the dots in the bottom row compared to the ones at the top, identifying the expansion of reactivities in a very consistent fashion. What we can also see is that as in the previous data set that Transgene have published with the MVA backbone, NK cells are activated. So in the very left panel, you can see the induction activation of natural killer cells. So this suggests that the virus is highly effective at engaging the innate immune system. Most excitingly, though, what we are seeing is also that we are activating effective cells, both in the CD4 and in the CD8 population, the 2 pics on the right-hand side. And in conjunction with this, a decrease in the overall naive populations. And the T cells that are activated also have evidence of induction of effective markers and memory. What is really intriguing is that we had aimed to also monitor the quantity of the circulating human DNA because we argued, in these patients, there wouldn't be very much to be getting on with in terms of measuring logical response because by definition, the patients in complete response at the time of engine to the study. So we can't really get any better than that on imaging. But the [ ongoing ] suggests that if you look in a more sophisticated way and sequence the quantity of individual circulating molecules that represent the mutations, then you might still be able to pick that up. And the data is an undergoing analysis. This is taken from the ovarian how that just identifies that ctDNA in this accepting this method goes really nicely with a more classical marker of CA125 protein expression, a commonly used market for the quantity of ovarian cancer cells. Would you mind -- great. So the trial here is HPV negative tumors, enrich for TIL low. We know that 85% of these patients don't have very many immune cells. And so if you've got an HPV negative tumors, you're almost self-declared to have TIL low tumor. We picked patients with high stage to large tumor size, low involvement under capital spread. And really clinically, this is the bad end of the immune low cell tumors with a median progressive-free survival of just about a year. And just to reiterate, these are the patients that we've already identified in the previous slides as the group that we would be targeting. The study is, as I said, an adjuvant study after the section chemo radiotherapy and the vaccine is getting a single agent. And we continue until either disease progression or [indiscernible] up, and we compare patients who have been vaccinated upfront in a randomized way to patients who are followed only, but of course, for whom there is also a vaccine. And the really neat piece of this is that in the parallel control group, this will give us the opportunity to vaccinate patients with the same vaccine concept but now with the recurrent and measurable disease. And of course, that also allows us to test whether the unmanipulated interval between surgery and recurrent has been accompanied by any genomic or immunological changes in the tumor. I think in the absence of immunological pressure that is unlikely to be the case, but we'll have to see. So the trial then gives us 2 opportunities. One is to assess the progression-free survival in the vaccinated versus a nonvaccinated arm, as well as a smaller number of patients in whom we can actually assess whether in combination with standard of care, the hopes that, that would be mainly anti-PD-1, this vaccine can regain control of the patient's tumors that have been -- that have recurred. So the data looks to the oncologist is sounding. So at the top arm are the data from the first set of patients. And you can see the swimmer plots that have been aligned by the length of follow-up. And so far in the vaccine to patients that have been vaccinated early, there have been no relapses. Whereas in the patients who have been followed only, there have been 3 relapses. That is 3 7% relapses in the patients that have been observed as opposed to 0% in the patients that have been followed up. Randomized multicenter. So we expect this to be a true reflection of the reality. But of course, it is a small trial. We're looking for a total of 30 patients. The trial is fully enrolled. 20 patients have been randomized, so we've got 10 more to go. And then hopefully, we'll be able to confirm that the data will remain the same. So the state of the art is then that effector T cells are a condition without which cancer immunotherapy cannot work. We know that checkpoint inhibitors benefited small percentage of patients. They awaken or release previous T cells. That is great if there are not. But it doesn't work if there are not enough T cells. And beyond anti-PD-1, the other checkpoint inhibitors have only yielded a relatively small incremental benefit. In contrast, cancer vaccines are, at the moment, the only tool we have to train cancer cells in the patient. And my expectation is that they will form the backbone of cancer immunotherapy to the future. And that really will be starting off with vaccines in combination with something else such as, for example, anti-PD-1 antibodies. But that, of course, is for the next iteration of trials with this. TG4050, specifically, combines all the features that are likely to deliver clinical efficacy. So a highly immunogenic, very well tolerated and really well understand MVA backbone. We now know that the neoantigen targeting induce specific T cells against the neoepitopes and astoundingly that it is clinically feasible. And so the trial encompass really several decades worth of clinical learning and of adaptive learning and identifying and optimizing clinical trial settings and keeping this into randomized, multi center trials. In summary then, I think this is a little bit astounding effort because it's safe and immunogenic, and the early data really suggest clinical benefit. And if that is the case, then the sample size effect must be large if it is detectable in such a small cohort. So I think the smart design will also give us a lot of evidence of the biomarker program that were defined in the mode of action, demonstrating the link to circulating free DNA, identifying markers of early recurrence, and then hopefully also demonstrating that in the therapeutic setting, so the place where most vaccines have not worked so far, this will be able to convince the community that this actually works. And of course, I'll hand over to Maud in a minute, who will talk to us about the ovarian cancer trial. My belief is that this trial and this approach is set to deliver a landmark change in the field by demonstrating the clinical efficacy of cancer vaccination. And using -- in this case, the MVA by platform, it will, I think, define a starting point for rational commentarial immunotherapy because it will start from an optimal patient setting, from which we'll be able to work forward and assess what we need to do differently in patients with less favorable setting. I think this will underpin immunological patient base cases of [indiscernible] approaches and of course, the extension to other solid tumors and clinical settings is obvious. And I think no one will fail to notice that this is already in a tumor type that hasn't really been the hallmark indication for cancer immunotherapy. And clearly, for me and most importantly, I think this kind of approach offers hope to patients with really terrible and often fatal cancers. And really, if we can achieve that, then this is really all worthwhile doing. Thank you so much.

Thank you so much, Christian, for this presentation, this first very encouraging clinical data in head and neck. And now we will move to the presentation of Matthew Block, who is medical oncologist at Mayo Clinic, and he will speak more precisely on our trial in ovarian cancer. Matthew?

Well, thank you. I am happy to be here virtually. I am from Minnesota, but currently traveling in Tennessee. And by way of introduction, the focus of my research is to better understand the mechanisms by which cancers interact with the immune system and how they avoid immune-mediated detection and eradication. I study therapeutic vaccines as well as oncolytic viruses as ways to induce antitumor immune responses. And I study immune checkpoint inhibitor combinations as a means to potentiate antitumor immune responses. And then as a medical oncologist, I also take care of patients, I treat patients with gynecologic cancers, including ovarian cancer, and I treat patients with melanoma and other skin cancers. So ovarian cancer is known as the silent killer because it is most often diagnosed only after it is Stage 3 or Stage 4. Patients with early-stage disease do not typically have symptoms from the cancer, and there are no effective screening tests. There's no ovarian cancer equivalent to the mammogram or to the PSA test. And so patients who are fit for it receive aggressive treatment with a combination of cytoreductive surgery and multidrug chemotherapy, typically with paclitaxel and carboplatin. Remission after initial surgery and chemotherapy is quite common, but it is rare for patients to be cured of their disease. Remission is also -- relapse is also very common. And you can see this Kaplan-Meier curve on the lower right from a relatively recent clinical trial. And you can see the progression-free survival of patients. And again, while remission is common, most patients have relapsed by 2 years, and over 90% of patients have relapsed by 4 years. Due to its high recurrence rates, ovarian cancer is the most lethal of the gynecologic cancers. So because recurrence is so common, many investigators have studied maintenance therapies as means to prolong remission after initial treatment. Bevacizumab, a monoclonal antibody targeting VEGF, is approved for use as a maintenance therapy, both -- it's actually given both concurrently with chemotherapy and as maintenance therapy after chemotherapy is completed. And it shows, as you can see in the upper left, Kaplan-Meier curve, an improvement in progression-free survival. However, as you can see in the upper right, there is no demonstrable benefit in overall survival when bevacizumab is used with first-line treatment. Another approach that investigators have taken is to test PARP inhibitors. And these have shown a great deal of promise as first-line maintenance treatments. However, benefit from PARP inhibitors is not distributed evenly among all patients with ovarian cancer. Patients with a BRCA mutation, as shown in the bottom left Kaplan-Meier curve, have a dramatic benefit from PARP inhibitor therapy in the maintenance setting. However, and I apologize that the size of the font is very small in the table, but the table is just to show that patients who have no BRCA mutation derived less benefit. We can classify patients as having homologous recombination deficiency. About half of ovarian cancer patients have homologous recombination deficiency. And these patients derive a moderate degree of benefit from PARP inhibition, whereas patients without homologous recombination deficiency derive marginal benefit perhaps 2, 3 months compared to placebo. So while the maintenance treatments represent improvements, the improvements are incremental. They're primarily improvements in progression-free, but not overall survival with the possible exception of BRCA-mutated patients with PARP inhibitors. So one of the things that we'd like to do in ovarian cancer is detect residual or recurrent disease before it becomes clinically evident. As I mentioned earlier, once ovarian cancer is clinically evident, the disease burden is very high. And so CA125, or the secreted portion of MUC16, has long been used as a tumor marker for ovarian cancer. Once the CA125 increases to above 2x the upper limit of normal, we consider the disease to have recurred biochemically. However, this typically precedes clinical recurrence or symptomatic recurrence by about 3 to 6 months. A more modern way to detect residual or recurrent disease is through the use of circulating tumor DNA, or ctDNA. And this can be detected in plasma from patients by either next-generation sequencing or by digital droplet polymerase chain reaction. In some patients, this is more sensitive than CA125 for detecting recurrent or residual ovarian cancer. However, ctDNA has not yet made it to prime time as a replacement for CA125. And what's been shown is that if we detect recurrent ovarian cancer earlier, we will treat patients earlier, but we don't necessarily see an improvement in survival. This is shown in a randomized clinical trial in which patients underwent serial CA125 draws while they were in remission after first-line treatment. However, the results of those blood tests were not revealed to the patient or their doctors until they went to twice upper limit of normal. And at that point, there was a randomization. And for half of the patients, the result was revealed to the patient and the provider, and they would start chemotherapy immediately when they had recurred biochemically. In the other half of patients, the elevated CA125 was not revealed to either the patient or the doctor, and so they did not start chemotherapy until they develop symptoms or physical exam findings just of recurrence. And as you can see in the top Kaplan-Meier curve, the patients who had the CA125 result revealed started chemotherapy an average of 4.8 months before the patients who did not have the CA125 revealed. However, the bottom Kaplan-Meier curve shows that survival was nearly identical. And so we generally don't think that we need to start cytotoxic chemotherapy in an asymptomatic patient with an elevated CA125. We typically wait until either the patient develop symptoms or we can see rapid radiographic progression. However, since it is standard practice to monitor the CA125, we think that when patients present with an elevated CA125, this may be a window of opportunity for disease treatment, including the use of vaccines and other novel agents. So with this in mind, we designed the TG4050.01 study to look at the use of the TG4050 vaccine in patients with early recurrence of ovarian cancer. So patients want to undergo their standard surgery and postoperative chemotherapy. This would result in remission for about 80% of patients. And then we would recruit patients while they were in clinical remission. At that time, the patient would submit archival tumor and fresh blood for development of the TG4050 personalized vaccine. And then we would simply wait until the patient developed an asymptomatic relapse with either an elevated CA125 or small lesions on a CT scan or both. If patients progress rapidly and had clinical relapse, meaning symptoms, then they were not eligible for the vaccine and would go on to receive chemotherapy. But those patients who had asymptomatic relapse were treated with the vaccine. Here, you can see the results in the first 5 patients treated on the study. We had 1 patient, patient #4, who had both radiographic lesions and an elevated CA125 at the time she enrolled and she was stable for 11.4 months after the first injection before she gradually progressed. Another treatment, patient 1, was treated after her CA125 became Elevate. And she actually experienced a normalization of CA125 and did not have clinical progression for 9 months on study. At that time, she was still in remission, but unfortunately died of an unrelated chronic illness. We'll look a little more closely at that first patient. This patient was a 73-year-old who have been diagnosed with Stage IIIC, high-grade serous carcinoma who did not have a BRCA mutation, but had an elevated homologous recombination deficiency score and a P53 mutation, those are nearly ubiquitous for serous ovarian cancer. Her first-line treatment was paclitaxel and carboplatin for 6 cycles, which is the standard, and she opted not to receive maintenance PARP inhibitor therapy nor bevacizumab. She was enrolled after her CA125 had reached twice the upper limit of normal, and she had a confirmatory CA125 that also was twice upper limit of normal. Her CT scan was mildly abnormal with some small lesions that were not meeting the criteria for measurable disease, and she was not symptomatic. As such, we treated her with weekly TG4050 for 6 weeks. And in that 6 weeks, her CA125 fell sharply, although not quite under the threshold of normal. Interestingly, her circulating tumor DNA rose during the vaccine induction period. After vaccine induction, she went on to receive every 3-week maintenance vaccine doses. And after the first of those, for CA125 had normalized, and her CT scan findings had also improved. ctDNA lagged behind, but eventually went into the normal range. This wasn't the only threat to the patient though, and she also had a history of hypertension and some episodic atrial fibrillation aortic stenosis. And she ultimately died of flash pulmonary edema unrelated to the vaccine when she was in remission and had not had any side effects. So to summarize, asymptomatic patients with evidence of recurrence by CA125 or minor imaging findings do not benefit from immediate initiation of cytotoxic chemotherapy but this represents a window of opportunity in which we can treat ovarian cancer patients with a personalized vaccine. The manufacture of the personalized vaccine is feasible and requires about 4 months from the time of study enrollment until we can treat the patient. And while the number of patients that we've treated, thus far, is quite limited, the results are promising and suggest that the TG4050 personalized vaccine as of monotherapy can delay or even reverse early findings of recurrent ovarian cancer. So I'll stop, and thank you for your attention.

Thank you very much, Matthew, for your excellent presentation. And now before opening the session to questions, I just wanted to -- just to conclude, those presentation on TG4050, saying that, of course, every day, we are accumulating new data and the new data will be subject for communication in H1 in 2023 in large Congress. And they are very important for us because they help us to move forward and design what we are going to do in Phase II for TG4050. So having said that, I would be very happy with, of course, our speakers to answer any questions you may have, which may come from, of course, audience, but from Internet as well. And I think with me will be -- as a person who will provide us with a question coming from the web.

[indiscernible]

I'm wondering whether there is a running hypothesis on why this therapeutic modality actually works in anogenital cancer but not in head and neck cancers, for example, that are HPV 16 positive? Is there running hypothesis that does have to do with the structure of cancer or maybe the local immune environment? And then my second question is on TG4050 regarding the neo antigen vaccine design. So you mentioned that you can include up to 30 antigens per vaccine and that you identified approximately 120 targets. I was wondering whether those targets included also shared antigens and whether you saw responses against these antigens between different patients. And then my final question is regarding TG4050 in ovarian cancer. Does asymptomatic relapse always resolve in a clinical relapse? Or are there also cases in which that does not occur? Thank you.

Thank you for your questions. So maybe I will answer the first question on TG4050 and Jean-Pierre can, of course, complete my answer. Actually, the reason why anogenital cancer were selected and no longer head and neck cancer is not related to an inefficiency of the vaccine. It's very simple. Initially, we got head and neck cancer in the first part of the recruitment, and we got a response. But pembrolizumab got approval in the first-line treatment of head and neck cancer in combo with chemotherapy, less often used in immunotherapy. And for that reason, we had no longer any patients because one of selection criterion is not having received any checkpoint. So it's not related to any issue with the mechanism of action. Are you -- do you want to add something?

No, yes. I'm good with your answer. So it's only a question of opportunity. In U.S. and Europe, PD-1 antibodies are reduced in head and neck cancer. And there is -- for a reason I will not comment today, we still don't have any approval for patients with cervical and perineal cancers. So unfortunately, it provides patients for clinical trial.

[indiscernible] next question.

Yes, I'll take the second question on the antigens that were identified. So in fact, when you look at the total patients that were sequenced and for which we've done the exercise, we have identified quite a few of antigens, and we have a pretty good picture of what's going on in those patients. Obviously, we do find that some genome are more mutated than others. For instance, I mean, a majority of our head and neck patients, but also in patients are mutated for, for instance, for P53. And when you look at the -- I would say, 2 or 3 genes, they basically mutated in the majority of patients. Nevertheless, this recurrence in a mutated gene doesn't mean that the mutation is the same. And when we look at like more 100 patients for which we've done the exercise, we did find the same mutations only in 2 patients or perhaps 3 patients that were like recurrent. So I wouldn't say that we've been able to identify the -- a shared pattern on the shared mutation that we could use from one patient to the other. This is only about the identification. It doesn't mean that those mutations are particularly efficient to a stimulation by the vaccine. Does that answer the question? And the third part? I think there is a third part?

Yes. And I believe this question related to ovarian cancer. Maybe Matthew, can you answer this question? Did you hear the question, Matthew?

So I'm not able to see or hear.

Sorry, sorry. You did not hear the question. So the question was related to the fact if there is an asymptomatic relapse, the necessary -- it is necessarily followed by a clinical full-blown relapse or not? That's the question.

In the vast majority of cases, it is followed by a clinical or full-blown relapse, but the timing can vary widely. In some patients, there is a low amount of CA125 produced and the patient may relapse clinically even without an elevated CA125. That's fairly uncommon. The most common is for there to be a gap of 3 to 6 months between the biochemical relapse and the symptomatic relapse. Sometimes it can take up to 12 months, but what we saw in that first patient on the clinical trial where the CA125 increased and then went back down and there were imaging findings to confirm, is practically unheard of. So we -- we would not expect a patient to have a relapse and then eradicate it on her own, so to speak.

And so coming from Internet, we have few questions which are also related to ovarian cancer. The first one is why doesn't the chemotherapy in asymptomatic patients with CA125 lead to clinical benefit? So this is the trial, the trial you showed. Matthew, maybe you can comment on that? Why would the vaccine do better there?

So that's a great question. Chemotherapy for patients with biochemical recurrence can be very useful. But it -- I think the importance of that trial is that the timing does not matter. In other words, if we delay chemotherapy until the patient is symptomatic, then the patient is exposed to less chemotherapy, has fewer cytopenias and other hematologic deficits from the chemotherapy and has fewer other side effects. So there is benefit to delay, but there is still benefit from chemotherapy unquestioned. I think the advantage of the vaccine is that it does not cause the same types of toxicities that chemotherapy does. I kind of tell patients that there is a limit to the amount of chemotherapy a patient can receive over a period of time. That limit is different in different patients. But we often reach a point in which -- we have to start reducing the doses of chemotherapy because of hematologic toxicity. And if we give too much chemotherapy too soon, the chemo is still not curative, and the patient will ultimately need more, and sometimes she's unfit to receive additional chemotherapy when she needs it more. By contrast, the vaccine doesn't cause any cytopenias and made by working by a different mechanism, may eradicate some of the more slowly dividing cells that are not sensitive to chemotherapy.

Another question for you. How many more before, it's a different phrasing of what you said before, but how many months before symptomatic relapse would be considered as clinically meaningful for TG4050? So you said that there is -- it could be 3 to even 12 months between the first sign of asymptomatic relapse and full-blown clinical relapse. So what would you consider as a significant clinically meaningful for vaccine?

Yes. So that's a tough question. What the FDA has considered clinically meaningful for, say, bevacizumab and PARP inhibitors is a benefit of about 6 months. So going from 3 to 6 to maybe 9 to 12 months of a delay would, I think, be something that might lead to regulatory approval and so forth. Of course, what we want is what that first patient achieved, which was a remission, which who knows that could have gone for longer and actually not succumb to other illness.

Thank you. And maybe a question for Jean-Pierre. What are the key takeaway from ESMO 2022 that are available for the Transgene pipeline? Identify, and I mentioned the adjuvant trial of [indiscernible] in head and neck, checked that 1412 which were negative, and we were eager to get the results because it has changed the therapeutic landscape of the adjuvant treatment of head and neck, but it was not the case. But maybe you have not tested other important news from ESMO, which may have some impact?

That's a difficult question. But probably, I would say, first, as how do oncologists because I finished my training a few years ago. I would say that if you don't reach treating metastatic disease, the level of 50% of response rates that was -- we were discussing few hours ago, you will never deeply modify the natural history of the disease. And there is no example in the field of oncology in my memory where a drug, whatever is coming from chemotherapy targeted therapy or immunotherapy, that deeply modified the natural history of disease used at the adjuvant time. When you did not show on the metastatic disease that it's clearly modifying the destiny of patients and of more than 50% of patients. I mean it needs to work very efficiently at a metastatic level to be one day efficient when you use that with a prophylactic strategy. So it has been the case in the field of immunotherapy when we use it for patients to treat it for melanoma or lung cancer or bladder cancer as an example, but it has [indiscernible] to be effective in the other subgroup of cancer patients. So that's why, again, we do believe that what we do at the level of the beginning of a proof of concept, being able to modify what's going on in the metastatic disease in head and neck cancer patient, if it's a very crucial step. If we succeed in showing that we do something good for 50% of patients, then I guess on strategy with HPV vaccine as an example, we'll have to switch very quickly in adjuvant setting.

As far as the ovarian cancer is concerned, Matthew, I don't think you're attending ESMO, but there was an update on the trial [indiscernible] in BRCA-mutated patients and the confirmation of the durability of the effect of [indiscernible] specific population, around 20% of the ovarian cancer population, do you agree with that, Matthew?

Yes, about 2025, depending on the study, percent of patients with ovarian cancer have BRCA mutations. These patients have always been known to derive higher benefit from PARP inhibitors than patients without a BRCA mutation. There are some recent data suggesting an overall survival benefit in that 20% of patients. I don't think we know yet whether we are curing patients or simply delaying recurrence, but the delay is fairly profound. It's a benefit of years for those patients. And so we're encouraged by that. But Obviously, many patients, even with BRCA-mutated patients who are being treated with PARP inhibitors still develop recurrence and so -- it's encouraging, but doesn't obviate the need for new therapies.

Thank you, Matthew. Yes. [indiscernible] I have a few, I would say, general questions. First on design of TG4001. Just curious if you ever considered looking into use of IL2v to avoid Treg stimulation as basically, we've seen this approach being quite broadly used in the industrial?

Actually, it's -- I would say it's a legacy design with an IL-2, which is not mutated and binding both [indiscernible] tumor receptor potentially. Nevertheless, it's given in the vaccine, which is non-replicative, so it's expressed at the site of priming or close to the site of priming. So it's very unlikely that it will result into a larger Treg stimulations and that there is a specific need to use a mutated IL-2. This is one aspect. The second aspect is that historically, both in 4001 and other design or the past vaccine design that used the same IL-2, we have monitored Treg prevalence and both in the circulation and sometimes in the tissue, and we could not really see any form of increase after a relatively intensive vaccination schedule. So yes, it's a question we don't have a definitive answer, but it doesn't look like it's being an issue here.

Can 4050, basically, for myvac, just curious -- if you could sort of highlight again, how do you account for clonality of mutations within the algorithm?

Yes. So clearly, the selection should be based on basically [indiscernible] sequencing. So then this would be a gold standard where you know exactly what's the prevalence of the mutation you put into the vaccine. This is not something that we can do particularly clinically. We can do it on like experimental use, but it's not something that we can develop at least today for patient use. So -- but still it's something we use to benchmark ourselves somehow experimentally. Now in the current design and the envisioned design of the product for the routine practice, I would say, what we do is that we reconstruct the phylogeny of the tumor by trying to understand which are the clonal mutation, meaning the mutation that we would find into basically other clones, because it has been sure that those mutations are more efficient for vaccine design. And basically, what we do is that we give an advantage or the system gives an advantage to those mutations when they are selected, and we do that essentially based on the [indiscernible].

On the clinical data, just curious if you basically -- if you look in the totality of the T cells and how many of those actually are specific for neoantigens that equated in the vaccine? And if you looked at our markets of T cell expression as well?

So yes, the answer is yes and yes, in short. So we have looked at every single basic mutation and how much T cell response we got against those mutations. We have also made sure those mutations are only directed against the mutated is a form of the protein and not a wild type 1 or a closely related sequence. This is one thing. And the second thing is that we have characterized not specifically exhaustion markers, but many markets that are associated to T cells. And what we could see is that those T cells have an effect of phenotype. They do not expressing specific exhaustion markers, at least at the time where we have made the test. Obviously, we have very preliminary data. We'll come up with more. We'll come up with more characterization of the response and more information on the actual activation status of those [indiscernible] so far so good.

Thank you for very interesting presentation. So I have several questions. The first one is to Jean-Pierre. So basically, in the TG4001 trial, so you have a large number of patients that seem to show at least stabilization. And then some of them are relapsing. So I was just wondering whether you have the chance to assess to tumor biopsies so that you would -- because it would be a perfect starting actually to demonstrate at least some immune response and possibly some tumor escape?

Yes. We have an academic secondary biopsy programs. But I'm not sure that the patients included in the trial and those who are relapsing after a long period of stabilities have been accepted a new biopsy in the trials. So I have to double check that point, but I'm not sure. I know that we have also an academic program concerning PBMCs and we're going to also be able to see in the peripheral setting what's going on in terms of T-lymphocytes and also specific from the antigen E6 and E7. So today, I have no answer to that question, but it's clearly one of the questions we're going to address in the future because the collaboration between Transgene and the academic teams, likes of Christian and the team of [indiscernible] is very efficient and going back between the teams that probably one of the reason why we like collaborating with Transgene very much and for also long time.

These are responses. And so do you have, in some way, any correlation between the quality or the intensity of the responses and the clinical responses?

[indiscernible] follow me, but we're still expecting the results that are looking at, as an example, the complete phenotype of CD8. The detrimentals -- the complete sequence of the PCR of lymphocytes that Christian will do in the future. So this remaining equation are burning equation, and we would love to share the results with you today, but I guess this will be early next year. Because at the [indiscernible] level, that would be key answers in order to know what's going on. So before getting enough time to see what's going on in patients, as you -- as it has been mentioned, there was true relapse in the controlled group and no relapse in the treated group, but is it a signal, I don't know today to be honest, it's not largest plan of patient to treat today very confident and tell you signal. But I would really love to share with you today what's going on at a very -- at the level of CD8 trials which are specific of each antigen in all the trials, HPV on one arm and on the other arm the 4050.

And I have a quick question to Christian -- are we too late? Okay. The last question. So basically, you mentioned that with the TG4050 trial, you had evidence that there was not only expansion of preexisting T cells, but also induction of new antigen-specific T cells. So -- did you have a chance because you mentioned that there was some follow-up with [indiscernible]. So because then following, for instance, typically the quality of pre-existing T cells before and after treatment following [indiscernible] would give also some information about the functional status, the polarity of the cells and perhaps you see here the direct impact of the vaccine on the quality of the T cell response?

So there'll be 3 pieces. One is the -- what happens in the blood compared to those patients where we have slow frozen tumor to do single cell RNA sequencing in the primary tumor before resection because that will give us really quite clear evidence of what was there before the tumor. At the moment, the measurements are what is present in the blood before vaccination and then after vaccination. So that already gives us 2 extra pieces of information. It will allow us to compare baseline reactive T cells transcriptomically to antigen-specific T cells that are present after vaccination also as well as those T cells that are only present after vaccination. So we'll be able to compare whether at a single cell level, the T cells reactive to neoepitopes after vaccination are different to the ones that were before vaccination. I think that will begin addressing the functional questions that have the questions about the functional capacity and the exhaustion phenotype that have been asked already. And I think what we would predict is that the cells from what we know so far, will turn into a more activated immunophenotype post vaccination, and we hope to be able to confirm that at an epitope-specific level also.

Yes, concerning the longitudinal monitoring with -- staining, indeed for 2/3 of the response, if you take the total of response observed, 2/3 were absent prior to vaccination and 1/3 is amplified after vaccination. Obviously, we do not know whether -- I mean, it's a bit of specific, but we do not know whether it's the same [indiscernible] and that's an answer that we'll come up with TCR sequencing of positive [indiscernible] somewhere next year probably.

The question from [indiscernible] very, very interesting question. And then the time for a break -- very quick break because otherwise, we are really, really late, so a couple of minutes. And then we'll be back for oncolytics. Thank you, thank you, Christian. Thank you, Matthew. [Break]

In terms of critical mode of action for oncolytic viruses. We'll then jump into examples of what was achieved together with the lead university hospitals and understanding the [indiscernible] of the product in several routes of administration. And we'll get some questions for -- at that time point before he will leave and we will jump back on the normal program. I will be continuing the session, presenting you our recent development and the new product we plan to move into clinic next year. And we will have Steve Bloom, our Chief Business Officer, presenting opportunities for collaboration on this platform. We have heard about the [indiscernible], the development we can do with time vaccines I just want to position oncolytic viruses. They are very different from the other one. They are also based on viral vectors, but we have selected predicative viruses that would specifically replicate in tumor cells, and that would be the site of action for all this class of product. They will engage [indiscernible] immune infiltration and by targeting the tumor be able to remodel the tumor phenotype. And that would be basically the big difference between this technology and the previous one. If I just recall some basic, I'd say we usually consider that oncolytic viruses combined 3 manufacturers in the tumor environment. They would, by themselves be able to, in fact, replicate and induce a viral dependent cell lysis. That's the reason for the historical name of oncolytic. We know now that most of the efficacy comes from the engagement of immune sales, that would be able to reach the tumor reputation side for the virus. Prior -- will act as a signal for engagement of both -- and immune responses. And we also, as said before, use the substantial of the vector to directly express in the tumor some payloads that would diffuse from the application side. and be able to either repressive mechanisms or boost in active mechanisms. They would also be able to bring in the tumor some new modalities for activity, like what we have in TG6002 that is direct suspension in tumor of some enzymes that will locally convert the proton to an active cytotoxic drug. So we have this kind of targeted chemotherapy on top of the viral induced cell, immune recruitment and potential new modality of treatment that would be targeted to the tumor specifically with minimal exposure of the serum and tumor sites. What is important is also to confirm that we have at the site of viral application all mechanisms that are necessary for triggering a strong immune induction. We published some time ago, the results demonstrating that and confirming that oncolytic viruses when replicating and using cell desk in fact, do match most of the major hallmarks of index. That's important. And the release of all those signals and the condition of the signals is really instrumental in driving the immune response towards something productive not only against the viral fiction, but against the tumor antigens. What is also important for us is that using this oncolytic platform as a platform for the discovery and development of new product to be able to demonstrate its versatility. And we have a lot of examples internally and as part of our collaboration programs with other companies, showing that a large diversity of molecular payloads could be encoded and expressed from the site of. This diversity ranging from small immune factor like cytokines or small factor ligands that could be encoded in via genomes, 2 very large payloads such as full-length antibodies or large enzyme systems that were also expressed at high yields. And we have this knowledge on the promoter design, our ability to engineer recombinant assets to control the level and the timing of -- in the tumor. So what is recalled in the very beginning of the lecture, the fact that box viruses are large cargo. It's well documented that they can encode for up to 2025 KB of Transgene -- and keep in mind that for example, the -- would be 1.5 kb. So plenty of room in the cargo for targeted delivery in the tumor. I would give you some kind of flavor on the mechanism of -- from this product, BT01, the name suggest has been developed together with another company called [indiscernible] in Sweden, our good friends at discovering and putting in development very original antibody settings. In that case, it's a full-length antibody optimized for the [indiscernible] part of the receptor to engage the ADCC. The antibody would recognize the CTLA-4 target, that is well known to be present in the surface of intratumoral Tregs. And we also expressed the MCSF to act as a multifunctional cytokines in the tumor environment. It was demonstrated in previous programs like the 1 with [indiscernible] by Amgen or, our own product. It's also the case for [indiscernible] would bring a lot in the possibility to activate and mature in monocytes into macrophages and -- cells directly in the tumor. I can also promote the skewing towards the immunocompetent M1 phenotype for macrophages. And as you see here on the slide, we have optimized the design to reach the maximum functionality of the covenant antibodies, what is important in this ambition is a good balance between the light and heavy chain and by using in that case, 2 identical promoters, but in some cases, might rely on 2 different promoters who have been able to obtain the domain function of the antibody in tumor. For the demonstration that I will just develop just after. We also have a -- product adapted for clinical research in mice. That's -- the same design, but the -- and the antibody would be customized for their most targets. Just in a nutshell relevant examples. I think you see here that we've been able to demonstrate that the product is active in [indiscernible] so mice model and a large diversity of these models. We have displayed 5 of them that range from so-called old tumor with a very large tumor infiltrate in terms of T cells and even in terms of -- cells to cold tumors that are deserted tumors with virtually no immune cells present at the time of the treatment. And for those models, we could demonstrate some activity. Of course, the alter the better. But you see here that even in very cold or deserted tumors, we could achieve some survival, and it is associated with the tumor in flux for 4 cells and relevant immune cells. What is important also to demonstrate is that this activity is correlated with induction of strong and long-lasting CD8 positive T-cell response. When analyzing the specificity of the Neuroform T cells or T-cells. It's also very important to demonstrate that we've been able to generate a majority of tumor-specific T cells compared to -- T-cells. It's about 1/10 of them. So it's a question that can have on don't we have a majority of T cells raised against the vector up against the tumor antigens. And this type of experiments clearly demonstrate that a very large part of the T cell response is against the immuno antigen. And we know that these T cells are most in memory T cells and that could be demonstrated by rechallenge experiments in which, for example, we treat mouse grafted with 1 specific model. And the surviving mouse would be rechallenged with another tumor that would be immunologically different from the initial 1 and whether there is a difference in terms of behavior upon vaccination between these 2 groups. And what you see here is that the population that was treated with 1 specific tumor would have developed a tumor specific response to protect the survival against challenge, whereas mice treated with different tumor would almost all die within 1.5 month. What is so important and also demonstrative of a strong systemic T cell response is this type of experiments called abscopal response in -- model. where we equipped the mouse with 2 tumors. Only 1 of them will be treated with vaccines and we look at the evolution of the size of the second 1 and treated tumor. You see here a per panel that bottom will grow fast in the absence of treatment. What is impressive is that treatment on 1 side, you see that the most of the mice would also present control of the tumor growth on the non-injected flank. Only 2 of the mice did escape from this treatment. So that's demonstrative really of induction of immune response -- but a systemic response that could reach non-injected cyto tumor. And that's the rationale also for us to move into metastatic stage diseases starting from either local treatment or from intravenous administrations hoping to reach 1 application site, but for which the answer could translate into action in non-treated tumors. And when analyzing in depth the phenotype of the T cell responses, that's the right-hand panel, you see that we have really been able, in this injection at the priming site to induce a large expansion of the population of T cells. We have been able to decrease the proportion of exotic T cells. That's true in the tumor, but also in the circulation and also to be able to demonstrate a strong decrease in the population of intratumoral Tregs. And it's also partly true, but on true in non injected lesions, but a significant amount of the Tregs are also depleted in this non injected lesion. And when also further analyzing what are the pathways in us besides the induction or decrease of exhausted T cells, we can go in what is happening for other cell populations -- and by using differential gene expression analysis, we could confirm that a large component in this immune remodeling of the tumor micro environment is associated with activation or expansion pathways of a large diversity of sales relevant for expansion of the second -- also for mobilizing other type of responses. And we could also demonstrate specifically that among the populations that are in use, we have this DC-1 subpopulation of APCs that have been really boosted by the treatment. And it's also very important in demonstrating the ability of the product to also favor antigen display and expand the [indiscernible] so all those results plus, of course, many other results we've been able to collect in the last 2 years together with our colleagues at the invent led us to the positioning of this product in the IT route as a start. To demonstrate that, for example -- lesions treated with BT-001 can, of course, be controlled in the evolution and resolve spontaneously after induction of the virus. But also we will monitor activity on non-injected lesions and want to be able to demonstrate that we've been able to generate long-lasting circulating response that would act also on -- cells. The first part of the trial has been almost completed. We are, yes, enrolling the very last patient at the higher dosing plan in this -- program. The next step, of course, that would be very relevant is combination with pembrolizumab. We already have the agreement from MSD for free supply of [indiscernible] and we should be starting this Part 1 B of the trial at the beginning of next year. All those patients are, of course, carefully monitored for a long period of time. We know from our competitors that some responses might take some time to be detectable, several months of injection. So we -- today, of course, short-term monitoring has been performed, but we want to keep those patients under mentoring to be sure that we have a full control of what would happen in the months after treatment. We could from some of those patients demonstrate that both the antibody and hopefully GM-CSF or express in the tumor. Of course, it's a safety study also. So far, no reports of adverse events. The product is well tolerated. We have no spreading of the viral genome from the tumor into blood or biological fluids at the moment. So confirming if needed, the item of specificity. And we are, as I said, now entering into the higher dosing where we expect a larger fraction of the patient to respond. But for the low doses, we have been able to observe already 1, 1 tumor control in 1 patient at the lowest dose level, which is an achievement, of course various numbers at the stage. Something important in our development of this -- platform is our collaboration with AstraZeneca. You might remember that we signed this collaboration deal 3 years ago. It's a very large collaboration with -- that could lead up to 5 new products in the frame of this collaboration. We, of course, have had the challenge to develop 5 products, some being simple that are very complex. So really -- has pushed our technology to the limit. So far, so good. I would say in the sense that most of the preclinical programs have been performed in-house and most of the products have been transferred to AZ for in vivo analysis, the -- duty to characterize the product in their joint model in their premises. The good point is that for the first product delivery per easy, we already have 1 option license exercised last year. And we know when we have worked together to make this product become a clinical development, and we have got some good feedback from AZ, confirming that they really want to move in the clinics as early as beginning of next year. If I -- just a few words on what we are actually doing internally in terms of research. We'll have reports from -- reported on all in the IT route. But really the key challenge for us is to be able to demonstrate that the product would be efficacious in the IV route to target advanced stage metastatic diseases. So we -- there are many, many limitations that have been reported to use oncolytic viruses in the IV route. Most of them are reported in this cartoon that was published some time ago by Martin, but there are many papers highlighting the mutations for using OV in the IV route, and we are addressing that in the research. So we are the different venues. Our teams are exploring. You see that start from the below part in terms of preventing neutralization by circulating antibodies preventing capture by endothelial cells or whatever nonspecific interactions we could have in the [indiscernible] One way would be to, of course, reformulate the product or change the surface properties of the virus. We have tried via collaboration with both companies or academia, several technologies to be very direct, none of them have been so far demonstrating good efficacy. So most of the -- our attempt to change the -- properties translated into loss of efficacy and loss of conductivity of the product, but we will look for new technologies is available. What is maybe more relevant is that to be able to force the transfer from the blood to the tumor by local physical stimulation -- and you might have seen that paper we published some time ago, using a -- capitation to transiently permeate the -- and favor of the transplanted tumor, the technologies developed by -- is still prototypic but we monitor the progress and hope that we will have something ready for clinical development in the next coming months. Unfortunately, the available ecographic machines are not suitable for this development at the moment. Another route is to boost by combination with other agents, the replication or the ability from the very early infected sites to have a strong expansion of the viral infected cells. So 1 maybe contribution could come from the condition with no -- mRNA, and we have this ongoing collaboration with small companies based in Boston called combined therapeutics, and we are currently exploring several candidates for this optimization of the replication from the very early affected sales. Too early to report on the results, but we hope that in the very next month, we'll be able to communicate at congresses what we have achieved so far. Maybe the more potential would come from the left-hand panel part of this figure. So we have a lot of internal projects demonstrating that by changing acting on the arming of the platform, we could change the immune phenotype, decrease some sub populations, decrease the level of immunosuppressive cells, boost the proportion of immuno -- sells. So ongoing programs, we might report also soon on those candidates. What is also another venue we are exploring is the use of targeted inhibitors for some immunospecific pathways like the interferon gamma intratumoral response. And you might have seen this collaboration we have with -- was provided technology based on [indiscernible] for targeted delivery of inhibitory RNA to target is this pathway. Something also important is to demonstrate that oncolytic virus could combine with cutting-edge technologies used now in the treatment of tumors like CAR T cells. And you have this very efficacious collaboration with this change companies called -- developing their own CAR-T cells for solid tumors and believe as we do that co-treatment with OV equipped with specific attractant for T cells, make sense there. And we are, of course, hoping very soon publish those results. All those developments are, of course, aims at selecting 1 product. You all know that research might be disappointing and resi game, but these are the kind of 2 full panel of action we have taken to be in a position to be the first having coincide approaches targeting the IV route. If I come back to the clinical portfolio. You see that we have our development around TG6002, and I will leave the floor to Adele to comment on the very first results we have obtained with 6002 in the IV and IT route. We also have this collaborative program with by invent on BT-001. And we also expect a lot, of course, in the very forthcoming months around the development of a product together with -- and maybe to come later on some developments from our own research programs, and I will, at the end of the day, a report on our IL-12 expressing oncolytic virus. And of course, the best is yet to come with other companies. So we said that, I will leave the floor to Adel, who is working at the Leeds University of -- acting as a medical oncologist and a lead of Transgene research team. Very strong and long-lasting collaboration with us. I'm very happy to hear you at sharing your observation on this very important product for us in terms of lessons learned from the development. Thank you very much for the introduction for the current invitation to visit Transgene. So the products that we have been working on our 600 TG6002 [indiscernible] So I just wanted to introduce the team in leads. So running at a translational early phase clinical trial requires a really very large team. So the lead of my transitional laboratory, [indiscernible] there in the audience. I have a large laboratory group -- it requires the input of interventional radiologists and standard radiologists, a large early phase clinical trials team as well as the surgeons. And in Leeds, we are lucky that we can do this very efficiently. And we have a very efficient pipeline of oncolytic virus studies. So in which types of GI cancers could oncolytic virus make an -- and when I'm considering GI cancers that oncolytic viruses could make an impact, what comes into my mind is which ones are more likely to be immuno-sensitive and for TG6002, which encodes enzymes that convert inactive 5 FC chemotherapeutic into 5FU, active 5FU and considering which ones are 5FU sensitive. And the cancers that come to mind are colorectal cancer, hepatocellular carcinoma and cholangiocarcinoma, both in the new adjuvant setting as well as in the second-line palliative setting. And then another consideration is the route of administration. So we know that you can deliver an oncolytic virus into tumor via transdermal intratumoral injection that you can definitely get the virus there. But how far does the virus spread throughout the tumor and how well tolerated is this procedure. Intravenous therapy ensures that the virus if it reaches the tumor is well dispersed throughout the tumor. And the procedure can be repeated very easily in the setting of systemic therapies for patients with cancer. However, we don't know just how much virus gets into the tumor. And the third way of delivering virus is through local regional delivery, these methods include intrahepatic artery infusion, isolated lymph [indiscernible] routes. So today, I'm going to talk to you about intravenous delivery and intrahepatic artery delivery. The first study that we undertook with Transgene was with [indiscernible]. This is the preoperative -- study where we injected a standard dose of -- being a modified [Indiscernible] vaccine that expresses GM-CSF, and we injected a single standard dose ahead of planned surgical resection of colorectal cancer liver metastases. The primary objective being the presence of virus in the tumor -- when you inject intravenously how much virus gets into the tumor and secondary objectives are safety and changes in the immune tumor micro environment. So patients received a single intravenous dose ahead of planned surgical resection approximately 14 to 21 days afterwards. And what we found was that there were changes in the peripheral blood parameters as you can see there in the bottom right-hand box with activation of the immune system, increased PD-L1 expression as a result of virus delivery. We've hand that in 2 of the 9 patients treated that there was tumor necrosis -- in 1 patient, there was a complete pathological response following a single intravenous infusion of. In another patient, significant pathological -- so the patients with complete pathological response presumably didn't need to have major hepatic surgery, but you don't know that until you take out the liver. What we also found was that there was an increase in neutralizing antibodies, as you would expect. And also that the virus was carried in the plasma component of the world and not carried on the cells. We found the presence of virus in the majority of tumors that we treated, and this was at variable doses within the tumor. And our in vitro assays showed that the virus only replicates in the tumor and does not replicate in the normal level. We also found the presence of large amounts of CD8 T cells in the tumor specimens in all the patients that we treated. And we showed that there was a long-lasting adaptive immune response against the cancer. So we showed it by way of an IFN-gamma ELISPOT that we had increased numbers of T cells that are producing IFN-gamma in response to a tumor-associated antigen, carcinoembryonic antigen, and that this continued at least 3 months following surgery. So that single infusion of -- resulted in a marked T cell response against TEMSA that continued well beyond the time of surgery. So just to summarize that, intravenous reaches metastatic tumors. There is an inferior response that induces innate and adaptive anticancer immunity as evidence for human crisis and there's the upregulation of immune checkpoints. However, there was a little hypotension in some patients. And we wanted to see if we could optimize the delivery of the virus to the liver tumors, potentially by intrahepatic R3 infusion. So moving on to TG6002. This is the next development of the vaccinia virus -- vaccine that includes enzymes, which convert 5FC into 5FU. It's being tested in 2 simultaneous clinical trials, 1 via intravenous delivery and 1 via intrahepatic heart delivery in patients with colorectal cancer. For the trial via intrahepatic artery delivery, it's patients with liver-dominant colorectal metastases. For the intravenous study, patients are randomized to 1 of 2 arms. In the first time, patients received 3 infusion on days 1, 8 and 15, and then the second arm, they also received 3 infusions, but on days 1, 3 and 5. And the doses are escalating up to 3x 10 to the 9 PFU. So in the intravenous study, we found that TG6002 replicates in tumor tissue without signs of further spread into normal tissues, that the virus does reach the tumors, and this is found by tumor biopsy, especially at the higher doses of TG6002. So in the patients administered 3x10 to 9PFU we find the presence of virus in the majority of patients. We also found the presence of 5FU in the tumors indicating that the virus is replicating, producing the enzymes that convert 5-FC to 5-FU and the 5-FC is given orally. And we also found that the 5-FU has sustained in those patients up to at least 2 weeks and at times longer following the virus administration. There was, again, an onset of neutralizing antibodies, as you would expect, but this did not seem to inhibit the activity of the virus. So the peak serum 5-FU was maintained despite the levels of neutralizing antibodies. So this was the findings in the intravenous study, the clinical results continue to be correlated for that and will be released soon. Moving on to the intrahepatic artery study. So the intrahepatic artery route is routinely used in patients with liver tumors. And it is frequently used for patients with primary liver tumors, but can also be used for patients with liver metastases. The idea here is that it ensures a greater dose of the drug is delivered directly to the tumor where it is required. So in this study, we used the same virus. We use it in patients with liver-dominant colorectal metastases -- we gave a single infusion on day 1, followed by 10 days of oral 5-FC. And if everything goes well, the patient has a CT scan after 4 weeks with the potential for a second cycle of the same treatment. This is the team here and needs administering the virus to 1 of our patients is done in the interventional radiology theaters. And you can see on geography of the hepatic artery there showing perfusion throughout the liver. We treated 15 patients to date, starting dose of 1/10x6 PFU and escalated to 1/10x9 PFU tenth -- we found that the treatment is again safe that no maximum tolerated dose was reached. And according to the protocol, that was as far as the study was planned to proceed. In terms of laboratory immunological activity, what we found was that in the highest dose cohort, so cohort 4 that we saw an increase in CD4 and CD8 T cell infiltration into the tumor, and this was much greater than we saw in the lower dose cohorts. We also saw an increase in PD-L1 expression in the tumor in cohort 4, but not so with the lower dose cohorts. So again, this shows some times 10x9 PFU was sufficient to draw immune cell infiltration into the tumor and that there is immune activity leading to upregulation of immune checkpoints. These graphs are probably a little too small, but essentially, it shows in the first 3 cohorts that we are getting immune activation. We are getting the expression of co-stimulatory immune checkpoints such as OX40 as well as co-inhibitory immune checkpoints such as PD-L1. And very nicely, we saw a decrease in CTLA-4 expression. So TG6002 leads to a reduction in CTLA-4 expression amongst a cohort of immune cells, indicating either that those cells are less exhausted and more immune active or that there are less regulatory T cells, similarly with TIM-3 and other co-inhibitory immune checkpoints. We also saw in the -- this is data from just the first 3 cohorts. We are analyzing Cohort 4 with the highest dose that we do see increased T cell interferon gamma responses to the tumor-associated antigen CEA. And we also see a little activity against the virus itself. So T cell activity against the virus, which is no bad thing because if the virus is inside a tumor cell, then elimination of T cells, hybrid virus leads to anticancer immune responses. And this was an assay that we did very recently looking at calreticulin. Calreticulin is a biomarker of immunogenic cell death. And we see little activity in the first 3 cohorts, but we see a peak of activity in Cohort 4, indicating onetime 9P induces immunogenic cell death in those patients. And then looking for the presence of virus in the intrahepatic artery study, we saw a very little virus at 1/10X6 PFU a little bit at 1/10X7 the majority of patients being tumor via positive at 1/10X8 PFU with ongoing analysis at 1/10X9, but looking very positive in terms of the amount of virus reaching the team. So that's the summary of our work with TG6002 in patients with colorectal metastases. And thank you very much for listening.

Thank you, Adele, for this presentation. As I said before, you will have to fly back to U.K. So if you have any kind of burning questions or want to questions before the lease please do that now.

Just a quick question I'm just curious [indiscernible]

So for pre-OpEx, where we had the entire surgical sample, we could see specific foci of replication 2 to 3 weeks after injection. So presumably, when you inject intravenously, you get a little bit of virus that reaches the tumor and that there are specific areas of reputation within the tumor that you can detect up to 3 weeks after getting that dose. In the TG6002 studies, there was a biopsy that we're taking. And the biopsy will only tell you about the bits that you -- so -- but we were able to find virus at the higher doses in the majority of this biopsied indicating to us that it's likely to be everywhere in the tumor.

I'm sorry. But maybe regarding PD-L1 and T 600 with TK602, we see that there is in the plasma systemic levels? Do we also see that for PD-L1?

[indiscernible] higher dose, where we expect those responses, but as of now, no [indiscernible] answers.

And is the thinking then also that you need to have a certain threshold in the?

You're right. Many, many discussions are ongoing. One of them being that we might have also been too high in terms of viral infusions, generating major, I would say, fibrosis or whatever retention mechanisms -- we know also that we might have over boosted the immune response against the vector. So this might be an expansion on 1 side. The other 1 is that it takes some time. So time points, I don't have in mind the time points, but also we have to carefully look at the optimal time points for this same thing.

Yes. Do you have an idea of the level of 5 that you reach the tumor, how do they compare with the standard chemotherapy levels? 5-FU has been doing the assets [indiscernible] 5-FU in tumor in comparison to systemic delivery of 5-FU?

I don't have the number on the top of my head, but when we compare, we reach a similar level to already administered prodrug of 5-FU.

I see that the calreticulin maybe is too few samples that appears in the higher -- so does it correlate with the levels of 5-FU. It seems there is a trend of correlation between the dose of 6002 and the level of 5-FU, but it's hard to say because the number of samples are quite low. Thank you so much. Nice to see you all again. I'll see you soon, hopefully, take care.

Thank you, Adel. And of course, if there are any kind of questions you would like to ask, we would be happy to transmit to Adel or even work internally on answering on that. Next, part of this presentation will be around our brand-new product expressing IL-12. So it's something we are the first now, that's the first time that we report on this product, so privileged communication. Here is the product design. So you might recognize the way we construct our product, combining IL-12 cassette with full-length antibody compared with what we did with BT-001, we have used a different set of promoters for the antibody part and also actively worked on optimizing the promoter selection for IL-12. The target product profile for this specific one is to target immunosuppressed solid tumors, where immune remodeling of the TME makes sense. We know it's the case in many diseases that have proven to escape from primary line of treatment, which might have generated insufficient tumor infiltration or accumulation of T cells that would be exhausted T cells or imbalanced population of T cells compared with APCs in the tumor. Of course, in this development, we have in mind to fully exploit what we've learned from development of 6002 in particular, to go in the IV route to target deep lesions and advanced stage diseases. The tumor targeted IL-12 therapy has been documented for a long time. The challenge is that the therapeutic window for IL-12 is quite narrow. We need to reach a rather high amount of IL-12 in the tumor, but avoid reaching high level in the circulation. The maximum dosing reported to be 0.5 microgram per kilogram or kind of average Cmax around 100 nanograms per milliliters. So we have those very precise constraints in terms of balance between the intratumoral concentration and the circulating concentration. And we believe that therapeutic targeting systems might achieve those very ambitious numbers. What is important also is that the product to be able to be positioned in the modern settings should be combinable with the approved checkpoint inhibitors or most recent chemotherapy. And of course, to be able to demonstrate that used in the second line, [indiscernible] with those therapies. The question of having product expressing both IL-12 and possible second antibody, of course, is still being characterized in preclinical. And we have another product that might also make sense with a single agent, but we believe that really having those two armings that would work synergistically in the tumor makes a lot of sense, especially if the antibody that are not disclosed today would act on the balance between effector and helper cells. IL-12 is a kind of consensus. It must have -- and of course, we'll discuss that in the next slide, the intensity of the competition also reveals that this must have for endotherapy. IL-12 is a potent proinflammatory type cytokines. It has been used in a large number of preclinical demonstrations, but also we have a lot of knowledge from early clinical trials demonstrating its ability to boost both in innate and adaptive responses, acting on multiple cell populations from NK to T cells at large, inducing differentiation of most relevant helper 4D cells and skewing the mechanisms towards TH1 response. It would also indirectly act on tumor cells immunogenicity boosting expression of MHC class I molecules, but also working on macrophages and immunity cells in the tumor. This strong activity is, of course, well demonstrated, but counterbalanced by the multiple reports on adverse event when using IL-12 directly in the circulation. And we need some mechanisms to favor accumulation in tumor and avoid the overall exposure of tumor organs. So this consensus on IL-12 is translated into a very high competition in the field, multiple technologies have been explored in this perspective. The use of mRNA technology of recombinant proteins and fusion proteins to achieve proper targeting to the tumor and minimal exposure of nontumor organs and obviously also viral vectors. And in the field of viral vectors, we are the key competitors that we have facing our development. You can remark easily that most of the development are still in the IT route only. Rival 1 developed by Turnstone and Takeda in North America has the ambition to go both in IV and IT as we might have. And you might have seen recently that there has been a big change in the leadership on these programs. Takeda stopped its development on this product, and we are waiting on what could be the next steps to move forward for this product. So a large number of competitors with IL-12, but very few willing to address the challenge of going in the IV route. What can we say already in terms of activity of this product candidate. We have, as we did for BT-001, assessed the product efficacy in several models from CT26 as a reference model to very cold tumors, the code 1 being but also a very challenging tumor being this breast cancer model in EMT6. So we could detect responses in most of those models using monotherapy or combination with anti-PD-1. So again, proving that those two mechanisms are synergistic. But most of the activity in this combination is coming from the oncolytic virus. What was also important is to confirm as we also did in BT-001, but now we have a larger set of immune characterization of the clonality and the diversity of the T cell responses. You see here that we've been able to characterize at the 10 and the 14th were quite early on in the process the induction of both antitumor and antiviral responses. So mostly, we have recall from memory T cells against the tumor and also fast induction of T cells against viral antigens, but we know that those responses are not very long-lasting, except for the tumor responses. Important to demonstrate that we have a strong memory cell mechanisms engaged in the tumor response. You see here the results that we could collect in the CT26 model, demonstrating that even after a recent challenge, we have a very strong efficacy. So again, confirming that we have been able to raise memory T cell response and part of that being resident memory T cells. And what is also important is to demonstrate that very efficacious response could be observed. If you just look at that after the session. Compare this efficacy with the one we could obtain in the IT route with BT-001, we are much stronger in the ability to raise a memory response here. This key role of CD8 positive T cells could be demonstrated by some depletion experiments using polyclonal antibodies, you can deplete either CD4, CD8 or NK cell populations, specifically. And you see that upon depletion of CD8, you have a complete loss of the efficacy, a partial loss for CD4 also demonstrating that they are partly involved in making antigen and those CD4 populations being mostly TL helper cells rather than effector CD4 cells. NK sales contributions was also detected still to be analyzed, but it looks to be important at early stage of the antitumor response, not really on the long-term mode of action. If I expand these conclusions on the contribution of CD8 T Cells in terms of benefit for the whole body, this is the typical experiments that we usually carry on confirming that CD8 positive T cells are induced and would act on multiple lesions. So we have this double flank xenograft model where we inject one lesions and see the way the second lesion injected would evolve. You see here, as we did for BT-001 that we have a strong abscopal response both tumor being controlled and most of the mice fully controlling the non-injected lesions upon treatment. For this specific product, we could go very deep in terms of analyzing the molecular pathways involved in anti tumor response. You see some for instance, very small and most eligible, but you see here that the volcano plot reveals a large transit response after product treatment. This happened true after empty vector injection, but the stronger response came from the IL-12 arm virus, and you see induction of a very, very large number of pathways in both injected and non-injected lesions. When you go deeper in the oncology of the responses, you see that multiple classes of pathways could be triggered and very early on in the process. As soon as D15 and D17, we are with the maximum specific response that will be very long lasting, but in the very first days after administration, we have multiple immune cells being activated or in filtering the tumors. When we look at those subpopulations more accurately, comparing the empty vector and the IL-12 armed virus, what we basically could easily see here is that, we have the strong infiltration of the tumor by CD8 positive T cells, but also neutrophils, DCs and T regs, and this massive infiltration of T regs is also the rational for maybe a second arming we could put in the virus. So we are, of course, continuing characterizing the activity in price models. But all those tools that we are developing will also be made available for the clinical development because these are the key questions. We also have to document in human. So to summarize where we stand now with the development of IL-12, expressing VV. We have this potent another candidate being characterized in preclinical models. We have been able also to take into account some lessons from the development of TG6002 improving the potency of the vector. And we -- for those of you who are specialists in vector technologies, you might have detected that we have slightly different vector than the one we were using for our previous development. This one would have an additional deletions for the GM 2L that we reported 2 years ago to be a viral component interacting with CD86 that certainly is beneficial to be removed from the viral design. We have been able to optimize the promoter sequence for both IL-12 and the recombinant Mab to be implemented in the product. And in the meantime, we have also improved the GMP manufacturing process to be able to control in the GMP product, the level of residual IL-12 that will be unused the patient. The tumor specificity should be very strong, and we will be, of course, cautious to confirm that we have tumor-only application for the product in the dose relation program to be planned. We will, of course, use the transcriptomic signature to analyze from the biopsies, the modification of the product in the tumor. But we know already that the -- even a triple diluted vector is well tolerated, primate experiments were very reinsuring regarding the safety of director, of course are still considering additional pivotal studies if needed, to manage the potential over expression of IL-12. But with the GMP processes we have now in place. I think we are on the safe side for this question. The discussion is very active on what could be the best indications for developing this product. Lung cancer has been today the champion in this discussion, considering the medical need, the characteristic of the patient escaping from the first-line treatment and availability of those patients for further development. So thank you for your attention. We'll take the questions after Steve's presentation, and the opportunities wish to reinforce on this Invir.IO platform. IL-12, of course, being developed by transgenes, but we have not yet disclosed all other options we have engineered in the lab and that could be venues for partnerships, but also we are ready to consider kind of customize the development programs with companies as we did with AZ. Steve?

Thank you, Eric, for that excellent overview of Invir.IO platform. And good morning and good afternoon. I'm Steven Bloom, Chief Business Officer for Transgene. And I'm going to build on what Eric said and quickly go over why the best is yet to come with the Invir.IO platform. So the Invir.IO platform is a pretty versatile approach to creating oncolytic viruses. There's four real advantages to the platform. And clearly, one is safety and selectivity. And the second is the ability to create large payloads and put multiple payloads onto the virus itself. We also have the ability to take a look at various solid tumor targets. And we can actually think about the size of the market relative to solid tumors. And I'll talk about that in a few minutes. And then we have also the ability to make the product, obviously. So when you think about the versatility of the platform, it gives us a competitive advantage in our ability to develop oncolytic viruses going forward. So oncolytic viruses have had an interesting sort of time line over the last 120 years. You can see that there was a lot of activity early on, but lately in the last 15 to 20 years, there's been a bit of an increase in the level of activity with some programs being approved around the world and we feel that a Transgene that the platform right now is at a tipping point where we could potentially take our Invir.IO platform forward. And as Eric alluded to, make multiple contracts working with companies going forward. So if you look at the oncolytic virus development space right now, it's pretty active. There are well over 100 programs being developed both preclinically and clinically. A lot of these programs are in the early stages of development, Phase I to Phase II. A small piece of these are actually IV programs. And what I want to really focus on is what we've been alluding to, most of the presentation from Adel and Eric is the opportunity to go into the IV space and target really solid tumors as a potential market opportunity and really think about ways that we could work with companies that are developing their own programs and develop together different constructs that could go after deep solid tumors. So if you think about sort of the platform as it is, we have several advantages. And I'm going to sort of overview -- OVs are being developed for lots of solid tumors. We also can take a look at programs as I mentioned, IV programs in the clinic. And then we have the ability to talk about different -- pretty hard to read, there we go. Okay. Thanks. IV administration of OV creating many potential solid tumor pathways and then combination strategies with checkpoint inhibitors that would allow us to work with pharmaceutical companies going forward and boost the activity of some of their programs as well. I want to talk a little bit about the solid tumor opportunity. You could see that there's a fair amount activity in the space, solid tumors such as melanoma, pancreatic cancer, lung cancer, we talked a little bit about colorectal cancer. So this is where really the opportunity exists for different partnerships with companies going forward that are developing their own programs in solid tumors. When you look at the oncolytic virus development path, there are a fair amount of encoded genes by cancer type. We've mentioned earlier that we're working in some of those areas with some of our programs with some of our partners, as Eric mentioned. And we are -- and we can take a look at the space right now and think about the various companies that are in the marketplace. And it's a very small group. It's a group of companies that we're probably a part of and that when you think about the IV opportunity and the opportunity to sort of take a leadership position in the space with two programs in the clinic, we certainly feel like over the next several years, we can develop different programs and contracts that will allow us to maybe move forward into a leadership position in the space. So what could we do talking to companies? And we've already been talking to companies and we'll continue to discuss with companies how we might be able to help them going forward. So thinking about life cycle management, brand leaders, franchise leaders. They think about their programs currently, but they also think about their programs going forward. And Eric mentioned the novel partnerships that we have right now with AZ and BioInvent creating novel constructs, focused on various indications going forward. That's one approach we could take. The second approach we take is to synergize with other IO programs. The third approach is to take a look at pharmaceutical company, deprioritized assets. Why did they not work? What were things that happened in the portfolio where a program is now on the shelf. We possibly rescue that program if there was a toxicity signal, for example, and pair up our oncolytic virus platform with a program like that and figure out a way to maybe resuscitate that program going forward. And then there's a general approach to life cycle management, which is I'm sitting back looking at my lead program. And I see various issues down the road, either competition or IP issues or other marketplace changes that could come up. And could I work with a company like Transgene to extend the life of my lead program going forward. So these are all ways that we might be able to partner with companies, and we've been engaged in some of these conversions and there's been some good responsiveness from companies that we've talked to. So in conclusion, great science, real growing pipeline and a focused business plan. Hedi mentioned, being a world leader in the immunotherapy space that's something we clearly aspire to be. We will continue to grow the Invir.IO platform and we see in the next 6 to 9 months, several opportunities to discuss with companies, the very ideas that I just mentioned in the previous slide. Being a partner for companies going forward, as I mentioned before, and then the commitment to continuously improve our backbone with future generations of IV backbones and other oncolytic virus backbones that might allow us to differentiate ourselves in the marketplace. So when you conclude from Adel's presentation, Eric's presentation, and my discussion about opportunities with the Invir.IO platform, we feel the time is now for Transgene to step up and think through how we could develop innovative novel programs going forward on our own or with companies that we would partner with going forward in the future. Thank you.

Thank you very much, Steven. So I hope that in this session, we've been able to inform those of you that are not familiar with the technology, to bring those of you who are specialists in our most recent advances in the IV route. You heard from Adel that we could detect and confirm viral replication from the IV route to note the dosing range, where we can expect replication detection in the circulation on reported genes. And we learned from early development where they had surgical pieces that the [indiscernible] of the tumor could be confirmed, something that we, of course, hope to be able to do in the next step of the BT-001 development program. Something, of course, we have not been able to disclose now, but will certainly be communicated very early on next year is the result of our collaboration with AZ. We, of course, rely a lot of them willing to communicate on what we did together. And we know, for example, that the next SITC meeting, there will be a presentation on what we did together. So really good timing. Important moment we are living with our collaborators in the clinical development. Sorry for not sharing with you today, brand-new results on the BT-001 trials, but we are actively working at collecting data and biological information from the IT route in addition to the already published IP results. So there is room for questions now.

Thank you, Eric. Thank you all. I was wondering because you mentioned that for the IL-12 construct, you plan to use it in lung cancer. So since you are going to use it IV, what will be your mode of delivery?

Well, we are going to inject intravenously. The plan is to give optimized regimen, we have defined for TG6002, meaning the 1 that we defined, and that's the plan at the moment.

So you think injection will lead to a sufficient...

Well, to be on the safe side, we will repeat after 3 weeks against the injection. So as shown with TG6002 by Adel, it looks like even though neutralizing antibody are there, they are not interfering completely with the activity of the virus and the expression of the payload. So to be on the safe side, I agree with you, fuel injection might be not sufficient. But the plan is obviously to move forward monotherapy to combination with PD-1. That's the plan.

Two quick questions. How do you explain the fact that despite antiviral immune response, there is no impact on the efficacy of your oncolytic virus? And the second one, is there any specific predictive or therapeutic biomarker that you can use with your oncolytic virus?

Yes, we know that we have some anti-vector antibodies, part of them only being neutralizing antibodies when used in titration assay. We know that the way the virus would infect cells is not based on a specific receptor mechanisms that could be prevented by the binding of most affin antibody. So our vision today is that we might have antibodies covering the surface, but it would be not enough to prevent memory infusion mechanism that are responsible for the uptake of the virus by -- especially by DCs and other cells. We also know that the level of neutralizing antibodies or the titers we could patients are very variable from -- and so only very few patients exhibited high titers. So we had reactivation possibly of smallpox vaccination, but it's not the main reason for this raise of neutralizing antibodies, more it's more induction of novel B cells. And that's the reason also for the intensified administration regimen going every 2 days rather than every 2 weeks to hopefully diminish the onset of the B-cell response. I hope answer your question. But mostly, I would say, from what is reported on the neutralization of virus infections, usually, it is well described for adenoviruses or small viruses where we know we rely a lot on the receptor interaction for virus infection and cell entry. It's not the case for small pox viruses that are large viruses, mostly impacting cells via membrane fusion mechanism not so sensitive to neutralizing antibodies. And the titers that we could confirm in the labs being needed for a full blockade of the virus entry was never reached in our patients. Regarding the second question on the biomarkers, again, for that reason that we have no receptors that could predict best infected cells. We have no direct markers on target sales. What we know are more, I would say, general markers maybe under the pre-existence of antiviral response, but we have no plan to implement those markers. I think we don't see very direct biomarkers with predictive responders and looking at our biomarker specialist, but I don't see any relevant biomarkers. At least that's not a plan that we have for the lung cancer trial.

Just a question directly related to this one because, so you say that there is a high interim individuality in terms of antibody fighters. So is there any relationship between antibody production, T cell response against the virus and T cell response against the payload?

Okay. Of course, it would be much simpler if we had those type of answers. Today, the numbers are not so high to have a statistical of course, analysis. But from what we could analyze there is no correlation for example, patients with higher titer, we are not dose exhibiting the lesser production of the 5-FC 1, sometimes the opposite. So no general trends appear at the moment in our analysis at a critical rate possibly.

So we've tried hard to do this type of correlation. It turns out, it's much more complicated than that because I said, Eric, the Vaccinia virus do not use a specific receptor. So even if you get antibodies around the viral particles, it does not prevent infection of cells. That doesn't mean that there is no neutralization. There is a neutralization, but much more probably in the form of the neutralization you see for RNA therapies, meaning a neutralization that is mediated by a cellular immunity and other activation of NK cells. So I'm afraid there is one, but probably not as simple as I have a title of neutralizing in vitro antibody and they are related to the activity of the virus. Concerning the correlation with the cell response, we have not done formal correlation between antibody titer and T-cell response. But when you look at the work from med care and all these guys that have studied the question a lot, it's actually turned out to be something beneficial because if you have a T cell response against antibody -- against the virus, you end up having a T cell response against the cells that are infected and the cells that are infected are the tumor cells. So we are most looking for that.

Just so you touch upon your [ S1 ] presentation, TG6002, you look at different administration and different schedules. And it was mentioned that basically with high concentration intensive schedule, you triggered some limited mechanisms. I'm just curious if you have any hypothesis or any working what it is currently, what those limiting mechanisms were?

So I was just mentioning about actually, I had that in mind. So just like the observation that [indiscernible], for instance, can have for the vaccine or the early work of [indiscernible] from BioNTech on their RNA therapeutics. So when you over activate the innate community with an RNA or with a virus, you do trigger some neutralization, which is cell-mediated and not antibody mediated. It seems in the more intensive schedule we have tested in the 6 or the 2 trials that we do observe this type of mechanism in some of the patient groups, and it's actually reflected both on the activity of the payload and the persistence of the virus. So how does that translate to the patients? We don't know. But that's probably this type of mechanism. We are taking steps to address that, and we'll have further data to answer and support this hypothesis in the months to come.

Maybe to come back on the IL-12 construct, just to be sure I understand what you said previously in terms of where you might go, you said after first line, so I guess, this time, we are in metastatic setting in lung cancer and probably first line after PD-1, PD-L1 or PD-1, PD-L1 plus chemotherapy once the patient escape. I was more surprised by the way you think going monotherapy or combination. And so did I understand correctly that you may assess both of them? The reason I'm asking is that I would think of keeping PD-1, PD-L1 and adding IL-12. But what if and how can you go monotherapy if for instance, an ADC TROP 2 comes in between? So monotherapy looks like a more challenging type of fruit.

The issue is very simple. It's regulatory because to start with, we need to data on using the virus as a single agent. And we cannot right away start combining with whether it's an ADC or chemotherapy agent or an anti-PD1 or well. So -- and moreover, we are expecting transactional from translational analysis view because Kaïdre mentioned dose effects -- but possible dose effects. So we need to accumulate a lot of results and we are waiting, we are expecting biopsies at different time points. We are expecting to follow cDNA to see whether there is some impact on cDNA. And it's needed the first to start with the oncolytic virus as a single agent. But you know it's a limited number of patients, and it's a 3 to 6 study design. So it will be quite short and not a huge number of patients to start with.

Thank you, Maud. May I suggest that we move to the next session that would be both by Pedro for the scientific perspective on what we have discussed today and we ask Pedro to contribute on kind of putting everything together in the frame of a larger vision and providing you with comprehensive analysis of our technologies compared to the state of the art. And Hedi would conclude after that. So Pedro is coming from University of Lausanne. He's been Professor there of immunology and cancer therapy and is now the Scientific Director of the Ludwig Cancer Center in Lausanne. And furthermore, I would say Pedro is the Chief Editor of the Journal for ImmunoTherapy of Cancer. And for that reason, he has a very broad vision on what is going on in the field. The progress is made by the worldwide community in this very hot topic, and it was good that he accepted also to share with you how we would see the positioning of Transgene in this vertiginous competition area. Thank you, Pedro.

Thank you very much, Eric, for your kind introduction. So I'm going to try to make a brief overview along the lines Eric mentioned. So basically, this is a time of great excitement, as you know, immunotherapy has literally revolutionized the treatment of cancer since the first approval in 2011, it actually has spurred [indiscernible] billion dollar business. And the treatment is actually prolonging life and producing even tumor cures. And -- but there is a gap. And the gap is that only 20% to 30% of cancer patients at the best benefit from these interesting therapies and 70%, there is a need to democratize, so to speak, immunotherapy of cancer and extended to the majority of cancer patients. And here is where we see as community the great value of therapeutic cancer vaccines. As was mentioned earlier, is certainly all evidence in the preclinical work point to the promise of vaccines as a way to induce tumor reactive T cell responses, CD4 and CD8 and also to guide those responses to the tumor and to make the resistant patients actually sensitive to this very successful immune checkpoint blockade therapy. So the goals of cancer vaccines are manyfold. And the more important ones are, in fact, the difficult to read here. So to recruit the highest ability TCR T cell clonotypes. And to actually induce long-lived memory T cell immunity. And so in terms of recruiting the highest ability TCRs, of course, is a game of selecting the appropriate antigens, the appropriate dose and the timing of the vaccines. And in terms of inducing long-lived T cell immunity, of course, this is the central character of vaccination and probably the most important feature of a vaccine induced T cell response. And yet, we don't know as immunologists, how to do this molecularly, but viruses know very well how to do that. As you know, viruses used as vaccines can induce long-lived, actually life long live immunity if we think about some of the common viral vaccines. And so I see here a big advantage of using viral vectors in general as a vaccine vectors. Now molecularly the 5 vaccines consist of 3 units, antigen, adjuvant and the carrier. And of course, here, the antigen is clearly the major determinant in successful vaccine formulation and many antigens, actually thousands of antigens are available today for vaccine development. And so there is a big challenge there as to the choice of the antigen for appropriate vaccination. These antigens have been grouped in different categories. The most interesting ones are the shared tumor-specific antigens followed by the overexpressed antigens. The mutated unique antigens that today are equivalent to the neoantigens and of course, the virus encodian antigens. And there are interesting databases. This one well created, but of course, there is now the opportunity for artificial intelligence-driven mining of all the data sets that are out there in the public domain. So you can imagine that there has been intense early clinical trial testing of vaccines, therapeutic cancer vaccines even Phase III trials in many tumor types such as prostate renal cell carcinoma, lung breast cancer glioblastoma, melanoma, lymphoma and actually quite many others. And even one that actually used naturally isolated antigens from glioblastoma, which is the core business of this gem and biotech company Immatics Biotechnologies. And the common denominator in most of these clinical trials is that, #1, we know how to vaccinate. These are immunogenic to strongly immunogenic vaccines. But #2, that there is a modest disappointing clinical benefit. And so the game today is in understanding what are the reasons for failure and how we go about that in the business of making cancer vaccines really clinically efficient and not only immunologically efficient. And so there are a number of reasons that can be identified. Probably the most important one is that the repertoire of T cells that we are addressing with the vaccine is highly tolerant to self antigens. And the majority of those tumor antigens are self. And so that is one major challenge. The second one is that monovalent antigen vaccines mainly to immune selection and tumor escape. And when you use them in a highly metastatic patient, highly immune selected or immune edited tumor, the chances for escape are manifold. The delivery methods are suboptimal and probably the most formidable barrier is the immune-suppressive tumor microenvironment. So one major focus in recent years is identifying the appropriate antigens and the concept today is that it is neoantigens that is the antigens that arise from genetic mutation, somatic mutations in the tumor that are probably the most immunogenic, the most appropriate antigens for vaccination. And basically because it was already mentioned, there is no central immune tolerance to these antigens. But a drawback of this is that there are known two new antigens alike, and I'm exaggerating just a bit here. But this, of course, cause for personalized vaccines, and you are actually addressing that with your platform. There have been already clinical trials testing this concept with synthetic peptides on the left or with RNA formulated vaccine on the right. Note, the logistics that are pretty heavy and second, the time that it takes to formulate this multivalent neoantigen base vaccines for each patient. So there has been even a Phase Ib trial, 85 patients vaccinated with long synthetic peptides representing 10 to 20 neoantigens per patient. And there has been also the use of mRNA-based vaccines now going back to share tumor antigens as down here by [indiscernible] the people in Germany and some -- this is some of the findings in general, encouraging findings of adequate immunogenicity of these vaccines and even some hints of clinical benefit. So in all these cases, what happens, as you know, is a vaccine induces killer T cells that go to the tumor site and eliminate tumors. Here, there is another important concept that has been underlying all this afternoon, and that is of the immunogenic cell death. What is immunogenic cell death is let's say, if we take [indiscernible], the program cell that is [indiscernible] the good between mark type of cell death. As you know, if we think about we are renewing our gut every 3 days, and that means that billions of cells are dying in our gut. And this death silent is immunologically silent. And that is good because that avoids the induction of order immunity. And then there is this type of immunogenic cell death that is visible to the immune system. And that leads to the induction of immune responses against the cellular components. And you see there at least on the left of agents that handled these pretty nasty agents like chemotherapy, radiation therapy, phototherapy, but you have also a virus, and that is also a major advantage of using viruses in this case for their oncolytic properties that lead to immunogenic cell death. Here, you have -- I lifted from a paper actually published in the journal I see here, on some of the best-in-class oncolytic viruses. So you see that Vaccinia compared favorably to help a simple virus Tregs, which has actually FDA approved for the intratumoral treatment of some cases of melanoma. And so here, we have, in recent years, the field moving back from a very antigen informed vaccine development to an antigen agnostic type of vaccine development facilitated by these oncolytic viruses that can do the job of releasing antigens for the immune system to see. And in this case, the logistics is simplified. And then you give the immune system, the choice to pick up the antigens irrespective of whether they are shared tumor antigens or somatic mutations, giving rise to neoantigens that tumors have them all. And then here is, again, some of the conceptual basis of this in situ vaccination by the oncolytic virus action. And maybe to finish another important concept is that of immune fitness and of course, there are many factors that in -- that define the ability of each one of our immune systems to react more or less to vaccination in this case, including environmental factors, diet, microbiome and also age and a genetic makeup and so on. And there is a need to capture that kind of immune fitness and all the new technologies, multi-omic technologies driven by artificial intelligence really treat all those data will allow to also include in the algorithms of vaccination and evaluation of the impact of vaccination, not only the baseline immune response, but also the baseline immune fitness and it is clear that in many cancer patients, the more advanced the cancer, the more advanced AH of course, this leads to a much reduced chance of having an appropriate vaccine-induced immune response. And hence, the idea to go to apply to move these vaccines to the early stages of angiogenesis and to the adjuvant setting in the tumor-free high-risk relapse as you have in [ antitumoral ]. So I'd like to finish here by saying these are exciting times. Vaccines will come of age. The question is whether vaccines, cancer vaccines would work or not work. I think that is not the question. The question is when, and I think that the next decade, we'll see now the first vaccines with clinical efficacy coming up to the floor. And maybe now I take out my hat from the university and take my hat from Editor in Chief of the Journal of ImmunoTherapy of Cancer, and I'd like to say that reflecting that enthusiasm, precisely the paper that you went over in detail, which is the same reach paper characterizing the BT-001 virus together with BioInvent was actually selected by the editors of the journal as the base paper in the oncolytic and local therapies of the journal, which were actually 38 papers. And this is confidential because Citi has yet to announce that during the annual meeting. Thank you.

Thank you, Eric, and thank you, Pedro. Wow, what a day. We're so nice to hear the team gathered here and our clinician partners going in depth into the science that is behind our products and the clinical need that is the fundamental reason that we are here and that our products are addressing. I think you've understood that we are at the right place at the right time with a lot of exciting products. We spent several times, we mentioned our partners, our industrial partner that are key in developing our products. I want to mention AstraZeneca. It's been a very productive scientific partnership along the last 3 years, also generated EUR 23 million revenue for our company, which is never negligible. Also, keep in mind our partnership with AZ and the one with BioInvent. Here, we are -- the power of two is at work. Also, we are cutting the cost of our developments by 50%. And without these partners, TG4050 and BT-001 would be not as smart products as they are. We reviewed all the data that we have had in 2022 and gave you the latest information on the progress we are making. We also introduced new exciting ideas for the future. I want to mention, of course, our new IL-12 oncolytic virus that should start a nuclear trial in 2023, targeting the lung cancer, as we've discussed, and really designed for intravenous administration. Also, you have heard from Eric somewhere like continuous improvements of the backbone of shuffling. This is the work we are currently doing to build a new backbone that will be better tolerated, real design for intravenous administration more activity in C2, hence, more oncolytic. It's a bit too early to talk about too much details about this program, but this will come in the next years. Really short term, what's ahead of us? We are still in Q3 2022 and Q4 is knocking at the door. So now I'm sure you have in mind that in Q4, we'll have the internalysis for TG4001, our most advanced product in Phase II, and that will be the first randomized trial results for an HPV-induced anogenital cancer in the world. Also next year, we will communicate new data about the intravenous delivery for oncolytics and the progress of our new programs. Once again, I would like to thank all of you for your support, for your challenge, for your questions. Thanking all the team, the 160 people at Transgene who are doing such a great job that we've seen part of -- just a small part of it today. You are welcome anytime in Strasbourg, please don't hesitate. Once again, thanks for being here today to listen on the webcast. See you soon. Have a good evening.