PDS Biotechnology Corporation (PDSB) Earnings Call Transcript & Summary

Hello, and welcome to the PDS Biotechnology Post ASCO Conference Call and Webcast. [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 Post ASCO webcast. With me today are Dr. Frank Bedu-Addo, Chief Executive Officer; Dr. Lauren V. Wood, Chief Medical Officer; and Dr. Seth Van Voorhees, Chief Financial Officer. Earlier this morning, PDS Biotech issued a press release summarizing the data presented yesterday afternoon at the American Society of Clinical Oncology Annual Meeting. The company's press release is available on PDS Biotech's website at pdsbiotech.com, and a recording of this webcast will be posted to the website later today and will be archived there for future reference. Before we begin, I would like to caution listeners that comments made by management during this 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 company's business operations, financial operations and results of operations and the company's ability to respond to the related challenges, including those noted in this morning's press release, please refer to 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 8, 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. Over the next hour or so, we will discuss the interim data from the NCI-led Phase II clinical trial studying PDS0101 in combination with 2 investigational immunotherapies. Dr. Frank Bedu-Addo will begin the discussion with an introduction of the study and an overview of the rationale behind the use of the triple combination. Dr. Lauren V. Wood will then walk us through the detailed efficacy and safety data. Dr. Bedu-Addo will conclude the presentation with a summary of how these data inform our ongoing clinical plans for PDS0101 and the implications for the company more broadly. Following today's prepared remarks, 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.

Deanne, thank you very much for the introduction. I would like to thank all our attendees for your time and interest in joining us today for a review of the data presented yesterday at the ASCO conference. A key area of focus for PDS Biotech is developing oncology products that overcome a significant limitation of immuno-oncology today, which is the in vivo induction of effective tumor-targeting killer T cells, also known as CD8 T cells. The most successful immunotherapies to date, the checkpoint inhibitors, are highly effective at blocking the immune checkpoints and essentially decamouflaging the tumors to make them more visible to the immune system. However, less than 20% of patients respond to checkpoint inhibitor treatment, meaning that 70% to 90% of all patients fail checkpoint inhibitor treatment. It has been reported that patients who respond to checkpoint inhibitor treatment have preexisting killer T cells necessary to attack the tumors exposed by the checkpoint inhibitors. The Versamune technology has been designed to promote a powerful in vivo killer T cell response by inducing the right phenotype of killer T cell in the right quantity and with the essential killing potency. All 3 characteristics are necessary to induce a clinically effective antitumor response; the right phenotype, right quantity and adequate potency. Versamune is also designed to induce what is known as a memory T cell response, which has the potential to lead to durable and sustained clinical responses. Thirdly, as you'll see today, VISION is designed to induce a powerful antitumor response without the side effects typical of oncology products or immunotherapy. Next slide, please. Okay. The National Cancer Institute led triple combination trial we will be reviewing today is evaluating the novel combination in 2 distinct groups of patients. First is the group we refer to as being checkpoint inhibitor naive. These are the patients who have usually failed both chemotherapy and radiation treatment. For these patients, the standard of care is checkpoint inhibitor therapy. The response rate of checkpoint inhibitor treatment in this population of patients is reported to be about 12% to 24%. Very importantly, this is the response rate we will compare to the triple combination within the checkpoint inhibitor naive group. The historical median life span for these patients is about 7 to 11 months. About 80% of these patients will fail treatment with the standard of care and will be classified as checkpoint inhibitor refractory. This is the second group of patients evaluated in this triple combination trial. Due to lack of options for this patient population who have failed all treatments, selected therapies may be repeated. The response rate in the checkpoint inhibitor refractory population is reported to be about 5% to 12%. Again, it is important to note that this is the response rate we will compare to the triple combination within the checkpoint inhibitor refractory group. The historical median life span with the stage of disease is only about 3 to 4 months. So a very difficult-to-treat population, okay? So moving on to PDS0101. What is PDS0101? PDS0101 combines the Versamune technology platform with small proteins from the HPV16 viral protein that get expressed or are present in the cancer cells. PDS0101 is, therefore, specifically designed to treat cancers caused by an infection with HPV type 16. The vast majority, 70% to 80%, of these HPV-associated cancers are caused by infection with HPV16 specifically. The interim data we will see today strongly suggests that in these very ill patients, PDS0101 may be promoting the induction of HPV16 specific tumor-targeting killer T cells resulting in the killing of the cancer cells and subsequent tumor reduction, therefore, leading to clinically meaningful responses. The data also suggests that if we can rationally design immunotherapeutic combinations that include agents that can promote the induction of potent CD8 killer T cells as well as CD4 helper T cells, that we may be able to induce powerful antitumor clinical efficacy. Now the 2 agents combined with PDS0101 in the triple combination are bintrafusp alfa, also called M7824, which I will simply call bintra, and NHS-IL12, which is also called M9241. Both agents are owned by Merck KGaA known as EMD Serono in the United States. The National Cancer Institute performed a preclinical study of the triple combination, which was published in the Journal for Immunotherapy of Cancer last year and is available on our website. The results are summarized on the slide. The blue panels are stained sections of the HPV16 positive tumors. With bintra alone on the top, we see little to no T cell infiltration and 0 out of 16 had tumor regression. However, with the dual combinations that include PDS0101 and with the triple combination, we see dramatic induction and infiltration of HPV16-specific T cells into the tumor. And as you can see here on the bottom panel, the tumors light up like a Christmas tree with the red and green spots, which are killer and helper T cells, respectively. In this case, we see 13 out of 17 or 76% experiencing tumor regression. Now let's take a look at the number of T cell clones. In the bintra-treated animals, we see 22 T cell clones. With the triple combination, even though we have induced over 100-fold more T cells, we only have 3 T cell clones. This result is very important and suggests that Versamune recruited a large number of T cells and trained those T cells to be highly uniform in their phenotype and behavior, leading to effective targeting and killing of the HPV16 tumors. The early data we will be reviewing today suggests that Versamune may be achieving a very similar effect in the human cancer patients. Now the next slide shows how we envision the 3 agents could be working together to create powerful antitumor effects. Bintra or M7824 is an effective checkpoint inhibitor that decamouflages the tumor, making it more visible to the T cells. NHS-IL12 targets the tumor and causes inflammation or lights up a flare, making it even more visible to the T cells. Versamune recruits T cells and trains them to recognize the HPV16 proteins and then arms the HPV-specific T cells to attack and kill the exposed tumors. So with that introduction to PDS0101 and the triple combination, I will now hand over to Dr. Lauren Wood, Chief Medical Officer of PDS Biotech, to discuss the clinical results. Lauren?

Thank you, Frank, and thanks once again to all of you for joining us this morning. As Frank mentioned, these data represent the first proof-of-concept data we've had for our lead Versamune-based oncology product, PDS0101, in advanced cancer. I'll begin with an overview of the clinical trial design for this investigator-initiated study of PDS0101 in combination with bintrafusp alpha, also known as M7824, a first-in-class bifunctional checkpoint inhibitor, and M9241, an antibody conjugated cytokine designed to facilitate entry of the cytokine IL-12 into the tumor. Moving forward, as Frank did, I'll refer to bintrafusp alpha as bintra. The study is designed to evaluate the treatment combination in both checkpoint inhibitor naive and refractory patients with advanced HPV-associated cancers that have progressed or returned after treatment. Most HPV-associated cancers associated with greater than 95% of all U.S. cases are represented in this NCI data set. From the literature, we know that 70% to 80% of these cancers are caused by HPV16 infection, the most oncogenic high-risk HPV type. These cancers include anal, cervical, head and neck, vulvar and vaginal cancer. The composition of tumor types is similar to that seen in the overall population with the majority of patients having either head and neck or cervical cancer. In the trial, objective response rate, known as ORR, is measured by radiographic tumor responses according to RECIST 1.1. The study will ultimately evaluate the objective response rate in 56 patients. Today, we will review an interim look at the data that includes a total of 25 patients, representing roughly half the patients to be accrued to the study. The study enrolled a challenging and difficult patient population to treat. Of the 25 patients evaluated in this data set, 96% had failed both chemotherapy and radiation treatment; 56% had also failed checkpoint inhibitor therapy; in addition, 36% of patients had failed 3 or more prior anticancer treatment regimens. Patients also often come to the National Cancer Institute in Bethesda, Maryland, when they have exhausted all other standard of care treatment options. And we see that reflected in these demographic data. Importantly, of the 25 patients, 18 were HPV16 positive and 7 were HPV16 negative. The median follow-up represented in this data set was 8 months. Let's begin with the 6 HPV16 positive checkpoint inhibitor-naive patients. Objective response, again, is defined by RECIST 1.1 as a reduction in tumor burden of at least 30% or more. In these patients who had not previously received checkpoint inhibitors, the triple combination achieved an 83% objective response rate. As a reminder, this patient population is very difficult to treat. The objective response rates reported to date, again, as Frank highlighted, in advanced HPV cancer patients who have failed prior therapy is generally around 12% to 24%. Of the 5 objective responses in this population, 1 has already achieved a complete response. Importantly, this triple combination shows promising durability in these HPV16-positive checkpoint inhibitor patients, as 80% of these patients have an ongoing response at a median of 8 months of follow-up. One patient came off the combination, halting the response. Additionally, all 6 patients are still alive. To give you some context, this patient population has a historical mean survival of 7 to 11 months with standard of care checkpoint inhibitor therapy. These preliminary interim results suggest that PDS0101 induction of in vivo highly active tumor attacking HPV16 killer CD8 T cells documented in the published preclinical animal studies, as discussed earlier by Frank, might also result in effective disease reduction in humans. Moving now to the 12 HPV16 positive patients treated in a checkpoint inhibitor refractory arm. These are patients who have failed treatment with chemotherapy, radiation therapy and checkpoint inhibitors. In this population, the triple combination achieved tumor reduction in 58% of patients. These 12 patients include the initial 8 patients reported in the abstract, where 5 of 8 or 63% had tumor reduction. Of the 4 additional patients in his updated data set, 2 patients already have ongoing tumor reduction, but have not yet met the criteria for objective response. As might be expected, the objective response rates reported in checkpoint refractory advanced HPV cancer patients are even lower than those naive to checkpoint inhibitors, generally, only 5% to 12%. Encouragingly, similar to checkpoint inhibitor-naive patients, the triple combination also shows promising durability in these HPV16 positive checkpoint refractory patients. Specifically, 86% of patients have ongoing tumor reduction, and 80% of patients have ongoing objective responses at a median of 8 months. The 10 of 12, 83% of these patients are alive at a median of 8 months is notable, as this checkpoint refractory patient population generally has a historical mean survival of less than half that, only 3 to 4 months. These preliminary results suggest PDS0101 induction of in vivo, highly active, tumor-attacking HPV16 CD8 T cells even in extensively treated and likely immunologically limited patients has a potential for effective disease reduction and ongoing durable responses. As with any combination regimen, a common question that arises is the relative contribution of each of the individual components in the triple combination to the encouraging results seen so far. Specifically, the top question posed to Dr. Strauss following his ASCO presentation yesterday was, do you believe all 3 therapies are contributing to the clinical benefit? The data on this slide in 7 HPV16 negative patients helps elucidate the role of PDS0101 in the triple combination. You'll recall that this trial is being conducted in patients with advanced HPV-related cancers, agnostic on the strain of HPV required to qualify for enrollment. It's important to understand that PDS0101 is actually a molecularly targeted immunotherapeutic that leverages the specificity of the immune system to definitively and exclusively attack tumors expressing only the target tumor antigens, which in this case includes HPV16 E6 and E7. As can be seen in the bar graph depicted here, among the checkpoint inhibitor naive and refractory patients in this study, 67% of HPV16 positive patients experienced tumor reduction at a median of 8 months. In contrast, in the 7 HPV16 negative patients, those with a HPV type other than HPV16 that do not express the molecular targeted PDS0101, 0 of 7 patients experienced tumor reduction or an objective response. These observations suggest that HPV16-specific CD8 and CD4 T cell induction by PDS0101, as predicted by preclinical studies, may promote tumor reduction and enhanced clinical benefit of the triple combination. Results in these 7 HPV16 negative patients also suggest a potential critical role of PDS0101-induced CD8 T cells in promoting survival in the triple combination treatment. In these heavily treated advanced cancer patients, remarkably, the majority of patients are still alive at a median of 8 months of follow-up; 89% of HPV16 positive patients and 57% of HPV16 negative patients. These preliminary data are particularly encouraging as they document impressive survival responses regardless of prior checkpoint inhibitor exposure, as was noted by Dr. John Hyngstrom in his discussion of session abstract presentations at yesterday's meeting. Turning now to the safety data. A very important consideration for combination oncology treatment regimens is to avoid additional or excess toxicity associated with limited antitumor activity. Importantly, PDS0101 does not appear to compound toxicities of the triple combination therapy. The adverse events documented to date with the triple combination are consistent with those previously observed with bintra and M9241 monotherapy treatment. Specifically, grade 3 treatment-related adverse events occurred in 40% of patients. The most frequent treatment-related adverse events were anemia due to gross hematuria, decreased lymphocytes and the presence of flu-like symptoms. As would be expected with both PDS0101 and M9241 being delivered subcutaneously, injection site reactions were seen in 20% of patients. Four patients who originally had grade 3 toxicities with a triple combination, including M9241 dosed at 16.8 micrograms per kilogram, tolerated the combination when the dose of M9241 was lowered to 8 micrograms per kilogram without any further grade 3 or greater toxicities. Again, as we seek to understand the contribution of individual components to the safety as well as the efficacy profile of the triple combination, it is important to note that no new or worsening toxicities were observed from the addition of PDS0101 to the combination. We look forward to the data from the continued evaluation of these patients as well as the addition of more patients to the data set to answer these very important questions. I'll now turn it back over to Frank to summarize these key findings and the implications for PDS Biotech more broadly. Frank?

Thank you, Lauren, for reviewing the exciting data. The interim data demonstrates the potential critical role of PDS0101 in the triple combination and suggest strongly that PDS01 may be effective in priming the immune systems of these very ill patients to induce HPV16-specific T cells to effectively fight the cancer. Most telling to us at PDS Biotech is the group of patients who are checkpoint inhibitor refractory and who have failed all available treatments, including checkpoint inhibitors, and who historically have about 3 to 4 months to live. Even in this population, we are seeing, in the early data, 50% to 60% response rate and over 80% of these patients still alive at a median of 8 months. This is not at all likely to be random nor is it likely to happen by chance. This demonstrated potential of PDS0101 to efficiently induce the right type of HPV16 killer T cells in vivo in the right quantity and with the right potency even in patients who may have marginally functional immune systems has direct implications for our other -- 2 other ongoing trials. Both trials, as you may recall, are studying PDS0101 with current standard of care in a healthier patient population. PDS0101 is being studied in combination with Merck's KEYTRUDA in HPV16 positive head and neck cancer. KEYTRUDA is an FDA-approved standard of care in first-line treatment of head and neck cancer that has returned or continued to spread after treatment. In this trial, we expect KEYTRUDA to efficiently decamouflage the tumorous and allow the PDS0101-induced T cells to effectively attack and kill the exposed tumors. The response rate in this patient population with KEYTRUDA monotherapy is 20%. In this trial, we will be evaluating the response rate of the combination. In the MD Anderson-led trial, we are studying an even healthier population of pre-metastatic cancer patients with locally advanced cervical cancer. Here also, we see significant potential in the combination of PDS0101 with standard of care chemoradiotherapy. MD Anderson studies suggest better clinical outcomes in these patients whose immune systems are inducing T cells at the time of treatment. So to conclude, the preclinical studies appear to have been highly predictive of the early human results thus far. The preclinical results demonstrated T cell induction only in combinations containing PDS0101. Also, superior tumor regression was seen with PDS0101-containing combinations. The interim data we have seen today demonstrates tumor reduction only in patients who were HPV16 positive, suggesting strongly and confirming the preclinical data and the critical role of PDS0101-induced HPV16-specific T cells in the triple combination. In the HPV16 positive patients, at interim data, we see tumor reduction in 12 out of 18 patients, a 68% overall response rate, including both checkpoint inhibitor naive and checkpoint inhibitor refractory patients. In the naive population, specifically, we see tumor reduction and objective responses in 5 out of 6 or 83% of the patients, with 6 out of 6 or 100% of these patients still alive at 8 months. One patient, as of time of reporting, had reached a complete response. The historical median overall survival in this population is 7 to 11 months. In the checkpoint inhibitor refractory population, we see tumor reduction in 7 out of 12 or 58% of the patients. 4 of these patients were recently added, and 2 out of these 4 have already shown ongoing tumor reduction. And 5 of these patients, as Lauren highlighted, have attained an objective response, and 1 has recently achieved a complete response. 10 out of 12 or 83% of the checkpoint inhibitor refractory patients are still alive at a median of 8 months compared to the historical median survival of only 3 to 4 months. Overall, 89% of the HPV16 patients are alive at median 8 months, suggesting that the triple combination may be inducing a durable clinical response that could result in significant enhancement of the overall survival of these refractory cancer patients, therefore, allowing them to live a lot longer or even possibly achieve elimination of the disease in some patients. We look forward to developing effective immunotherapeutic combinations that may revolutionize the treatment of cancer to provide improved therapeutic options to cancer patients. Thank you very much for your time today, and the management team will be happy to take questions at this time.

Thank you, Frank and Lauren, for walking us through the data. That concludes today's prepared remarks. We will now be joined by Dr. Seth Van Voorhees, our Chief Financial Officer, and the leadership team would be happy to answer your questions. [Operator Instructions] So we already have our first question, and it's one that we've heard a few times before over the last couple of weeks, having to do with the path forward for the triple combination. So Frank, I will ask this of you. Given that while the triple combination data are very encouraging, we are talking about 3 clinical stage therapeutics. How is the leadership team thinking about the regulatory path forward for the triple combination?

Thank you, Deanne. I think in this -- with this study, the most compelling data is actually the 50% to 60% response rate in the checkpoint inhibitor refractory patients who have exhausted all treatment options and have only a 3 to 4 month survival with extremely limited options. We believe that this combination will most likely be of highest interest to the FDA in this refractory population. And this is also where they will be the highest incentive to move quickly with a pivotal trial, right? We would likely be discussing this with both partners, the NCI, the National Cancer Institute, and EMD Serono, in the near future. And I think we would like to have about 30 checkpoint inhibitor refractory patients treated with the triple combination before approaching the FDA to discuss a pivotal trial design. There may be a request to tease out the need for M9241, for example, in the combination, although the preclinical data suggests that all 3 agents have a role in the efficacy, right? So the historical lack of responses in this population may also lead to a more efficient or smaller trial but the eventual pivotal design remains to be seen, and we anticipate, in the very near future, having these discussions with the FDA to agree upon a role in design for the pivotal trial.

I have 2 actual follow-up questions kind of related to that. So the first is around, are there any expectations or any possibility that the current trial being run at the NCI could be converted or considered a pivotal trial and used for registration?

I don't think any of the partners believe that, that will be the case. It all comes down to the data, right? I mean, typically, I think the FDA would want to see a slightly bigger trial here. We're looking at 55 patients total in both the checkpoint inhibitor and the checkpoint -- checkpoint inhibitor refractory and checkpoint inhibitor naive arms. We believe that the FDA, even as encouraging as the data is, would probably like to see this evaluated in a few more patients than we are evaluating in the Phase II trial. So I think the greater possibility is that we would have to do -- perform a pivotal trial. However, there is a strong possibility and likelihood that this will be a relatively smaller trial just based upon the lack of efficacy in that patient population versus what we've seen with a triple combination. But most likely, the FDA would like to see a separate pivotal trial with a few more patients.

Similarly related to that question, kind of a tandem question. Do you believe that it possible that you could use the accelerated approval pathway for the refractory patient population, even with a smaller pivotal that you just referred to?

Well, I'll let Lauren address that question.

Well, the accelerated approval pathway is designed to facilitate approval of therapies for patients with huge unmet medical need. And clearly, the checkpoint refractory population does reflect that population. Again, as Frank noted, the design of a pivotal trial and the use of the accelerated approval pathway will really be generated by the data with the goal of scientifically validating the objective responses and the durability of the responses that we've seen in patients and confirming this efficacy moving forward. This NCI trial is a very impressive proof of concept. And I just want to remind everyone where we have come from. Our initial Phase I study was performed in healthy volunteers with cervical preneoplasia. And this is our first effort and first signal in utilizing PDS0101 in patients with advanced, recurrent, metastatic and treatment-refractory cancer. So while the signals are very promising, we definitely want to confirm them. And yes, we would explore using an accelerated approval pathway.

The next set of questions is around the delineation between those patients who were HPV16 positive and those patients who were HPV16 negative. So the first question, Lauren, I think, is to you. Were the HPV16 negative patients recruited as an internal control to better elucidate the specific effect of PDS0101 within the triple combination?

That's an excellent question, and the short answer to that is no. The trial was designed from the beginning to be HPV16 agnostic, specifically to be able to recruit, as quickly as possible, patients with HPV-related cancer so that we could get at the safety of the triple combination, again, which is very critical. We have all HPV cancer types represented. And it's one of the benefits that since the trial was agnostic, we could do this delineation and identify differences in responses between those who were HPV16 positive versus HPV16 negative. Importantly, in our other 2 Phase II trials, we have 1 similar approach to the NCI trial, which is in the MD Anderson trial, looking at locally advanced cervical cancer. Again, that is HPV16 agnostic, allowing all women with locally advanced cervical cancer to receive PDS0101 in combination with standard of care chemoradiation therapy. The same kind of analysis regarding the HPV16 positivity of those tumors and the response outcomes that we observe will be taken. In contrast, in our VERSATILE-002 study, looking at PDS0101 in combination with KEYTRUDA, that trial is restricted to patients who have confirmed HPV16 positive head and neck cancer. However, we know that HPV16 positive cancers represent 80% to 90% of the HPV positive cancers seen with head and neck squamous cell carcinoma.

Lauren, am I correct that with the NCI trial based upon the fact that they are not seeing any responses with HPV16 negative that they have stopped recruiting HPV16 negative patients?

But the original trial design was, again, agnostic when we started.

So Lauren, related to the HPV16 positive versus negative and kind of the responses seen therein, we have a couple of questions around how we should -- or what conclusions we should draw from the fact that HPV16 positivity was needed in order to see a tumor reduction, and yet, those even with HPV16 negative cancer seem to have good survival benefit. So I think it's a 2-part question. What conclusion should we draw from those data at this point? And secondly, for those HPV negative -- HPV16 negative patients, what mechanism are you attributing that survival benefit to, given the lack of PDS0101 kind of induction of T cells targeting that tumor?

Two excellent questions. I could hear the immunology universe just sparkling out there with questions. So the first issue is that we clearly see a parallel response in humans that seems to strongly parallel the preclinical observations of the triple combination studies. It is going to be confirmed when we are actually able to get the results of extensive immunologic studies that are planned by the NCI, including examining HPV16-specific immune lymphocyte subsets in the periphery as well as in tumor in some patients who have pre and post-treatment biopsies on study as well as examination of other surrogate biomarkers. Regarding the patient population that does not express HPV16 and does not exhibit tumor regression, but appears to have a very significant survival. One of the questions becomes, in the context of generating HPV16-specific immune responses. When both bintrafusp alfa and M9241 are administered, this decamouflaging of the tumor, it's possible that there may be antigen cross-presentation of some type that may possibly allow HPV16-directed CD8 T cell responses to potentially recognize other non-HPV16 high-risk phenotypes? The reason I say this is because in our Phase I study, in individuals who had cervical preneoplasia, over 2/3 of the subjects in that study had multiple high-risk HPV types other than 16 and some including 16, and we saw regression of these preneoplasia lesions in some as early as 1 to 3 months. So there's the possibility that there may be some antigen cross-presentation and cross-reactivity with non-HPV16 types that could be contributing to the response. It's a very, very fascinating and interesting question. And a deeper dive into the specific immunology is going to allow us to get at that question. The other thing that I think is going to be a very, very important surrogate biomarker is the NCI is also planning on looking at circulating tumor DNA, and it will be very interesting to see what happens to circulating tumor DNA in the patients with HPV16 versus those who do not have HPV16. Great question.

And so -- kind of in the same vein, given the complementary mechanisms that you just walked through, how should we think about the differences in activity that may result in other regimens, i.e., the one that's being used in VERSATILE-002, pairing PDS0101 with KEYTRUDA?

So our hope is that we know that we can, at least now from 2 clinical studies, induce with PDS0101, highly specific CD8 T cells that target tumor. I don't have evidence right now in terms of the peripheral immunologic subsets in the NCI population, but we clearly have evidence that with this combination regimen, we see reduction in tumors that actually result in objective responses that are also sustained. So the goal is, with VERSATILE-002, that we are seeking to reproduce a similar signal in terms of being able to objectively document tumor regression and objective responses. Importantly, we've amended the VERSATILE-002 study, which was initially designed to only treat checkpoint inhibitor naive patients with PDS0101 in combination with KEYTRUDA, which is approved by the FDA for the standard of care as first-line recurrent treatment for metastatic disease. We've amended the study so that we will now also have checkpoint inhibitor refractory patients, those who have progressed on treatment with checkpoint inhibitors, to see whether or not we have preliminary efficacy signals of the combination in this population as well.

And Lauren, I'll add a little bit to that. It's important to us to realize that PDS0101 was specifically designed to target HPV16, right? So the antigens included in PDS0101 are specifically HPV16 E6 and E7 antigens. And so that was -- that is critical for our initial proof of concept. What we will do after the proof of concept is concluded is very simply add other antigens that would help address the non-HPV types, right? So the -- just -- it's very important to remember that this proof of concept study is focused on HPV16 specifically because the vast majority of these patients are HPV16, and it's the most oncogenic type of HPV. And so it was important to demonstrate in this trial that if we can specifically generate those HPV16 targeting T cells and treat those patients, then just like we are doing with the rest of our pipeline, all we have to do is to add in those specific protein antigens for the other HPV types to then effectively treat those non-HPV cancer types. And so that's important in the progression of our development pipeline, both for HPV cancers as well as, as we'll hear on the Research Day meeting next week, what we are also doing with the pipeline products, where we are incorporating other protein specific to other tumor types beyond HPV, right? So just bear in mind, this is a proof of concept study, really demonstrated to show that Versamune can do what we designed it to do, which is take a specific tumor antigen and direct T cells specifically towards that specific targets.

And Frank, there are several questions about the pipeline and kind of what this could mean for the direction of the company. But before we go there, we have a couple of additional questions just about study design that I think, Lauren, can answer pretty quickly. Lauren, can you confirm that the responses were determined by RECIST criteria? And secondly, were those responses confirmed?

The responses were determined by RECIST 1.1, as noted in the study. There is also an exploratory objective that will characterize responses by immune-related RECIST criteria. They have not been centrally confirmed or confirmed by a blinded independent review. These are by investigator assessment.

And then one last question for you, Lauren, and we'll give you a little bit of a break. Can you speak a little to the severity and the duration of the adverse events that you described in the study?

So I can tell you that, as highlighted in the adverse events slide, I'll provide further insight in terms of the issue of hematuria related to mucosal bleeding and anemia. This occurred predominantly in patients with cervical cancer, who have received prior pelvic irradiation and brachytherapy. Once there was the dose reduction allowed of M9241, it was found that the triple combination was more tolerable. PDS0101 did not result in any new or added toxicities associated with the combination regimen. And with this modification to the NCI protocol, allowing the dose reduction, there was really a further reduced incidence in these patients. There's a specific effort to continue to recruit additional patients with cervical cancer so that we can see how the triple combination with a reduced dose of M9241 is tolerated. Most of the toxicities were tolerated, and there has not been anyone who was discontinued due to toxicity from the combination.

Frank, when you were discussing the rationale behind the use of the triple combination, one of the things you referred to was clonal specificity and that with M7824 by itself, you didn't -- you had 22 different T cell clones, and that was reduced to 3 with the triple combination. Can you speak a little bit more about why that's important?

Thanks, Deanne. Well, that is important because if you remember, as I just said a few minutes ago, Versamune is designed to train -- recruit and train T cells to be very specific in identifying their targets, right? And so here, starting out with 22 T cell clones, mean at least 22 different types of T cells. One of the things I mentioned earlier in the presentation is that for an immunotherapy to be effective, you have to have the right phenotype of killer T cell, you have to have it in the right quantity and also with the right killing potency. And so what this -- the meaning of this reduction in T-cell clones is we see that we went from 22 T cell clones with very few T cells. Now we've recruited a large number of T cells, and we see now that we have over 100-fold more T cells. However, even though we have recruited this large army of T cells, we've now trained our army to very specifically recognize who the enemy is and they are very well armed, and they're all now uniform, they've been trained to be very uniform in their behavior. So now we have a very uniform type of T cell that has been specifically trained to recognize HPV16, which is the protein that we combine with Versamune. And so that reduction in a number of clones is an indicator that the T cells are now very specific to the target that they have been trained to recognize an attack, which is very important because when you generate a large number of T cells, you don't want indiscriminate attack of other organs, right? You want these T cells to be very specific to a particular cell type, which in this case, are the cancer cells. And so that is what the meaning of that is that we've recruited this large number of T cells, but even though they are much larger number of T cells, they are very well-trained to be uniform in their behavior, which is identifying and targeting the specific target, in this case, the cancer cells.

We have a related question about the triple combination. It's a 2-part question. The first is that there are a few different therapies that are currently in the clinic targeting HPV and to claim to induce T cells. So based on that, why do you believe that NCI picked PDS0101 for study in this combination? And secondarily, if the answer to that question is T cell polyfunctionality, mechanistically, why does that matter?

Well, I'm not -- there are a number of other HPV immunotherapies, right, targeting developing products, immunotherapies to address the specific patient population. Again, one of the things I mentioned earlier is that we have had, for years, every cancer vaccine company has been stating that they induce T cells, right? We know today that not all T cells are created equal, right? As I mentioned earlier, you have to induce the right phenotype of T cell. It has to be induced in the right quantity and also with the right killing potency. You need all 3 characteristics to generate a clinically effective antitumor response. Simply generating a T cell response does not, by any stretch of the imagination, suggest that you will induce a clinically beneficial response, right? Those 3 characteristics are necessary. I think one of the key things that the NCI looked at in selecting PDS0101 was the data that Dr. Strauss showed regarding the -- from the Phase I human study, where it was shown that PDS0101 could induce a very large percentage of CD8 -- HPV-specific CD8 T cells. So as I mentioned at the start of the presentation, one of the big limitations of immunotherapy has been specifically inducing CD8 T cells, right? So that's very important. Polyfunctionality is also very important because today almost everyone is looking at induction of interferon gamma to quantify or to demonstrate induction of T cells. However, what we know in the field of immunology today is that T cells that induce -- what we call monofunctional and induce only interferon gamma are actually the weakest phenotype of T cell. And induction of these interferon gamma inducing T cells has never correlated with clinical benefits. The polyfunctional T cells on the other hand are now very well documented to be the most powerful and potent killer T cells, right? And so for PDS, it was important in our -- for example, as published in our Journal of Immunology peer-reviewed article, characterization of these polyfunctional T cells to demonstrate that the mechanism by which Versamune works, right, which is getting everything in the lymph node and upregulating the type 1 interferons locally within the lymph node is important in providing the right cytokine and chemokine profiles at the site of required T cell activation to allow these T cells to be highly polyfunctional and powerful in their killing potency. So my assumption is that these are some of the key things that the NCI looked for in determining what cancer vaccine they wanted to move forward with. And the data that we've generated today is highly supportive that this could potentially be happening even in these very sick patients, leading to the kinds of results that we're seeing today.

The only thing I would add, Frank, is that in our Phase I study, we specifically looked at these HPV16 cells, not only for interferon gamma but specifically for granzyme B, which we know is one of the key cytokines that is associated with functional cytolytic activity of CD8 T cells that are tumor specific or antigen specific.

Very important. Thanks for that addition, Lauren.

Thank you both. So given that the triple combination had very encouraging efficacy kind of in this interim data read, how do you envision this data supporting VERSATILE-002 or how might it inform kind of the plan for VERSATILE-002 and its potential as a pivotal trial moving forward?

Well, I mean I think the data is highly encouraging, right? From what I said, this was designed specifically to induce CD8 T cells. With the data we've seen in these very ill patients, who I would regard as probably being the most difficult to treat population that we could be dealing with, if in these patients, we adhere to be inducing these tumor targeting HPV16-specific T cells, that bodes very well for the study we do with KEYTRUDA, where we, again, here, we're looking at HPV16-specific head and neck cancer. Of course, we would have to run those studies. It's important to actually get the data. But I think it's very informative in terms of the mechanism and what we could potentially expect to see in the VERSATILE-002 trial, where, again, we're looking at somewhat similar combination of mechanisms, right? We are looking for the checkpoint inhibitor. We believe KEYTRUDA is highly effective in decamouflaging, exposing the tumor to the immune system. And here, it appears that PDS0101 may be highly effective in generating those HPV16-specific tumor targeting T cells. Another important factor is the preclinical data, right? We've seen in the triple combination in our Phase I study that the preclinical data seems to be highly suggestive of what could potentially happen in humans. And again, we see the same thing with the combinations with checkpoint inhibitors. So I think based on the mechanisms and the data we've seen today, we are highly encouraged that, hopefully, we will see positive results with the KEYTRUDA trial also.

And I would just add that the NCI results have already informed our approach to VERSATILE-002, and that is specifically, we've amended the study to include this checkpoint refractory population. And importantly, we have also amended the design to be a Simon Two-Stage Design so that we can see whether or not we see threshold preliminary signals in Stage I in both the checkpoint naive as well as the checkpoint refractory patients. And again, data drives everything. So we'll be looking forward to the data from VERSATILE-002 as well as the continued data from the NCI study.

And a related question around combinations of PDS0101 with other therapeutics that could have complementary mechanisms. Has the team considered pairing PDS0101 with oncolytic virus treatment regimens or alongside other checkpoint inhibitors?

Okay. Deanne, I think I'll take that. Yes, I think in terms of PDS0101, and also not just PDS0101, our pipeline, I think one of the things I mentioned earlier was rational design of immunotherapeutic combinations, right? Really understanding what each component of that combination is bringing to the table and ensuring that those combinations or those agents are complementary in how they activate the immune system and induce that antitumor effect. So I think that's something key that we continue to look at and determine what would be the best combinations and the best approaches. And so we will continue to do that. That's a key part of what we look at when we're trying to determine what kinds of combinations to evaluate our products. So you can see, for example, we have the combination with a checkpoint inhibitor, KEYTRUDA. We've also done the combination with chemoradiotherapy based upon preliminary data suggesting that T cell induction may help those patients have better clinical outcomes. And also, we are looking at 2 -- in combination with 2 novel clinical stage agents. And so we're always looking to be opportunistic in where we think we could have significant advantages. But what was also very important in this triple combination, in oncology combination, safety becomes very important. One of the big limitations of combinations in oncology is the compounded toxicities that you could see from the agents put together. So it was very important here, and this also informs what we could potentially see with VERSATILE trial with KEYTRUDA and also with chemoradiotherapy. It was highly encouraging to see here that PDS0101 did not compound the toxicities due to M7824 and M9241, nor did it induce any new toxicities, right? So that becomes very important as we position the Versamune technology and PDS0101 as key components of new combination therapies moving forward.

Great. Given the strong proof of concept data and the flexibility of the Versamune platform, are there additional potential tumor antigens that you are considering pairing with Versamune? Or are there potential near-term additions to the pipeline that you would want to highlight?

Yes. Our pipeline, we have quite a robust pipeline. So with PDS0102, we're working -- we're including the TARP antigen, right, which addresses prostate cancer, breast cancer as well as AML. And with PDS0103, we're looking at the MUC1 antigen, which is expressed in a number of solid tumors. We specifically focused on lung, breast, ovarian and colon cancers, right? Both of these products, we've gone through extensive preclinical development and demonstrated that we can induce CD8 T cells, very similar in profile and levels to what we see with PDS0101. With PDS0103, we're currently working with the National Cancer Institute. They are performing their independent studies. We have completed our formulation development of PDS. And so with both of these programs that are targeting non-HPV antigens and going into other cancers, that would be the second stage of our development, where we demonstrate hopefully proof of concept beyond HPV-associated cancers. And the goal is to hopefully get both of these programs into the clinic in the first half of next year. So these are moving forward quite rapidly. Lauren, is there anything you would want to add to that?

I think you've covered it. The key principle is the versatility of the Versamune platform to be coupled with common tumor antigens. And again, TARP and MUC1 cover a breadth of solid tumors that we think really provide an incredible opportunity for confirmation in human clinical trials of the ability of the Versamune platforms to, again, induce these tumor-specific CD8 and CD4 T cell specific antigens that target tumors and a broader array of solid tumors. [indiscernible] as soon as possible.

We have 1 final question. And Frank, this is for you as it relates to kind of business strategy moving forward. Do you anticipate that this data set will spur discussions of partnering with large biopharma or pharmaceutical companies? And if so, what types of partnerships do you anticipate?

Well, that's addressing stage 2 of our business strategy, right? I think it's a very important question because the first piece is really to demonstrate proof of concept. There hasn't been very much success with T cell activating technologies to date. And with the data that we saw preclinically and also the early human data, makes it very important for us to demonstrate solid proof of concept, which is what we are currently doing with the 3 ongoing Phase II clinical trials. Our hope is that these would demonstrate some solid proof of concept for the technology and which would allow the second piece -- part of the strategy to take hold and be initiated. As we've said earlier, there are a large number of identified tumor-specific antigens. PDS will never have the resources to develop all of those products, right? It's going to be very important after our demonstration of proof of concept to strategically either partner with some other larger pharmaceutical companies who may have complementary products that we would like to combine to move forward or to strategically out-license the technology for specific applications or combination with specific antigens. So that is definitely a key component of our long-term strategy. And we think the proof of concept studies will be quite mature, probably sometime in the second half of next year.

Great. Thank you so much. So that concludes the questions and the question-and-answer portion of our session today. Frank, I'll turn it over to you for closing remarks.

Okay. Thank you very much, Deanne. Well, I would like to thank all participants today for your interest and time in attending this presentation and discussion. We really appreciate all the questions. It's really interesting. We have some really good questions, as Lauren was saying, real immunological discussions and thoughts going on. But we really appreciate the support of all our investors and all the communities, and we look forward to really progressing our pipeline and revolutionizing the treatment of cancer. And as we mentioned earlier, we'll be having the Research Day meeting next week, where we'll discuss our pipeline in more depth. But again, thank you very much, and we look forward to continuing to revolutionize the treatment of cancer and look forward to presenting additional data as it becomes available. Thank you very much again.

Thank you.

Thank you. That does conclude today's teleconference webinar. You may disconnect your line at this time and have a wonderful day. We thank you for your participation today.