PDS Biotechnology Corporation (PDSB) Earnings Call Transcript & Summary

Hello, and welcome to the PDS Biotechnology R&D Day. [Operator Instructions] As a reminder, this conference is being recorded. It's now my pleasure to turn the call over to Deanne Randolph, Vice President, Commercial Development. Please go ahead.

Good morning, and welcome to PDS Biotechnology's Oncology R&D Day Teleconference and Webcast. With me today are Dr. Frank Bedu-Addo, Chief Executive Officer; Dr. Lauren V. Wood, Chief Medical Officer; and Dr. Jeffrey Schlom; Dr. Caroline Jochems; and Dr. Julius Strauss from the National Cancer Institute. I will provide formal introductions in a moment. But before we begin, I would like to caution listeners that comments made by management during the conference call will include forward-looking statements within the meaning of Federal Securities laws, including the Safe Harbor provisions of the Private Securities Litigation Reform Act of 1995. These forward-looking statements involve material risks and uncertainties, and the company's actual results may differ materially. For a discussion of these risk factors, including, among others, the risks related to COVID-19, the impact such pandemic may have on the business, on the company's business operations, financial operations and results of operations and the companies that all to respond to the related challenges, including those noted in PDS Biotech's SEC filings, investors, potential investors and other listeners are urged to consider these factors carefully in evaluating the forward-looking statements and are cautioned not to place undue reliance on such forward-looking statements. Please note that the content of this conference call contains time-sensitive information that is accurate only as of the date of the live broadcast, June 16, 2021. Except as required by law, the company undertakes no obligation to revise or update any statement to reflect events or circumstances that take place after the date of this call. With me today are a distinguished group of cancer researchers, who it is my pleasure to introduce. Dr. Frank Bedu-Addo has served as President and CEO of PDS Biotech since inception of the company. Dr. Bedu-Addo is a veteran biotech executive with experience successfully starting and growing biotechnology organizations. He has been responsible for the development and implementation of both operational and drug development strategies, supervising and managing both large organizations and emerging biotechnology companies. Dr. Bedu-Addo was the founding and senior executive at KBI BioPharma. As Vice President of Drug Development, he oversaw all business and drug development operations. Before his tenure at KBI, he successfully started and managed Cardinal Health's East Coast biotechnology drug development operations. Prior to Cardinal Health, Dr. Bedu-Addo as an Associate Director at Akzo Nobel, Senior Scientist at Elan, which is now The Liposome co. and Principal Scientist at Schering-Plough. In these positions, he contributed to the development of numerous drugs, including antiviral and anticancer products. Dr. Bedu-Addo obtained is MS in Chemical Engineering and PhD in Pharmaceutics at the University of Pittsburgh.

Caroline, are you hearing anything? [Technical Difficulty]

Dr. Lauren V. Wood joined PDS Biotech as Chief Medical Officer in February 2019, where she directed clinical development of the company's Versamune-based product pipeline targeting a broad spectrum of cancer. With 30 years of extensive clinical research experience at the National Institutes of Health, Dr. Wood most recently was the Clinical Director of the Vaccine Branch, Center for Cancer Research at the National Cancer Institute. While there, she oversaw the translational development of immune-based therapies for both cancer and HIV infection and was the co-inventor of 2 patented therapeutic cancer vaccine platforms targeting the TARP and HER tumor antigens. Prior to joining the vaccine branch, Dr. Wood was a senior clinical investigator from 1992 to 2009 in the NCI Pediatric Oncology and HIV and AIDS Malignancy branches, overseeing teams and investigating anti retroviral, anti-infective and immunomodulatory therapies for HIV-infected children, adolescents and young adults. Trained in both internal medicine and pediatrics with subspecialty training in allergy and immunology from NIAID, Dr. Wood received her MD from Duke University School of Medicine, MBA for Biology of Oberlin College. Dr. Jeffrey Schlom is Chief of the Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute of the NIH. He received his PhD from the Waksman Institute at Rutgers University. Dr. Schlom directs a translational research program in which in the latest advances in immunology and immunotherapy are used to design and develop a range of potential novel immunotherapeutic approaches for a variety of human cancers. His most recent work involves the development of novel therapeutic cancer vaccines, checkpoint inhibitors and immune modulators both as a monotherapy and in combination therapies. The program focuses on the design and development of novel off-the-shelf immunotherapeutics that can be translated from hypothesis-driven preclinical studies to science-based clinical studies both at the NIH and at numerous cancer centers throughout the U.S. Dr. Schlom serves on the editorial boards of numerous scientific journals. He has authored more than 800 scientific publications and holds numerous patents for monoclonal antibody and recombinant vaccine generation and uses. Dr. Julius Strauss is a Staff Clinician at the Laboratory of Tumor Immunology and Biology where he directs the Clinical Trials Group. His clinical research is focused on the use of novel agents capable of inducing the immune system to recognize and kill cancer cells. Dr. Strauss is very interested in the use of these agents in combination with each other as well as standard cytotoxic therapies in an effort to improve their efficacy. Dr. Strauss also has an interest in using these therapies to help patients with the fewest treatment options. Dr. Caroline Jochems received her MD from Gothenburg University, Sweden and her Ph.D. in immunology from the Institute of Medicine at the Sahlgrenska University Hospital at Gothenberg, Sweden in 2008. She subsequently joined the NIH as a Postdoctoral Fellow in the Laboratory of Tumor Immunology and Biology and was appointed as Staff Scientist in 2019. Dr. Jochems has authored approximately 50 scientific publications. Welcome to you all, and thank you for joining us here today. Over the next 1.5 hours, we will be reviewing a scientific foundation for the Versamune-based research in oncology. Dr. Bedu-Addo will open the session by reviewing the basic [ tenets ] undergirding the Versamune platform. Dr. Wood will then introduce PDS0101 and discuss the unmet medical needs in HPV-associated cancers and the preclinical results from the initial tests of PDS0101. Dr. Schlom will characterize the concept behind combining PDS0101 with 2 other novel immunotherapies. Dr. Jochems will walk us through the preclinical results testing these combinations, and Dr. Strauss will review the interim results from an ongoing Phase II clinical trial. Dr. Wood will close the session on PDS0101 with a review of the clinical plan for the product. We will then move on to PDS0102, where Dr. Wood will review the product design and TARP prevalence in cancer as well as the preclinical results to date and the clinical development plan for this product. We will then move on to PDS0103, where Dr. Wood will review the product design and MUC1 prevalence in cancers. Dr. Jochems will review ongoing work of tumor antigen redesign and preclinical immunogenicity. Dr. Wood will then review the clinical development plan for this product. Dr. Bedu-Addo will close today's session with an overview of the work ahead to building our Versamune-based pipeline into the next generation of cancer immunotherapies. At the end of each session of the presentation, we will open the discussion for a question-and-answer session. [Operator Instructions] With that, I would now like to turn the call over to Dr. Frank Bedu-Addo.

Thank you very much, Deanne. Well, I would like to wish all our attendees a very warm welcome. I would also like to say a big thank you to all our collaborators and partners who have contributed towards the development of what we believe could be a transformative technology backed by excellent science as we seek to significantly progress the field of cancer immunotherapy with a new generation of T-cell-activating immunotherapies. The National Cancer Institute presented some very promising early data from the PDS0101, M7824, NHS-IL12 triple combination at ASCO, and we'll discuss some of that data today. To start, I will walk you through some of the signs behind PDS Biotechnology's Versamune technology platform and how Versamune works to overcome some of the hurdles facing immunotherapy today. Now one of the most significant limitations hampering the development of broadly effective immunotherapies is the lack of effective induction of potent tumor-targeting killer T-cells in vivo. Now let's take the checkpoint inhibitors, for example. It has been reported that the checkpoint inhibitor is the most successful type of immunotherapy today despite their efficacy in blocking immune checkpoints and de-camouflaging or exposing the tumors to the immune system surveillance only work in about 20% of treated patients. This means that approximately 80% of patients who are treated with checkpoint inhibitors will not respond. It is also reported that the checkpoint inhibitors work in patients whose immune systems have generated preexisting killer T-cells that couldn't attack the exposed tumors. Some of these studies highlight the critical importance of T-cells immunotherapy and the need for effective strategies to promote T-cell induction. Now this is exactly what the Versamune technology has been engineered and demonstrated the potential to accomplish. Preclinical and clinical studies to date strongly suggest that Versamune is promoting the induction of large quantities of the right phenotype of T-cell with strong killing potency. Another characteristic of the Versamune technology that we will discuss today is the induction of memory T-cells. Memory T-cells are extremely important in the ability to induce a long-lasting, durable or sustained antitumor response as we will see in our preclinical and clinical studies. In oncology today, very often, efficacy is associated with toxicity. Compounded toxicity is one of the significant potential concerns with combination oncology products. At PDS Biotech, our Versamune technology, we believe, is unique in demonstrating the potential for strong potency without the toxicities typically associated with oncology or immunotherapy. I'll quickly review the current state of immuno-oncology. Cancer cells are well documented to have the ability to evade immune surveillance and to suppress the body's ability to effectively mount a T-cell attack. This is accomplished by a number of immunosuppressive mechanisms. The good thing is that a number of highly effective therapies have been developed to target and block some of these mechanisms. These include the checkpoint inhibitors, such as KEYTRUDA, which is being studied in combination with PDS0101; and a novel and highly promising bifunctional checkpoint inhibitor which combines an anti-PD-L1 checkpoint inhibitor with an anti-TGF-beta drug. This immunotherapy is also being studied in combination with PDS0101, as will be discussed shortly. Now despite these advancements, effective technologies to induce and activate T-cells are lacking. However, several of these approaches are in clinical testing. We will see today that an effective cancer vaccine or T-cell activator must access and activate several important immunological processes and pathways in order to generate a clinically beneficial T-cell response. So the discussion around T-cell induction is not a new one. Many of our audience have heard about several technologies which have been reported to induce T-cells. However, this has not yet translated into broadly clinically beneficial products. What we know today is that not all T-cells are created equal. What we have been saying is that it is critical to induce the right phenotype of killer T-cell in the right quantity and with the right killing potency. Only when the T-cells -- or the technology possesses all 3 characteristics will we be able to generate a clinically beneficial immune response. The slide I show here is taken from a Journal of Immunology publication by the laboratory of Professor Woodward at the Kentucky School of Medicine. And here on the left-hand side, you see a bar chart quantifying the T-cells induced by a number of technologies compared to Versamune. The dark green bars represent polyfunctional T-cells. Now these are T-cells which induce multiple cytokines and are well documented to be the most potent type of T-cell. The takeaway from the study is that Versamune induces not only a significantly higher quantity but also significantly higher quality of killer T-cells. Now this is very important. On the right-hand side, we see a tumor regression plot. This is a preclinical study. However, what is important here is that this is the TC-1 tumor model, which is the most widely used HPV cancer tumor model in preclinical studies. All our competitors have performed their studies in the same tumor model, and therefore, it allows us to effectively compare how the Versamune technology may be working -- or PDS0101, may be working compared to some of the other leading approaches in the field. Now here, this is quite an aggressive tumor. You see with the gray line, in the untreated animals, we see pretty aggressive tumor growth. Now if we inject the tumor antigen, so this is protein that is unique to the tumor we're seeking to treat, in this case, is HPV16, this is not presented to the immune system effectively, and we see very little effect. You can see that with the black line. The blue line is what we see when GM-CSF is administered with the HPV16 protein, GM-CSF being a powerful immune activator. Here, we see a slowing down of the tumor growth rates after -- with multiple doses. And this is very similar to what has been reported with most of the competitors in the field of HPV cancer immunotherapy. However, when we take the same HPV16 protein in the exact same dose and now combine it with Versamune, after a single dose, what we see here is, by day 35, complete regression of the tumors. And this is because of the Versamune's ability to present the protein into the right processing and immunological pathways, leading to effective priming of powerful antitumor responses, resulting in effective regression of these tumors. What is also very important here is, if you look at day 60 in these animals who have regressed the tumors, we can come back and reinject the cancer cells into the animals, and they are completely and very well protected against tumor reestablishment. And this signifies is that not only has a powerful CD8 or killer T-cell response being induced, but also powerful memory T-cell response has been induced, allowing the immune system to recognized for a sustained period that foreign tumor antigen and allows the T-cells to be available and active to kill the cells once the cells get reinfected with that specific tumor antigen. Okay. Now over here, what we're looking at is our Phase I our human clinical study results, and our Phase I study is evaluating PDS0101 as a monotherapy suggested strongly that the strong T-cell responses seen in preclinical studies do translate well to humans. In this study, we evaluated the safety and the ability of PDS0101 to prime the immune system to generate HPV16-specific T-cells. And here, what I'm showing now are the T-cell levels of the patients prior to injecting with PDS0101. And what we see now are the responses after 2 weeks, 2 weeks after subcutaneous injection with PDS0101. Now what the study also confirmed in addition to quantifying interferon gamma was granzyme B. This was important because granzyme B is associated with active killer -- CD8 killer T-cells. And therefore, in these studies, what we were able to confirm is that PDS0101 was generating the induction of high levels of tumor-targeting CD8 killer T-cells. Okay. So I'll move on now to an introduction to the Versamune platform, what exactly is Versamune. So Versamune is based on a positively charged lipid. The intellectual property covers a broad range of positively charged lipids. But one of the key things unique to the current lipid we're using in Versamune is the fact that it is a pure enantiomer. So these are lipids that contain a fatty acid portion, which is the water-insoluble portion, with a positively charged head group attached to it. Now what is important about this fatty acid section is the fact that it contains an unsaturated -- contains unsaturated lipids. Meaning, that in -- when the membrane is formed, these membranes will be much more fluid rather than rigid. And this becomes important when we get to the next stage of what Versamune does. But very importantly, these consist -- these lipids are called -- what we call racemic mixtures. Now the simplest analogy to a racemic mixture is our right and left hands, right? Identical, physical and chemical structure, but mirror images of each other. And here, what we use is we use the right-handed synthetic lipid in the Versamune. And what is unique and interesting here is the biological activity of this lipid is seen in the right-handed enantiomer and not in the left-handed enantiomer. And this is the first time that enantiomeric specificity has been demonstrated pertaining to immune activation. So let's go back to the slide here. And so these structures form, these nano -- spherical nanoparticles spontaneously in aqueous environment. They're called liposomal nanoparticles. So these are nanoparticles covered entirely on their surface with a positive charge. Now these nanoparticles are sized to mimic a virus, and that facilitates effective uptake by the immune system once they inject it subcutaneously into the body. And these lipids also activate what's known as the type I interferon immunological signaling pathway. And this also promotes activation and maturation of the immune cells called dendritic cells that pick up these particles after injection. So on the slide, this is a slide based upon data that was developed -- generated in the laboratory of Professor Leaf Huang at the University of North Carolina and Department of Molecular Pharmaceutics. And Professor Leaf Huang, the scientific founder of PDS. And what this shows over here is the enantiomeric specificity. We see very powerful T-cell response generated with the pure R enantiomer, which is currently used in Versamune, but almost no immune response generated with the left-handed enantiomer, the S DOTAP enantiomer. What's also very important and interesting finding here was the fact that immune responses to SDOTAP are actually further weakened in the presence of a tumor. Whereas the R enantiomer is able to overcome the immunosuppressive mechanisms activated by the tumors, therefore generating a very powerful T-cell response in the presence of a tumor or without the presence of tumor. Okay. So let's talk a little bit now about Versamune's mechanism of action and how Versamune actually works. So the slide I have here shows this simplified mechanism. So most tumors contain unique proteins or atypical proteins that can't be recognized by our T-cells. We call them immunogenic proteins or antigens. What we do is we combine the antigen that is specific to the cancer we're seeking to treat with the Versamune particles. Versamune is then able to present them into the immune system and prime or train the killer T-cells as well as the helper T-cells to specifically recognize that protein as a foreign agent in build up a T-cell response to kill, targeting kill cells that contain that specific protein. So one of the big obstacles in immunotherapy or T-cell activation, as you can imagine, is uptake. These have to be taken up efficiently by the immune system. One of the biggest obstacles has been access to what we call the MHC Class I presentation pathway, and I'll talk about the MHC Class I pathway again in a few minutes. But that has been one of the biggest obstacles to immunotherapy, is the ability present the specific tumor antigen into that processing pathway. So let's talk first about uptake. Uptake of the immunotherapy is extremely critical to an effective immune response. Very importantly, getting the immunotherapy into the lymph nodes. With Versamune, what happens is this is given beneath the skin subcutaneously. And what we see here are histology pictures showing the difference between RDOTAP and SDOTAP. But what you can notice in the RDOTAP portion is very heavy infiltration of cells we call monocytes, immune cells, into the injection site to pick up the Versamune nanoparticles. We see this very powerful response with our right-handed lipid. This initiates the immunological cascade, right? So importantly, very efficient uptake or pickup of the immunotherapy. Because of the positive charge, it forms a deepwater site of injection, so it provides a sustained duration during which the immune system can react and pick up those nanoparticles. What then happens is these nanoparticles -- what we found is that they get taken up almost exclusively by these professional antigen presenting cells of the immune system that we call dendritic cells. These get taken up by the immune system almost exclusively. Then RDOTAP nanoparticles are able to activate the dendritic cells, cause them to mature. And when this happens, the immunological mechanism occurring allows them to migrate into the lymph node. So what's happening here is these nanoparticles are taken up by the dendritic cells, the dendritic cells get matured and then they migrate into the lymph node. And so we get very high presence of these -- of the immunotherapy in the lymph node, which is critical to effective priming of T-cells. What's also been published by the Huang lab is that 4 hours after subcutaneous injection, about 80% of the dendritic cells in the lymph -- draining lymph nodes have taken up Versamune. So highly efficient uptake of Versamune, therefore overcoming obstacle number one, which is getting this into the lymph nodes. Now the second obstacle facing T-cell activation is once they're in the lymph nodes, they then have to present this into the Class I, what we call the MHC Class I, and MHC Class II presentation pathways. Now what's critical about the MHC Class I presentation pathway is that only a very small peptide can -- of about 8 to 12 amino acids can be presented into this pathway. The first obstacle is the protein that's specific to the cancer we're seeking to treat has to enter into the right compartments to be broken down into the smaller peptide. And then it has to enter into the cytoplasm of the cell to access the MHC Class I presentation pathway, 2 significant obstacles. How Versamune overcomes this is Versamune, as I mentioned, is based on an unsaturated lipid. It's positively charged and therefore with a very fluid membrane. Our cells are made up of negatively charged lipids. Versamune essentially fuses and mixes with what we call the endosomal walls of the cell, destabilizes those walls, cell walls, and allow that protein to enter into the right processing pathways. Once the protein is processed, that destabilization allows it to enter into the cell cytoplasm, giving it access to MHC Class I. This slide I show here demonstrates very highly efficient processing of the protein. So here, we're using what we call [ DQ turnover, it's ] of albumin attached to a fluorescent label. In its natural state, there is no fluorescence. When it is taken up in processed or broken down, it emits a green fluorescence so we can track it and determine when it's actually being processed and broken down into smaller peptides. And when it enters into the endosomes, due to the decrease in pH, it emits a red fluorescence. And so you can see here that with the presence of Versamune on the left-hand sided quadrants, we see very rapid induction of these green -- the green fluorescence, telling us that Versamune has promoted internalization and processing and breakdown of the protein. And then very rapidly, we see the red fluorescence, indicating that it has then accessed into the endosomes. Without Versamune, looking at the right-hand side quadrants, we see absolutely no presentation, no processing and entry into the cytoplasm. Right. So this study really demonstrates how Versamune very rapidly facilitates the processing and presentation into the cytoplasm. Now that was an in vitro study. Another study was done by the Woodward Lab, and this is also published in the Journal of Immunology, where they look -- did an in vivo study. And here, what's shown here, I won't get into too much technical detail, but what we show over here, with the shift to the left-hand side on both the CD4 helper T-cells and the CD8 killer T-cells, CD8 meaning that the protein was presented into the MHC Class I pathway and the CD4 indicating that was presented into the Class II pathway. What this study demonstrated was that, just like we see in vitro, in vivo, Versamune is capable in highly efficient in processing that protein and presenting it into both the Class I and Class II pathways, therefore overcoming a significant limitation of immunotherapy. Therefore, Versamune is able to prime and train both killer T-cells as well as helper T-cells to specifically recognize the cancer and the cancer antigen. Okay. Now that is critical to effective immunotherapy. However, what we have demonstrated is that it is not nearly enough. The T-cells are the attackers of the immune system. They are the soldiers of the immune system that have to go out and kill the cancer cells. So very importantly, what we have to be able to do is to recruit a large number of these T-cells to come into the lymph nodes to be trained. That is another critical process that has to occur efficiently. What this specific lipid does, once it gets into the lymph nodes, is it upregulates an important immunological pathway known as the type I interferon pathway. By activating or upregulating ting this type I interferon pathway, it induces or promotes the induction of a number of immunological proteins known as cytokines and chemokines inside the lymph node. That sends out the signals leading to heavy infiltration of T-cells into the lymph node, meaning that Versamune is able to recruit a large number of these T-cells. And so what you see over here on the right-hand side is, for over 7 days, we see heavy infiltration of T-cells into the draining lymph nodes, therefore providing the T-cells to the Versamune immunotherapy, allowing them to present the antigen and effectively prime a large number of T-cells to recognize the cancer. Now what is also important here is potency. So you can train the army, you can train the soldiers to recognize the enemy, but these soldiers have to be effectively armed. We need to provide them with the ammunition to go out and effectively kill the de-camouflaged or exposed enemy. And what's also important by activating the type I interferon pathway is that the cytokines and chemokines are induced in the lymph node that allow these T-cells to be polyfunctional and have potent killing efficacy. Therefore, effective recruitment, priming of killer and helper T-cells and providing them with the potency functionality to effectively go and kill the target cells. So what's unique about Versamune is its ability to facilitate each of these critical processes needed to induce a large number of high-quality tumor-targeting killer T-cells. And that's what Versamune has been able to do effectively. What we've also demonstrated is the mechanism by which Versamune upregulates specifically the type I interferons. And so with Versamune, what's also unique is that it's very -- it specifically activates type I interferons and does not induce nonspecific immune activation. And here, we have conclusively demonstrated that the type I interferon pathways are activated through activation of what is known as the MYD88 pathway. So Versamune does not activate what's known as the STING pathway. It does not activate what's known as the TRIF pathway. It's very specific to MYD88. And so when we evaluate this in mice that what we call knockout mice that do not express either MYD88 or type I interferons, we completely eliminate the immune response due to Versamune. So this is very conclusively demonstrated to specifically activate the type I interferon signaling pathway. Now I also talk about safety. What's also unique about Versamune is the localized immune response, which is directly responsible for both the potency and the safety profile that we see with Versamune. And so despite the fact that we show effective induction of cytokines and chemokines in the lymph node, the studies that were done to evaluate cytokine and chemokine induction in the bloodstream, or the circulating blood, comparing with a positive control, which is at TLR adjuvant, we see as the positive control. What we see here in the bloodstream is that when the TLR adjuvant is administered, within a few hours, we see heavy -- by 12 hours, we see spikes or increases in those cytokine levels within the circulating blood. These effects are responsible for what we see with many immunotherapies, that what we call inflammatory toxicity. However, with Versamune, as you can see, both with high-dose and low-dose PDS0101, we do not see any elevation above baseline of any of the cytokines and chemokines that were evaluated. And this is very important, meaning that, that immune response is localized at the site of required T-cell activation rather than getting into the circulating blood, which will be waste and also induce toxicity. And by eliminating this effect, Versamune is not only highly powerful, but also very well tolerated and so far demonstrated to have a high safety profile. Now the result of being able to piece all these immunological processes and activation signaling pathways generates a very powerful T-cell response. This is also a study that was reported in the Journal of Immunology by the Woodward Lab. And here, what we see is comparing the A and R. So we have RDOTAP, which is Versamune; plus the A, which is the antigens; G is GM-CSF. And so what we see here is that if you look at the naive, untreated mice, we see very weak T-cell responses in the tumor. When we combine -- when we administer the tumor antigen, which, in this case, is HPV16, we see a weak T-cell response, which is not really aided by combining with GM-CSF, the clinical-stage immune activator. However, once we combine this with Versamune or RDOTAP, without GM-CSF -- or with GM-CSF, we see a very powerful antitumor response. And the addition of GM-CSF, the immune activator, does not provide any additional benefit. What we see here is that Versamune alone, once combined with that tumor antigen, is able to present it into the right pathways and also activate the right immunological signaling pathways to generate a powerful T-cell response and infiltration into the tumors. What is also interesting here is that we are looking not only at the killer T-cells within the tumor microenvironment, but we're also looking at the regulatory T-cells, which are an immunosuppressive T-cell phenotype that's known to be upregulated in cancer patients. And what we see over here is that if you look at the untreated, the naive animals, we see a really high ratio of regulatory T-cells, immunosuppressive Tregs to killer T-cells. And when you see -- look at the antigen and also with GM-CSF, even the immune activated GM-CSF still results in a higher ratio of immunosuppressive T-cells to killer T-cells. However, when you look at the formulations contained in Versamune, now we see an alteration of the tumor's microenvironment to make it much less immunosuppressive, and now we see a significantly higher ratio of killer T-cells to immunosuppressive Treg cells. And again, this demonstrates the power of the Versamune technology in generating a powerful T-cell response and the ability to alter the tumor's microenvironment to make it much less immunosuppressive. So here again, we come back to the same slide I demonstrated. Now we've gone through all the mechanisms that Versamune activates, and now we understand the reason behind Versamune's ability to, first of all, induce the much higher quantity and quality of killer T-cells with a much higher percentage of the polyfunctional, powerful CD8 T-cells and how that now translates into highly effective antitumor responses. Okay. So I will now hand over to Dr. Wood to take it from here -- actually, no. I think I have a couple more slides to walk you through. One of the key things here with Versamune is, with the PDS0101, we're looking at a nonviral tumor -- a viral tumor antigen. And so as we expand beyond PDS0101, one of the things we wanted to understand is whether or not we can generate very similar antitumor responses in other solid tumors, which may not be caused by viral antigens. Examples of these are melanoma, prostate cancer, lung cancer, many of which we will be talking about today. But here is a study that was performed in one of the most immune suppressive animal models, the B16 melanoma model. And what you see over here is that, on the left-hand side -- and this is actually a study, the left-hand side it was done in the laboratory of Professor Leaf Huang at UNC Chapel Hill. And what they showed over here was that if you inject the TRP-2 antigen, a protein that is unique to the melanoma or B16 melanoma, we see very weak infiltration or generation of T-cells and infiltration into the tumor microenvironment, whether it's a CD4 T-cell or a CD8 killer T-cell. However, when they took the exact same dose of the antigen and combined with Versamune, all of a sudden, you see very effective T-cells, CD4 and CD8 T-cell induction, and infiltration of these T-cells into the tumor microenvironment. Now what I show over here on the right-hand side is the tumor regression plot. And so here, you can see that this is quite an aggressive tumor. Look at the black line. Now when we administer an anti-PD-1 checkpoint inhibitor, we don't see any antitumor effect. And that is understandable because, as I mentioned earlier, even with a very effective checkpoint inhibitor that's able to block those immune checkpoints and expose the tumor to the immune system, we still need those T-cells that can then attack and kill can exposed tumor. And we see over here that this tumor is so immunosuppressive that there are hardly any T-cells able to attack and infiltrate that tumor. However, when we take a suboptimal dose of the Versamune-based formulation with the TRP-2, now with the purple line, you can see an antitumor response. And when we combine it with the checkpoint inhibitor, with a checkpoint inhibitor now more effectively de-camouflaging that tumor, we see an even beneficial antitumor response. And so what this tells us is that it doesn't matter whether we have a viral antigen We have a nonviral antigen. So long as we can present it effectively into the right processing and presentation pathways and also activate the right immunological signaling pathways, we can generate a powerful antitumor response. The next slide shows a study that was also done in the Huang Lab at UNC Chapel Hill. And here, we're looking at metastasized tumor. So we're looking -- actually looking at lungs from the animals that have metastatic B16 melanoma. You can see the bottom negative controls. So the first, the bottom row are the untreated animals. The black stains are actually the tumors on the lungs of these animals. And the negative control, these are animals that got the Versamune without the tumor antigen. So there was no way to train those -- the immune system or T-cells to specifically recognize the cancer. And then on the top row, we have the lungs from the healthy animals. And then Formulation 1 and Formulation 2 are prototype Versamune-based immunotherapies containing different antigens. And here, we can see after a single dose, we can see the power of the immunotherapy in clearing the metastasized tumors, again, demonstrating that very similar to what we've done with the viral cancer, we can do -- potentially achieve very similar effects with the nonviral tumor antigens. Okay. Now what we have done with PDS0101, to put all these pieces together, is now the formulation. How do we maximize the immune system's ability to take up this formulation, process it and present it to the immune system? And what we have done with PDS0101 is to have multiple what -- HPV E6 and E7 multi-epitope or long peptides. And the proprietary approach we utilize to do that, most people are probably envisioning that our antigens are encapsulated in the nanoparticles. Well, that's not what we've done. Encapsulation is limiting in the amount of payload that you can actually deliver to the immune system. And with immunotherapy, very often, there are weaker antigens that have to be delivered in larger doses, and encapsulation becomes very restrictive. What we did is we came up with a way to make our antigens also into nanoparticles to facilitate uptake by the activated or mature dendritic cells. And so we made these to form what we call micellar particle. So they form micelles, which are also particulate. And therefore, the immune system is able to pick them up. The Versamune essentially destabilizes the endosomal walls and allows these particles to enter effectively into the right processing and presentation pathways. Now what we've demonstrated with our patent here is that, if we formulate the PDS0101 with the exact same dose of Versamune in the exact same dose of the antigen, 1 encapsulated, the traditional approach; and the other made by our proprietary micellar formulation, here is the difference you see. You see very weak immune responses with the traditional approach and very potent CD8 T-cell responses when we utilize the proprietary micellar approach. And this is the approach that we've taken into PDS0101 Phase II human clinical trials, demonstrated to have potential potency as well as safety. Well, thank you very much. I will now hand over to Dr. Lauren Wood to take us through development of PDS0101 for HPV-associated cancers.

Thank you, Frank. PDS0101 is designed to treat cancers caused by HPV16, which represents 70% to 80% of HPV-associated cancers. Approximately 43,000 patients are diagnosed with HPV-associated cancers annually in the U.S. Very importantly, despite the introduction of prophylactic vaccines for HPV, the incidence rate of anal and head and neck cancer is growing. This population represents significant unmet medical needs across the spectrum of HPV-associated cancer. Our strategy to develop PDS0101 has been to use it in combination with established as well as investigational in immunotherapies for rapid proof-of-concept and risk mitigation. Specifically, we have 2 Phase II trials looking at PDS0101 in combination with FDA-approved standard of care. The first Phase II trial looks at PDS0101 in combination with KEYTRUDA in the first-line treatment of recurrent and metastatic HPV-positive head and neck cancers who are checkpoint inhibitor-naive. This study has also been recently amended to include the checkpoint refractory population. In collaboration with investigators at MD Anderson, we are also looking at PDS0101 in combination with standard of care chemoradiation therapy in women with locally advanced cervical cancer. Our novel combination, that you'll be hearing about in much greater detail from our esteemed colleagues at the NCI, involves PDS0101 in combination with promising investigational immunotherapeutic agents. You'll specifically be hearing about the triple combination of bintrafusp alfa, a biofunctional checkpoint inhibitor; and M9241, a tumor-targeting NHS-IL12 tumor cytokine; and PDS0101 in the treatment of advanced HPV-related cancers. One of the things that's very important to highlight is, in addition to all of the mechanisms of action reviewed by Frank in detail regarding the efficacy of Versamune when coupled with different tumor antigens, is actually the ease and simplicity of the formulation. Versamune platforms have been specifically engineered so that they can be delivered subcutaneously. There is no need for intratumoral or intranodal delivery. On the left-hand side of the slide, you can see the 2-vial formulation. On the left-hand side is the Versamune lipid nanoparticle formulation. And on the right, the second vial is the HPV mix micellar antigens. PDS0101 in formulation is mixed prior to injection. And in the middle of the slide, you can see an electron micrograph of PDS0101. The string-like spaghetti represents the micellar HPV peptide mix, where the round circles represent the lipid nanoparticles of Versamune. We call this the spaghetti and meatballs mix, which actually dendritic cells love. And it facilitates uptake of both the Versamune and the micellar peptide antigen with then activation of the dendritic cells, the endosomal processing that Frank alluded to and migration of these dendritic cells that are activated to lymph nodes, with dramatic expansion of potent and powerful T-cells. On the far right-hand side, we just highlight that the PDS0101 formulation is delivered subcutaneously. You'll be hearing in detail about this Phase II study that was recently reported last week at ASCO. Again, this is a study of 3 investigational immunomodulatory agents in patients with advanced HPV-associated cancer. The goals are to examine objective response rates in patients-who are both checkpoint inhibitor naive as well as those who have failed checkpoint inhibitor therapy. We anticipate enrolling 56 patients in this trial, and completion of enrollment is expected by the end of this year, early next year. I'd like to highlight that preclinical science is a core value for PDS Biotechnology, and the elegant science done by our colleagues at the NCI is reflected here. This is an image from the Journal of Immunotherapy of Cancer publication from Dr. Jochems, Dr. Schlom and Dr. Strauss and their group. And it highlights a very important principle in terms of what we are seeking to observe preclinically as well as clinically. In this tumor model, when either PDS0101, bintrafusp alfa or M7824 agents are delivered alone, you don't really see very significant tumor infiltration, which is represented in the top panel. However, when you deliver the triple combination of all 3 agents, you see significant induction of T-cells that migrate to the tumor and light up the tumor like a Christmas tree as reflected by the red and green dots in the lower panel, which represent CD8 killer T-cells and CD4 helper cells, respectively. I'll now turn over the presentation to Dr. Jeff Schlom so that he can provide the background for this groundbreaking therapeutic approach. Jeff?

Thank you, Lauren. As a disclaimer, I want to mention myself, Dr. Jochems and Dr. Strauss work at the NCI, and we're doing this work as part of a Cooperative Research and Development Agreement, a CRADA, with PDS. So we're not here to promote any particular company or technology, but we're here to talk about the work that we're doing in collaboration under this CRADA. And what I -- just as a very brief introduction, I want to say that the -- in recent years, we've learned an enormous amount about the complexity of the human immune system. And most importantly, the complexity of immune modulation, both in the periphery and the tumor microenvironment. Let's see. I'm trying to -- yes. So the point I want to -- you've already heard how important HPV-associated cancers are. The point I want to make here is the overall response rate for FDA-approved agents in this area ranges from 13% to 24%. And it's, in real world, it's more like 15% response rate. And you're going to hear quite a different story from Dr. Strauss in a little bit. Next slide, please. This is something that Dr. Gulley and myself put together. We were asked to write a viewpoint for JAMA. And really, this is a cartoon that denotes the complexity of cancer immunotherapy, both in activation of the immune system, but also what's going on at the tumor microenvironment. Next slide. And what we see here in this particular study, both preclinically and then transferred to clinical studies, we've looked at 4 different phenomenon in the immune system: The first is the activation of T-cell response; the second is the potentiation of that immune response, both systemically and more importantly, in the tumor microenvironment; the reduction of immunosuppressive entities and even the alteration of the tumor phenotype to render tumor cells more susceptible to immune-mediated advices. And we have the next slide and the last slide. Keep going, it's animated. So one more. Okay. Thank you. So what you can see here in these 4 phenomenon, these are the agents that we've used, the HPV PDS vaccine to activate immune response; the tumor-targeting IL12 immunocytokine, which activates the immune system both systemically and at the tumor microenvironment; the reduction of the immunosuppressive entities, both you get a twofer, with the bintrafusp alfa with the anti-PD-L1 checkpoint as well as trapping TGF-beta, which is, of course, is immunosuppressive. And we've shown that the TGF-beta also can alter the phenotype of tumor cells, making them more resistant to therapy. so trapping TGF-beta makes tumor cells more sensitive to immune-mediated attack. So now I'm going to hand this over to my colleague, Dr. Jochems, who's conducted the preclinical studies.

Thank you very much, Dr. Schlom. I want to talk about the preclinical studies, testing these 3 agents together, and they were recently published in the Journal for Immunotherapy of Cancer. You've already heard a lot about HPV-associated malignancies, but I just want to reiterate again that there's a very poor prognosis for advanced disease. The agents we have used are, as you know, PDS0101, but also bintrafusp alfa, or M7824, which was obtained through our CRADA partner, EMD Serono. It is a bifunctional fusion protein which consists of human IgG1 anti-PD-L1 and 2 extracellular domains of TGF-beta receptor 2. So the PD-L1 portion binds the molecule in the tumor microenvironment so that the TGF-beta trapping mechanism can work in the tumor, where it is needed. It was well tolerated in the Phase I study. And the toxicity we've seen is similar to that of anti-PD-1 or anti-PD-L1 therapy. Furthermore, in an additional study in HPV-associated cancer, there was a 30.5 response rate with single therapy using bintrafusp alfa. And we also found an increase in HPV-specific T-cells in these patients after treatment with bintrafusp alfa even though they had not been exposed to a vaccine. The third agent in our combination is NHS-IL12 or M9241. It is also from EMD Serono, and it is an immunocytokine. So it consists of 2 IL12 heterodimers that are fused to the NHS76 antibody which targets histones that are exposed inside the necrotic tumor. The Phase I study was safe, and we found high levels of interferon gamma and influx of lymphocytes into the tumor microenvironment. We have several publications investigating these agents. This is just a list of publications with bintrafusp alfa, where we started with the initial in vitro studies then moved into vivo animal studies and finally, now the patient studies. And it's the same with NHS-IL12, the LTIB did the initial studies in vitro, in vivo and now in patients. The tumor model we use is the one Frank mentioned earlier, TC1. It's a syngeneic lung carcinoma line in that was transformed with HPV16 E6 and E7 by TC Wu at John Hopkins, and we received the cell line directly from him. And this is our schedule. So the tumors are implanted on day 0. And then we treat with weak injections of PDS0101 in red arrows. And we treat with 3 treatments of M7824, bintrafusp alfa, every other day. And then NHS-IL12 was given as one dose, subcu. The reason for the short treatment with trap and NHS-IL12 is that they contain human parts, so we cannot extend that treatment in the syngeneic mice. The combination of PDS0101, bintrafusp alfa and NHS-IL12 resulted in a great reduction of tumor volume. And in the left graph, you have the tumor weights at the end of study. On the left, we have our controls, the PDS control and the RDOTAP control, which resulted in very big, vicious tumors. And then we have in red, the third lane, that's PDS0101 alone, which had a nice antitumor activity. The single treatments with the other drugs were not all that great. The double treatments were somewhat good. But in the far right column, in dark blue, you have the triple treatment using PDS0101, NHS-IL12 and bintrafusp alfa. And as you can see, this combination resulted in the best tumor control. Another way to show that is in the table on the right where we have the number of mice in each group with a tumor volume less than 300 millimeter cube. In the control groups, 0 mice in each group had tumor control. With the PDS0101, we had a few mice, we had 3 out of 16. But then when we get down at the very bottom to the triple therapy, 13 out of 17 mice displayed tumor control. We also looked at TCR clonality in the tumor. So tumor-infiltrating lymphocytes were purified, and then reisolated DNA from them and sent them to Adaptive Biotechnology, and they measure the TCR clonality. What the graph is showing is the number of TCR clones that make up 25% of the TCR repertoire. And it has previously been shown in many clinical studies that a lower clonality gives you a better tumor control. As you can see in the table, it's easier than in the graph, in the control mice, PDS control, 18 clones made up 25% of the repertoire. When we gave mice PDS0101, this decreased to 12. The bintrafusp alfa and NHS-IL12 didn't do anything and maybe increased clonality a little bit. But as we looked at the combination therapies, we can see in the second highlighted box, PDS plus bintrafusp, clonality was 8. In PDS plus NHS, there was 6. But in the triple therapy, we had a clonality of 3, which is really very low. And as I said, this has been correlated with tumor control in patients. In conclusion, these studies provide a preclinical rationale for the ongoing Phase I/II study run by Dr. Julius Strauss.

Thank you, Dr. Jochems. So I'm going to briefly go over data which was also presented at ASCO a week or 2 ago, interim data in the Phase II trial combining the PDS0101, the M9241 and the bintrafusp alfa in patients with HPV-positive and hPV16-positive malignancies. So the design of the trial is that patients with advanced HPV-related cancers received a combination of the bintrafusp alfa at 1,200 milligrams flat dose every 2 weeks, along with the M9241 at 16.8 mcg per kg, subcu every 4 weeks; along with the PDS0101 given as 2 separate 0.5 milliliter subcu injections every 4 weeks. Dose reductions for M9241, which is immunocytokine, to 8 mcg per kg were allowed, as well as skip doses for any agents for toxicities. HPV genotyping was done with the PCR-based assays if historical testing was not provided. The population is included patients with all types of HPV-associated cancers, including cervical, anal and oropharyngeal cancers, among other types. And then the primary endpoint was response rates and secondary endpoint was safety. On this slide, you can see the demographics of the patients enrolled, of the first 25 patients enrolled on this trial, with about 40% of patients or 10 patients having cervical cancer, about 1/4 of patients having anal cancer, 1/4 patients having oropharyngeal cancer, 12% of patients having [ ovary ] or vaginal cancer. About 80% -- or 80% of patients have received 2 or more prior lines of systemic anticancer therapy and all patients have received prior chemotherapy. And most notably, 56% of patients had previously received and progressed on standard of care PD-1 or PD-L1 inhibitor therapy. Based upon the HPV genotyping, 72% of the patients were HPV16. As of March 1 of this year, 25 patients have received the triple combination, and the median follow-up was 8 months. On this slide, you can see the safety data with the triple combination in the first 25 patients evaluated. In the table on the left, you can see the adverse events that were Grade 2 or greater that occurred in at least 5% of patients. 20% of patients had discontinuation of at least 1 study drug due to some toxicity. The most commonly seen grade 2 or greater toxicities were anemia in 48% of patients, lymphocyte decrease, flu-like symptoms, injection site reactions. Most of the anemia was Grade 2 and did not require any transfusions or any medical intervention. As far as Grade 3 toxicities, this occurred in 40% of patients. And they included anemia, which was specifically due to hematuria in 4 patients; rise in liver enzyme elevations, of AST, ALT, in 2 patients; flu-like symptoms in 1 patient; nausea, vomiting in 1 patient; leukopenia and lymphopenia in 1 and 2 patients, respectively; and 1 patient did develop a systemic inflammatory syndrome known as hemophagocytic lymphohistiocytosis. Of the patients who develop hematuria, all 4 patients. All of these patients were patients with cervical cancer which had prior pelvic radiation and brachytherapy. One patient with the transient Grade 3 leukopenia also developed transient Grade 4 neutropenia. This is the only grade 4 toxicity on study. Four patients who originally had grade 3 toxicities with the triple combination with a higher dose of -- with the starting dose of M9241 at 16.8 mcg per kg we're able to actually tolerate the triple combination with a reduced dose of M9241 at a 8 mcg per kg without any further Grade 3 toxicities. There are no treatment-related deaths on study. On this slide, you can see the outcomes of the first 25 evaluated patients. In patients with HPV16-positive disease, of which there were 18 patients, the response rate was 55.6%. That is by RECIST, which requires a 30% tumor reduction. Any tumor reduction was seen in 66.7% of patients. There's -- broken down by patients who had previously not seen checkpoint inhibitors and previously patients who have progressed on checkpoint therapy. For patients who were checkpoint-naive, the overall response rate was 83.3% in HPV16-positive disease. And for patients with checkpoint refractory disease, the overall response rate was 41.7%, with the tumor reduction seen at 58.3% of these patients. After a median follow-up of 8 months, 80% patients who had responses, those responses were still ongoing. Looking at the checkpoint -- at patients with checkpoint-naive disease, 6 out of 6 patients, or 100% of those patients were still alive. This compares favorably to the historical median survival for this patient population, which is median survival of 7 to 11 months. Patients with -- in patients with checkpoint refractory disease in this study, 10 out of 12 patients, or 83.3%, of patients were still alive after a median 8 months of follow-up. Again, this compares favorably to the historical median survival of patients with checkpoint refractory HPV-associated malignancies, which is, based upon other studies, in a range of 3 to 4 months. On this slide, you can see both the spider plot as well was the waterfall plots for the patients with HPV-associated advanced cancers. What you can note, based upon the different tumor types shown in different colors, is that responses were seen in virtually every tumor type evaluated. So these responses are not specific to 1 tumor type or another. They're just seen across the board in patients with hPV16-positive advanced cancers. What you can see on this slide is the how the colors reflect checkpoint-naive and checkpoint refractory status, with blue representing checkpoint-naive disease and red representing checkpoint refractory disease. As you can see, the overwhelming majority of patients with checkpoint-naive disease had a response. And the overwhelming majority of patients with even checkpoint refractory disease had tumor shrinkage. In conclusion, the triple combination of PDS0101, M9241 and bintrafusp alfa appear to have a manageable safety profile with early evidence of notable clinical activity for patients with advanced HPV16-positive malignancies, which again has been -- which has been discussed earlier in this presentation from my other colleagues is the predominant cause of -- HPV16 is a predominant cause of HPV-related malignancies, both in the U.S. and worldwide. Clinical activity was noted irrespective of the tumor type or the prior checkpoint status, either naive or refractory. The response rate overall in the patients with advanced HPV16 disease was 55.6% with tumor reduction seen at 66.7% of patients. In patients with checkpoint-naive disease, the response rate was 83.3%. And in patients with checkpoint refractory disease, the response rate was 41.7% with tumor reductions seen in 58.3% of patients. Again, put in perspective, the current standard FDA-approved checkpoint therapies for patients with these tumor types is about 15% to 20% in checkpoint-naive disease and about 5% or less in patients with checkpoint refractory disease. After a median follow-up of 8 months, 80% of responses are ongoing. All patients with checkpoint-naive disease remain alive, and that compares favorably according to historical controls with standard of care checkpoint therapies. And 83.3% of patients with checkpoint refractory disease remain alive, which also compares quite favorably with historical controls. Accrual to the triple combination is ongoing.

Thank you so much, Dr. Strauss. So you've heard about PDS0101 in combination with the investigational agents, as highlighted by both Dr. Schlom, Jochems and Strauss. I'll just briefly highlight our 2 additional Phase II studies, looking at PDS0101 in combination with standard of care treatments. Our PDS-sponsored Phase II trial examining PDS0101 in combination with KEYTRUDA is looking at the treatment of HPV-associated metastatic recurrent head and neck cancers. PDS0101 is delivered with standard of care KEYTRUDA. As I mentioned earlier, this protocol has recently been amended to include checkpoint refractory patients into -- as well as checkpoint-naive patients due to the high unmet medical need in this population as well as the promising early signal just highlighted by Dr. Strauss. We are looking at objective response rates in both populations as well as safety of the combination. We anticipate preliminary data in the fourth quarter of this year or early in Q1 of 2022. The study is a 2-stage design, and we are expecting an objective response rate in a minimum of 4 out of 17 checkpoint-naive patients, and 2 of 21 checkpoint refractory patients for subsequent Stage II enrollment to a total of 95 patients. In a nutshell, we're seeking to see objective response rates of at least 33% in our checkpoint-naive patients with this combination and an objective response rate of 20% or more in our checkpoint refractory population. I also want to highlight a Phase II collaborative study being conducted by Dr. Ann Klopp and Dr. [ Gishi ] at MD Anderson Cancer Center that's looking at a Phase II study of PDS0101 in combination with standard of care chemo radiation in patients with locally advanced cancer. Importantly, translational science undergirded the concept for this study as well, where Dr. Klopp and colleagues have demonstrated, as part of the Cancer Moon Shot effort, that patients who have an increase in HPV-specific CD8 T-cells have better outcomes following standard of care chemo radiation. So PDS0101 is delivered within 7 to 10 days prior to initiation of standard of care chemo radiation and then delivered for a total of 5 doses during delivery of those agents. The study goals are safety, the rate of regression and local control in patients with a primary tumor that's very large, greater than 5 centimeters. The study is looking at the combination in 35 patients. And we anticipate data being available in the first quarter of 2022. This slide highlights milestones. In terms of what we've heard today, we've heard the preliminary data from the triple combination. We expect to have data from the KEYTRUDA study in head and neck cancer by the end of fourth quarter of 2021 to 2022 and again, MD Anderson data in the early part of 2022. I'll now open the floor for questions. Deanne, I know that you are moderating those by the web chat, before we go on to our discussions of other agents in the Versamune pipeline.

Thank you all for very detailed discussions. We will now open the -- we will now open up the floor for questions. [Operator Instructions] So we have a few questions already. Dr. Wood, I will start with you. And the first question we have is, while the data from the NCI-led study are clearly very encouraging, how do we kind of pull apart the contribution of each of the components to the results that we're seeing here? Specifically, given that this PDS Biotech Oncology R&D Day, how -- what information do we have to really isolate the contribution of PDS0101 to the triple combination?

That's an excellent question, Deanne, and one that we get frequently from many individuals. It is at the core of any combination therapy, and that is what is the relative contribution of each of the respective agents? First, we know from the very elegant studies by the NCI, that the triple combination is really important for inducing CD8 T-cells and CD4 T-cells tracking into tumor. We know that Dr. Strauss presented data on the first 25 patients, 18 of which were HPV16-positive and had very significant objective response rates as well as tumor reduction. However, there were also 7 patients that were non-HPV16. So they don't express the molecular target that is targeted by PDS0101, which specifically targets HPV16 E6 and E7. And in these patients that were HPV-16 negative, we did not see or observe any objective response rates or reduction in tumor volumes. However, those patients were still alive. And I think that highlights the issue that with agents in the combination, even if there is not significant tumor reduction or reduction leading to objective response rates, we can see significant stabilization of disease that then results in prolonged survival outcomes. And that is quite notable among particularly the checkpoint refractory population, as Dr. Strauss highlighted.

Thank you so much. Dr. Straus, do you have anything to add to that? And also, I have another question specifically for you. What were the side effects or toxicity profiles of the 2 other agents, so bintra as well as NHS-IL12, that we had seen in -- that you had seen in previous studies?

Sure. So on the first point, so I think it's a very good question about pulling apart what amount of activity we're getting from each individual agent. And I do personally believe that each agent is adding to the contribution for activity. But I think you can only definitively get an answer to that based upon looking at these agents in doublet combinations, which we plan to do at some point in the future. On the second question of the side effect profiles. So of the other 2 agents, or each of the agents, so I believe, for the PDS0101 monotherapy, which Frank went through. On that Phase I trial, that were just basically injections site reactions, local injection site reactions and very minimal systemic toxicity. For the other 2 agents, the NHS-IL12 or M9241 immunocytokine, we do see about 50% of patients have fever and flu-like symptoms for a few days. Nothing on the order of cytokine release syndrome, more just fever and flu-like symptoms. Patients can sometimes get some asymptomatic lab liver enzyme elevation or mild [ cytopenias ]. But other than that, not much toxicity seen with that agent. And with the bintrafusp alfa, the toxicity profile we see generally very similar to what's been described with other PD-1 and PD-L1 inhibitors, which is kind of these rare idiosyncratic autoimmune toxicities. There are 2 additional toxicities we see with bintrafusp alfa, and that's mucosal bleeding, which is usually pretty minor, and the addition of hyperkeratotic skin lesions in the 10% to 20% of patients, which are benign skin growths which can be locally treated by cryotherapy or other therapies by dermatologists and sometimes self-resolved. So that kind of is generally the side effect profile we see with these 3 drugs. Hope that helps.

Thank you so much. Dr. Jochems, a question for you related the images that Dr. Wood shared earlier in her presentation looking at T-cell infiltration of the tumor with the triple combination. Do -- did you see similar T-cell infiltration with any of those agents in monotherapy or in double combination?

Thank you very much for the question. And yes, we saw a little bit of infiltration with the single agents or doublets, but there was a huge increase when we had all 3 together. This figure is in the paper that are mentioned. And it's really striking what a big difference the 3 together made, in the mouse model, at least.

Thank you so much. We have time, I think, for one additional question, and it's related to really the KEYTRUDA trial. So Dr. Wood, it's a 2-part question. How do the interim data that have been released so far inform your thinking about the trial in combination with KEYTRUDA? And secondarily, related to that, do you anticipate further expansion of that trial given the results that we've seen so far?

That's an excellent question. And one of the key objectives that we have is to see whether or not the preliminary signal in checkpoint refractory population patients that appear to be very promising reported by Dr. Strauss, with the triple combination, can be replicated or even approximated with the doublet combination of PDS0101 and KEYTRUDA in head and neck cancer patients that are both naive to treatment as well as checkpoint refractory. Importantly, it is critical for us to really see confirmation of this signal. And if we do, that would drive decisions about further discussions with the FDA in responses observed at the end of Stage 1 of this trial. Importantly, Unlike Dr. Strauss' trial, the KEYTRUDA, PDS0101 VERSATILE-002 trial exclusively looks at patients with HPV16-positive head and neck cancer. So the expectation is that if we are able to see a signal, we would see it, and we would see it as quickly as possible because all patients in the study are expressing the tumor antigens targeted by HPV16.

Thank you so much. We have several other great questions, but in the interest of time and kind of moving on to presentations about other products in the pipeline. We're going to close the questions around PDS0101 and move on now to PDS0102. Dr. Wood?

Thank you. So I'm briefly going to highlight the development of PDS0102 for TARP-related cancers. PDS0102 is designed to treat cancers caused by T-cell receptor gamma alternate reading frame protein, also known as TARP, which is expressed in both AML and as well as prostate and breast cancers. Approximately 470,000 patients, close to 0.5 million patients, are diagnosed annually with AML, prostate or breast cancer, most of which are associated with TARP expression. Importantly, TARP is a tumor antigen that was discovered by Drs. Ira Paston and Tapan Bera at the National Cancer Institute. AML patients have recently been documented to have 100% expression of TARP in both pediatric as well as adult AMA -- AML patients. Prostate cancer TARP expression is seen in approximately 90% of prostate cancers across a wide range of disease stages, including castration-resistant and castration-sensitive disease as well as approximately 50% of breast cancers. The TARP antigen that is used in PDS0102 has already been validated for use in humans as an immunotherapy. Here, I'm displaying results from a publication in Onco-Immunology from 2016 of the first-in-human study of TARP peptides delivered in men with PSA biochemical recurrence. Importantly, these were 2 short peptides that were delivered in combination either with Montanide ISA 51 VG or as an autologous dendritic cell preparation. These peptide combinations, this therapeutic vaccine approach, was shown to be highly immunogenic, safe and well tolerated, but importantly, was associated with significant slowing in tumor growth rates, as highlighted on the left-hand side of the slide. For all patients in the study, you can see the tumor growth rate represented by the green dots, pre-vaccine. And you see almost a 50% reduction in tumor growth rates post-vaccination. The right-hand side of the slide shows the change in tumor growth rates in the patients in the study over time. One of the things that I'd like to say as an immunologist is, is that at a potent, powerful, effective antitumor T-cell response is the gift that keeps on giving because of its potency as well as the establishment of immune memory, as Frank highlighted early in our discussions. We know that PDS0102 includes 2 long, overlapping TARP peptides. So they are much longer than the original peptides delivered in the previously described NCI study. These 2 peptides have evidence that they provide potentially superior induction of TARP-specific killer T-cells when codelivered with Versamune. Here in this slide, you can see that this TARP long peptide delivered with complete Freund adjuvant, a very potent immunostimulatory agent, but too toxic for use in humans, does not result in significant induction of TARP-specific T-cells. But when you deliver these TARP peptides that are longer with Versamune, you see a very dramatic increase in the number of TARP-specific T-cells that are observed. Our clinical strategy is to develop PDS0102 both as a monotherapy and in combination with established therapies in prostate cancer. We want to take this approach by examining PDS0101 -- excuse me, 0102, both in early disease as well as advanced disease. We believe that it's critically important with the Versamune platforms to demonstrate, with a different tumor antigen, that we see the same kind and levels of potent induction of systemic TARP-specific immune responses as well as demonstration of tracking of TARP-specific T-cells to tumor, as has been demonstrated in the preclinical studies performed by Professor Woodward at the University of Kentucky as well as Dr. Jochems with the triple combination at NCI. So we're proposing to look at PDS0102 immunogenicity and tumor infiltration as monotherapy and in potentially combination with checkpoint inhibitors in prostate cancer patients who are undergoing active surveillance to be able to evaluate this immunogenicity, pathologic response when delivered as a neoadjuvant therapy, either alone or in combination with checkpoint inhibitors. Importantly, since TARP is expressed in over 50% of breast cancers, which actually represents a doubling of the most effective molecularly targeted therapeutic for breast cancer, which is HER2 and represented at only 25% of patients, we would like to do the same thing. Again, confirming systemic immunity, safety and tumor infiltration in 2 different tumor types. In advanced disease, we would like to be able to explore PDS0102 safety and immunogenicity in combination with standard of care agents and regimens. Importantly, we know that prostate cancer tumors are historically cold tumors and hence don't respond to checkpoint inhibitors because there is a relative lack of evidence of T-cell infiltration into the prostate cancer tumor microenvironment. Our hope is that, after demonstrating early studies which document PDS0102 as able to induce tumor-specific immune responses, that infiltrate in tumors and prostate tumors are turned from cold to hot, that we would then proceed with combination therapies in the treatment of metastatic castration-sensitive as well as castration-resistant prostate cancer, the treatment of recurrent metastatic breast cancer as well as potentially the treatment of acute myelogenous leukemia. I'll next highlight the development of PDS0103 for MUC1-related cancers. PDS0103 is designed to treat cancers caused by mucin-1, also known as MUC1, which is highly expressed across a broad array of solid tumors and is associated with extremely poor clinical outcomes. This graphic represents MUC1 expression by tumor type. Over here on the left-hand side, you can see the highest levels of expression in nasopharyngeal, broncho stomach, colorectal tumors, gall bladder tumors. Tumors of the GU track, including the endometrium, fallopian tube as well as the uterus, the cervix and placenta. And then mid-range expression by very other common solid tumors with very negative outcomes, including non-small cell lung, esophageal as well as pancreas and kidney and urinary bladder cancers. Our goal would be to seek clinical trials to evaluate PDS0101 in tumor types that have the highest expression of MUC1 and the greatest differential expression of MUC1 between malignant and healthy normal tissue. As Frank highlighted previously, Versamune codelivered with different proprietary tumor antigens as well as shared tumor antigens results in high levels of tumor-specific CD8 killer T-cells but also not only are high quantity, but also high quality in terms of their potency. On the left-hand side of the slide is representative MUC1 antigen codelivered either with GM-CSF, at the far left; in the middle with the triple combination adjuvant; and then at the far right, delivered with Versamune. And the light green bars is T-cells, and in the dark green vertical bars, you can see T-cells that are potent and exhibit polyfunctional secretion of cytokines. We really know that it is these polyfunctional T-cells that get the job done and are responsible for the antitumor activity that's observed in vivo, in both preclinical animal models as well as in human clinical trials. On the right-hand side of the slide is a representative graphic which just represents these polyfunctional T-cells in a different manner and as a pie chart. The light orange, yellow represents monofunctional secretion of interferon gamma. The bright green represents secretion of interferon gamma and IL-2. The dark green represents secretion of interferon gamma and TNF alpha. While the red represents triple cytokine secretion of interferon gamma, TNF-alpha and IL-2. The one thing that I'd like for people to take away is, in the upper left-hand corner is our DOTAP, and you can see that there is a significant piece of the pie where there is induction of polyfunctional T-cells. Importantly, if you then focus to the lower right-hand side and you look at PMA/ionomycin, PMA/ionomycin is a positive control in many immunologic investigations because it is known to absolutely blast off T-cells. And I'd just like you to look and remember how comparable the pies are between RDOTAP and PMA/ionomycin, which has promise for antitumor efficacy in vivo. I'll now turn our presentation back over to Dr. Jochems to highlight the development of the MUC1 agonist epitopes that we are specifically developing for PDS0103 as part of our cooperative and collaborative research and development agreement. Dr. Jochems?

Thank you very much, Lauren. Let's see here. MUC1 has a normal function of protecting epithelial cells for the loss of homeostasis. Like Lauren said, it is expressed in over 90% of all carcinomas. So what happens is that the cancer basically hijacks the normal system and then uses it in a different way. It is [ abhorrently ] expressed in cancer, so it's expressed all over the surface of the cell instead of just at the apical surface, which is in the normal epithelium. The N terminus of MUC1 is a large extracellular portion. It's a mucin-type lipoprotein that disrupts cell-to-cell interaction and cell-to-extracellular matrix interactions. This part is shed in a large degree, and this is also the part that many -- no, I did not want to do that, but I guess that's good. So you can see it here. The MUC1-N is the large extracellular portion. And it's shed to a large degree, and this is also the portion of many prior vaccines against MUC1 have targeted. [ Bring back here. ] The C terminus of MUC1, in contrast, has just a tiny cellular portion, a transmembrane and an intracellular part. And it binds to the wind pathway effect of beta-catenin and works as a transmembrane receptor. It has been shown to be an oncogene. It drives lineage plasticity by inducing EMT, epithelial to mesenchymal transition, and it is associated with a more malignant phenotype and also with immune inhibition. It has been shown that MUC1 C is a druggable target. And right now, there are CAR-T cells, antibody drug conjugates and even a functional oral inhibitor under clinical development. Much of this research has been driven by Dr. Don Kufe at Dana-Farber. So once again, this is what the molecule looks like, with a large MUC1 N extracellular portion and the tiny MUC1 C portion. The LTIB has developed agonist epitopes to the variable [ nontandem repeat ] region, which is the oval in the middle of the MUC1 N section; and also to the [ nontandem repeat ], that's the P93L. And then we have multiple agonist epitopes to the MUC1 C portion. And these are specific for HLA-A2, A3 and A24. An agonist epitope. This is where we look at the whole sequence of the protein and then we figure out where you have potential binding regions for the CD8 T-cells, the cytotoxic T-cells that Frank mentioned. And by tweaking these sequences, by just changing 1 or 2 amino acids, we can make the binding much more efficient to the MHC, which results in better presentation and you get a better T-cell stimulation, hopefully resulting in better antitumor immunity. The top table is just a list of all the sequences we used in these studies, and they were published a few years ago in Cancer Immunology Immunotherapy. The bottom table just shows you that it's not so easy as to just look at a computer algorithm and then you've done. The predicted binding to HLA-A2 is what we get from the computer. We can show here that, in the red box, we have actually the predicted worst binders of these 5, which turned out to bind somewhat good, in some cases, some very good or not so good. But then in the end, these were the peptides that induced the strongest T-cell responses that produce the most interferon gamma and that killed tumor cells the best. So you can't just go by the computer algorithms. Here, I'm showing production of interferon gamma by T-cell lines that we have generated from cancer patients. So we take their blood cells and then we stimulate them with dendritic cells from the same patient and these dendritic cells have been exposed to the peptides that we made. So in the black full boxes on top, you can see the T-cell lines stimulated with agonist epitopes, our tweaked peptides. And on the bottom, this is in the first row, in the open squares, you have the native, the naturally occurring peptide. And as you can see, the agonist peptide T-cell lines produce more interferon gamma in all cases. The bottom 2 peptides, for those we're actually not even able to make any T-cell lines with the native peptides because they were such poor binders. But as you can see, the T-cell lines we made with the agonists produced a lot of interferon gamma, and they also killed tumor cells very efficiently. This is a table just highlighting 1 tumor cell line that we could kill with this T-cell lines that we made. MCF-7 is a breast carcinoma cell line, and it expresses MUC1 and is also HLA-A2 positive. And the E to T ratio, that's the effector cells or T-cell to target cell, tumor cell, ratio. And in white, you have the native peptides, and the gray rows represent the agonists. And as you can see, we had very nice killing with all our agonists at a higher level than when we made the T-cell line with a corresponding native peptide. On the right, you can see SK-MEL, which is a melanoma cell line. We use that as a negative control because it does not express MUC1, but it is HLA-A2 positive. And as you can see, these T-cells were not able to kill it. We could also demonstrate that these T-cells were specific for HLA-A2 by blocking HLA-A2, and in that way, decreasing the killing. This is a table just showing you all of the MUC1 agonist peptides that we have developed. On the left, you can see the MUC1 region that they target. So we have one in the non-VNTR region, 2 in the VNTR and then we have 7 peptides in the MUC1-C region. And these are all specific for HLA-A2, A3 or A24. You have our designations. And then as you can see in this table, all of these agonist epitopes were able to generate T-cells that were much more efficient than the native peptides. They could produce more interferon gamma, and they could all kill tumor cells expressing the native MUC1 much more efficiently than the T-cells that had been made using the native peptide. And this is very important because naturally, in the body, you're not going to have any agonist epitopes expressed. But what we're showing here is that, even though we tweaked the peptides and made our T-cells specific for a slightly different version of MUC1, we have really efficient killing. So in summary, we have developed 10 agonist epitopes for MUC1, and 7 of these are in the oncogenic C terminus. Compared to T-cells generated with the native epitopes, T-cells generated with the agonist show greater lysis of tumor cells expressing the native MUC1. All 10 of these agonist epitopes are included in PDS0103, which we're very excited about since we have such good results with PDS0101. And we have just received the final version of PDS0103 to the laboratory, and we're planning to evaluate activation of human T-cells in vitro. And then we want to test antitumor activity of this new vaccine in a new mouse model. So this is a triple knockout NSG mouse model. These mice do not have an immune system of their own. So -- but what we can do is we can give them an immune system, either from a healthy donor or from a cancer patient. And then we can match those -- that immune system with the tumor we put in. So we can use HLA-A2, A3 or A24 tumors to match the PBMCs that we have put in, and this will enable us to evaluate the specificity of this new vaccine for all 3 HLA types, A2, A3 and A24. So we're very excited to do that. Thank you very much.

Elegant science, which couples and enhances our enthusiasm to couple the agonist MUC1 epitopes with Versamune. I want to highlight for you that we do extensive research in collaboration with our colleagues, Drs. Woodward and Gandhapudi at the University of Kentucky to ensure that we optimize formulations of all of our products in the clinical development pipeline. As Caroline highlighted, PDS0103 consists of 10 MUC1 agonist peptides. We have investigated multiple formulations. And here is a representative formulation, EN10, which was tested in HLA-A2 transgenic mice, for us to be able to determine what the preliminary signal is regarding the potency and the induction of MUC1-specific T-cell reactivity. Importantly, what's displayed here is that vaccine immunogenicity was assessed using HLA-A2-specific epitopes B1a, B2a, C1a and C2a. And what you can see is, across all of these different HLA-A2 epitopes, we see very and potent induction of MUC1-specific T-cells in the spleen of these animals. Similar results were obtained with other PDS0103 formulations, and they were found to be equally potent in inducing this breadth of vaccine-specific responses, which we are very excited about. Our clinical strategy, again, in developing PDS0103, is a basket trial of MUC1-associated cancers in combination with established and investigational agents. First and foremost, looking at PDS0103 with FDA-approved standard of care for different MUC1 associated cancers and then potentially also exploring the triple combination of PDS0103 in combination with other novel immunomodulatory agents, such as bintrafusp alfa and M9241, similar to what was done in the Phase II study of PDS0101 in combination with these agents. Finally, I'd like to highlight PDS0101 using HPV mix with Versamune targets HPV-related cancers, including anal, cervical, head and neck, penile, vaginal, vulvar cancers; PDS0102, which I've discussed, targets AML, prostate and breast cancers; and then PDS0103 targets a wide variety of solid tumors. What we really find provocative in terms of potential future development paradigms is that clinical disease indications potentially that could be divined looking at 2 Versamune-based agents, that would include PDS0101 and PDS0103 in cervical and nasal, head and neck cancer; as well as PDS0102 and PDS0103 potentially in breast and prostate cancer. I'd now like to open the discussion up for questions regarding PDS0102 and 103, which we'll try and keep limited so that Dr. Bedu-Addo can deliver his final remarks. Deanne?

Thank you, Lauren. Yes, we have several questions, but I think have time for only a couple. One of the first questions, Dr. Wood, is for you around the MUC1 program. MUC1 has been used as a target in some previous work that has yielded disappointing results. How do you think about this program in comparison to some of the historic work done? And do you anticipate kind of more successful results with PDS0103 than have been previously seen?

So I think part of that answer comes -- to the question comes from the discussion presented by Dr. Jochems, and that is that many of the early studies targeted the N terminus of MUC1, which is shed. The focus with the PDS0103 agonist and product is using MUC1 from the C terminus. Importantly, as she's also highlighted, these epitopes have been selected to be agonistic and specifically manufactured so that they enhance the cytotoxic activity against MUC1-expressing tumor that is much greater than that is seen with wild type. And I think for tumors that express MUC1, which is very common, there's a level of tolerance. And so introduction of novel agonistic MUC1 peptides have the potential to induce enhanced killing. That's been observed, as Dr. Jochems noted, with these MUC1 agonist peptides without Versamune. I highlighted the fact that we've already seen significant induction when these peptides are codelivered with Versamune. So we're really excited about the potential to see a level of antitumor activity in preclinical animal models and then subsequently in human clinical studies that has not previously been observed.

Thank you. We have one last question that we will take. And again, Dr. Wood, I think this one is for you. So given that the Versamune platform seems to work with a number of different antigens, are you seeking or evaluating the combination of Versamune with antigens beyond those that you have just presented? And if so, how are you prioritizing that work?

Yes, we are looking at Versamune in combination with other tumor antigens. A candidate that we did not talk about here is PDS0104, which is Versamune codelivered with TRP2, a melanoma antigen, as well as other melanoma antigens. We also are seeking to conduct preclinical studies with other common tumor antigens that in the past have been disappointing in terms of clinical results and appear to be undruggable, but which -- for which there appears to be new activities. The specific tumor antigen I'm talking about is KRAS. As far as the prioritization of tumor antigens, of course, we are looking to investigate Versamune with tumor antigens that are overexpressed in solid tumors where there is still a huge area of unmet medical need to explore their therapeutic potential. And that's how the prioritization would take place.

Thank you so much. With that, I will turn it back over to Dr. Bedu-Addo to close out the session.

Dr. Bedu-Addo, perhaps you are self-muted.

Dr. Wood, would you want to present these slides? Perhaps Dr. Bedu-Addo is having some difficulty.

Okay. I'll proceed. And then as -- if Frank, if you're able to discover the mute issue, please chime in and take over. We seek to validate the efficacy and safety of the Versamune platform, again, across multiple tumor targeting antigens. This slide just kind of highlights some of the key milestones that we've achieved in terms of demonstrating the preclinical activity of Versamune-based platforms with different tumor antigens, both HPV16, melanoma antigens as well as MUC1, and then moving forward to confirming the activity in human clinical studies. Our goal is to, again, confirm induction of these tumor-specific antigens codelivered with Versamune in different antigen platforms, specifically PDS0102 with TARP, and PDS0103 with MUC1, and then continue to investigate their antitumor activity in human clinical trials as well as explore potential new combinations of Versamune with other novel tumor antigens. Again, Versamune has demonstrated the potential for immunologic compatibility with a wide array of tumor antigens. It's critically important to know though that a tremendous amount of science goes into the formulation work. The preclinical vetting as highlighted by Dr. Schlom, Dr. Jochems in their presentations before we actually proceed to human clinical trials. Versamune's unique flexibility means it may work well with a wide range of molecular tumor targets. I've already highlighted the 4 tumor antigens that we are utilizing with the Versamune platform. You've heard about PDS0101 through PDS0104. And the company is seeking commercial partnerships and research collaborations to explore Versamune's utility with other tumor antigens that have been identified as promising therapeutic targets. Over the next 18 months, PDS Biotech will be exploring research collaborations and partnerships to progress our pipeline, which we believe is very promising. Highlighted here are the key research objectives of each asset. Particularly with PDS0101 we'd like to document tumor infiltration of PDS0101-induced HPV16-targeted T-cells, which we believe we'll get preliminary signals from all of the Phase II studies that I mentioned to you earlier, as well as from a planned neoadjuvant study of PDS0101 and KEYTRUDA in HPV16-positive head and neck cancer. Again, with PDS0102, we seek to establish safety, immunogenicity, pathologic response of this tumor antigen, both in prostate cancer and in breast cancer, to again demonstrate the proof of principle, that when Versamune is delivered with this tumor antigen, you see development of potent systemic tumor-specific immune responses that then actually track to tumor and infiltrate with T-cells that are tumor-specific. And also to explore to use in acute myelogenous leukemia. For PDS0103, we'd like to establish, again, the safety immunogenicity and preliminary efficacy of MUC1 agonist epitopes codelivered with Versamune, and PDS0103 in advanced MUC1 cancers, a basket trial, basically targeting this population of advanced solid tumor patients that have a huge unmet medical need. And then in our pipeline, to explore the combination of Versamune with other tumor antigens that have been validated in animal models. I want to thank everyone for their time and attention during our webinar. A particular thanks goes to our scientific collaborators and colleagues at the NCI, Dr. Schlom, Dr. Jochems, Dr. Strauss, in presenting the very elegant preclinical and important clinical data from the triple combination study. Deanne, I'll hand it back over to you.

So we'll try to see one more time if Frank can join. Frank, are you there? Unfortunately, I think he may be having some technical issues. But I just wanted to echo exactly what Lauren said. Thank you all for joining us over the past couple of hours to really look at the science in more detail. And I specifically want to thank Dr. Schlom, Dr. Jochems and Dr. Strauss for joining us today as well as our collaborators at the NCI, Dr. Berzofsky as well as Dr. Leaf Huang and Dr. Jerry Woodward at the University of Kentucky. Thank you all again for your engaging discussion and questions. And this, as previously mentioned, this webcast will be posted to pdsbiotech.com for future reference, and these slides will be available on the website as well. Thank you all for your time again today.

Thank you. That does conclude today's webinar. You may disconnect your lines at this time, and have a wonderful day. Please now disconnect.