PDS Biotechnology Corporation (PDSB) Earnings Call Transcript & Summary

Hello, and welcome to the PDS Biotechnology Interleukin-12 KOL Roundtable. [Operator Instructions] As a reminder, this conference is being recorded. It's now my pleasure to turn the call over to Dr. Lauren V. Wood. Please go ahead, Doctor.

Good morning, and welcome to PDS Biotech's Interleukin-12 or IL-12 KOL Roundtable. With me today are Dr. James Gulley and Dr. Jeffrey Schlom 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 during this webcast may 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, 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 webcast contains time-sensitive information that is accurate only as of the date of the live broadcast, April 21, 2023. 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. Please note, it's important for all attendees to be aware that PDS Biotechnology is hosting this roundtable and webcast. Each panelist is a representative of the National Cancer Institute, speaking at the request of PDS Biotech and all information presented is consistent with FDA guidelines. With me today are 2 highly distinguished cancer researchers, who is my distinct pleasure to introduce. Dr. James Gulley is an internationally recognized expert in immunotherapy for cancer. He graduated from Loma Linda University in California with a PhD in microbiology in 1994 and an MD in 1995. As part of this 8-year MD PhD medical scientist training program, he completed a dissertation on tumor immunology. He subsequently completed his residency in internal medicine at Emory University in 1998 followed by a medical oncology fellowship at the National Cancer Institute. Dr. Gulley serves within the Center for Cancer Research, also known as CCR, of the National Cancer Institute as Co-Director of the Center for immuno-oncology, the Deputy Director of the CCR and the acting Clinical Director of NCI. He has been instrumental in the clinical development of multiple immunotherapeutic agents and has led multiple first-in-human immunotherapy studies through Phase III clinical trials. He was the coordinating PI of an international trial of avelumab that led to regulatory approval and was also the PI of the first-in-human international study of a first-in-class agent, bintrafusp alfa, which targets PD-L1 and TGF beta. In addition, he leads a number of rationally designed cutting-edge combination immunotherapy studies. Dr. Gulley is the interim Editor Chief of the Journal for Immunotherapy of Cancer, also known as JITC; is the Vice President of the Society for Immunotherapy of Cancer; and serves on many national and NIH boards and committees. He has been an investigator on over 200 clinical trials and has authored over 350 scientific papers or chapters, which have been cited over 25,000 times. He has made hundreds of scientific presentations at universities or national/international meetings and it has multiple awards, including the 2010 Presidential Early Career Award for scientists and engineers, the highest award bestowed by the U.S. President on investigators early in their careers. He was also awarded the 2018 Hubert H. Humphrey Award for Service to America for contributing to the health, safety and well-being of the nation associated with the FDA approval of avelumab for merkel cell carcinoma and urothelial carcinoma and has received numerous NCI or NIH Director awards. Dr. Jeffrey Schlom is Co-Director of the Center for immuno-oncology within the Center for Cancer Research of the National Cancer Institute. He received his PhD from the Waxman Institute of Microbiology at Rutgers University. Dr. Schlom directs a preeminent translational research program in which 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 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 translation, 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. Over the next hour, we will be discussing both the history and the future of Interleukin-12, also known as IL-12, in the treatment of cancer and specifically the differentiating qualities of NHS IL-12. Dr. Gulley will open our session by reviewing the history of IL-12 and the development of NHS IL-12, which was recently added to the PDS Biotech portfolio as PDS0301. Dr. Schlom will then follow and expand on the preclinical and mechanistic studies of NHS IL-12 as well as areas of potential research moving forward. Dr. Gulley will then conclude with highlights of PDS0301 clinical studies. At the end of the presentation, we will open the discussion for a question-and-answer session. If you have a question and would like to submit during the presentation, [Operator Instructions]. With that, I would now like to turn the meeting over to Dr. Gulley. James, good morning, and welcome.

Thank you so much, Lauren. And just really delighted to be here to give you a little bit of understanding of IL-12, which I really think is a really interesting molecule, and I'm going to hope to share with you why. And then why NHS IL-12 may be a very interesting molecule to bring IL-12 directly to the tumor microenvironment where it can do its most impact. So let me just start by saying that we've known for a long time that IL-12 is very interesting. So not only can it activate T cells, which we all know are very important for immune responses in patients with cancer, but it can also activate the innate immune system, the NK cells and the dendritic cells, which can present to the T cells. So this kind of -- this Swiss Army knife of a cytokine can really help do a lot of cool things that could make immunotherapy better and could potentially turn cold tumors hot. So let's talk first about some of the early clinical development of IL-12. So this was the first in-human study of recombinant IL-12. And what you can see here is that they want to start out with a test dose of the IL-12 just to make sure that nobody had any allergic reactions or anything bad, but it's a very low dose, and then they would come in 2 weeks later with the dosing of the recombinant protein. Well, they identified 500 nanograms per kilogram as a maximally tolerated dose, but when they went to the Phase II starting with that dose, they had substantial toxicities. And so they really didn't -- they put their clinical trial on hold where they wanted to figure out why they were seeing this difference because the only thing that was different was this very low dose, test dose that they gave at the beginning. Well, it turns out when they studied this, that there is a counter-regulatory mechanism whereby when you give the IL-12 following that, you get this burst of type 1 cytokines like gamma interferon. But following that, you get an increase in IL-10. And so once they figure that out, they were able to go back and do this study safely and show that they could give this. However, what was -- and this actually shows you that with the first dose, you can get this nice increase in gamma interferon, but it's also followed by an increase in IL-10, which can stay up. And you can see here that by the seventh dose the gamma interferon in the upper right panel shows that the peak is not as high, and the IL-10 is sustained higher. So unfortunately, because of this narrow therapeutic window seen with recombinant IL-12, you really didn't get much activity in most solid tumors. There was over a decade of clinical trials in the clinic. And what we saw was some activity in some lymphomas and in Kaposi sarcoma, but really limited activity in most solid tumors. Clearly, there was a immunomodulatory effects. But the toxicities were really problematic. And the requirement for frequent repeated dosing and a desensitization really limited the effectiveness of recombinant IL-12, which had a half-life PK ranged in minutes. So really trying to get back to what we want to do with IL-12. Then there was a decision made to see -- are there ways we could take this and target this just to the tumor to limit the systemic exposure, which is causing the side effects? So there was a molecule, which we're going to explain in just a little bit, called NHS-IL12, or NHS, which targets areas of necrosis that the IL-12 was bound to. So this NHS is a larger macromolecule. And given with the subcutaneous dosing, could then have this prolonged PK and decrease the peak systemic dose of the IL-12. So we're going to share some of that data in a little bit. And then also, we said, okay, we can also monitor this IL-15 -- sorry, IL-10 gamma interferon axis in our clinical trials. So let me just walk you through this. If you go and look at the cartoon in the lower right-hand corner, you can see this is the NHS-IL12 molecule. You can see that there are 2 IL-12 heterodimers fused to each one of the heavy chains of the antibody and that the junction between the antibody and the IL-12 has been deimmunized. Now on the antibody targeting portion, this really targets areas of tumor necrosis, where the cell membrane integrity has been lost and DNA has been exposed. And this happens in virtually all solid tumors. And what you can see is that it will bind to the DNA, either double-stranded or single-stranded DNA and the DNA histone complexes. And the nice thing about this is this can be then given subcutaneously to allow for us a slower sustained release to limit the peak dose of the IL-12 and enhance the pharmacokinetics and potentially pharmacodynamics. There is no antibody-dependent cellular cytotoxicity or complement-dependent cellular cytotoxicity with this agent. So this slide just depicts the fact that not only do you get CD8 T cell activation and NK cell activation as we talked about before, but also you get this CD4 naive T cells can be converted into the TH1 CD4 cells for optimal health in addition to the activation of the dendritic cells in the tumor microenvironment, which is going to be quite important. So one other thing that came from Hagen [ Keswick's ] Group and Emery was that really -- while you got activation of tumor-specific T cells in the draining lymph nodes to really get the best activity, you needed to have co-stimulation of those CD8 T cells in the tumor microenvironment. And this could come from the activated dendritic cells that the IL-12 can activate or directly from the IL-12 itself potentially. I'm just going to share this last slide before I turn this over to Dr. Schlom, and show you in mice that when you give the NHS-IL12, as you can see in the top panel, it will localize to the tumor within 72 hours and can cause up-regulation of the -- of inflammation within the tumor microenvironment. Now if you compare that with an antibody that also has an IL-12 bound to it but targets in [ oncofetal fibronectin ], this BC1 antibody, you can see there's much less binding to the tumor. So this is a really good way to get to the tumor and is non -- it is not -- it's tumor agnostic. So you can have multiple different tumor types targeted by NHS-IL12. In addition, if you look at patients treated with a similar antibody, the parent antibody to NHS, you can see that there is lighting up of this lung lesion, this lung tumor in this patient. This is a patient treated in China where this tumor necrosis targeting antibody, TNT, is being given with a ready nucleide. But the -- and this is not a fully human antibody, but what we are using though is a fully human antibody. So next, I'm going to turn this over to Dr. Schlom.

Thank you, James. What I'd like to do is talk to you about the potential use of NHS-IL12 or PDS0301 in what we now call this post checkpoint therapy era, where checkpoint inhibitors have been approved and are useful in approximately 20% of patients with solid tumors, but which leaves approximately 80% of solid tumors needing more effective therapeutic regimens. And in the last several years, we've learned an enormous amount about the human immune system and the tumor microenvironment and the complexity of both of these. And this cartoon, which was published in the Journal of American Medical Association, that Dr. Gulley and I put together, really indicates that the various ways that one can achieve an effective immunotherapy. And this would involve, a, the potentiation of an immune response, the induction of an immune response, the reduction or elimination of immunosuppressive entities and the alteration of the tumor microenvironment to make it more amenable to immune cell attack. So you've heard about the various properties of IL-12 and NHS-IL12, and now I'm going to talk about exploiting these properties in combination therapies. You see in the left part of this slide from Dr. Gulley, but I want to draw your attention to the immunohistochemistry in the middle panel, where you can see targeting of necrotic areas in the tumor by NHS-IL12, and just to let you know, and you'll see this over and over again, on the right-hand panel in 2 models, NHS-IL12 outperforms murine IL-12 in terms of monotherapy as a single [indiscernible]. But we spent a lot of time learning how to use NHS-IL12 and indeed the vaccine developed by PDS, PDS0101, which is an anti-HPV therapeutic vaccine. And you can see in the left-hand panel, if you just use the vaccine alone, PDS0101, you -- 3 out of the 10 animals have displaced of antitumor activity; 6 out of 16 with NHS-IL12. But in combination of the 2, you see 10 out of 16 animals with antitumor activity. And then when 1 adds in this checkpoint inhibitor TGF beta inhibitor by functional, the antitumor activity becomes even stronger. And this -- when we took this apart, you can see that the number of T cell clones in the specific clones in the tumor microenvironment increases with -- as you add on each of these 3 modalities. And this is shown in another study where instead of the bintrafusp alpha, a checkpoint inhibitor was used. And you can see on the immunohistochemistry on the right, you get much greater infiltration of the tumor when the vaccine, NHS-IL12 and the checkpoint inhibitor are used together. But I want to talk about the unique properties of NHS-IL12 and tumor targeting and how it can be exploited. In this case, with standard of care, docetaxel. On the panel on the left, you can see on the bottom left, the areas circled in the tumor are the areas of necrosis. And this is quantitated in the middle panel where you can see that docetaxel will increase necrosis in the tumor. And in the right-hand panel, you can see the binding in the tumor of NHS-IL12 correlating with the level of necrosis. Now how does this translate into antitumor activity? It translates into extremely good antitumor activity. You can see the survival curve on the upper right. By the way, on the left-hand panel, you can view -- it's probably too small to see, but recombinant IL-12 doesn't work in this area. But on the bottom right, I want to show you the profound effect that NHS-IL12 in combination with docetaxel has in terms of enhancing certain genes such as granzyme, which are, of course, very important for [indiscernible] activity of NKs and T cells. So we have really mind how these agents work together. Now in this era of checkpoint inhibition, where there is many, many tumors are resistant to checkpoint therapy. We've developed models that can simulate that by knocking out checkpoint in the tumor. And in this model, you can see on the left-hand panel, there is no PD-L1 in this particular mouse tumor, yet this combination of PD-L1 works -- with docetaxel works extremely well in the absence of any checkpoint to target. I next want to talk to you about another way of exploiting the uniqueness of NHS-IL12. And this is using this in combination with an epigenetic modifier of the tumor. In this case, an HDAC inhibitor called entinostat. Now there are 5 HDAC inhibitors approved by the FDA, but they're all in heme malignancies, and none has been approved thus far in solid tumors. But there's more and more evidence coming out that combining that every genetic drugs, such as HDAC inhibitors with other therapies, can enhance therapeutic efficacy in solid tumors. And I want to show you some of the data, I think my estimation is the strongest data yet of exploiting epigenic modifiers with the use of NHS-IL12. And this was shown in 2 studies recently published in this one in Nature Communications and the other in SITC. And this just goes to show you -- I'm touching the surface of this data, but it just goes to show you that the NHS-IL12 by itself in this model has minimal therapy; the epigenetic modifier, HDAC inhibitor, has minimal therapy but the combination of the 2 has profound antitumor effects. And this is just 1 cycle of each. And you can see on the left, the antitumor. In fact, on the right, the survival. And the survival in the far right is the -- shows that the -- there was immune memory when those hosts would challenge more tumor. And my last data slide shows you that we've looked at 3 very, very difficult models. These 3 models shown up on top are totally resistant to checkpoint therapy. You can see that in all 3, the checkpoint is in blue. They do not respond at all to checkpoint therapy, but they responded very well to the combination of NHS-IL12 with the epigenetic modifier. Now in addition to these models being resistant to checkpoint, they also harbor defects in antigen-presenting machinery and MHC, which is a major area of problems. So we overcame both of these areas of potential immunosuppression. And again, I'm just touching the surface of the mechanism of how this works. But just to show you on the panels of the bottom left, we see a switch in the macrophages from the bad macrophages [ M2 ] to the good ones [ M1 ], a great activation of CD8 T cells and a dramatic increase in the CD8 to T regs regulatory T cells in the tumor microenvironment, ratios we've never seen before, 300:1 in these ratios. And you can see in the immunohistochemistry the profound effect it has -- this combination has on moving immune cells, both CD8 and CD4 cells to the tumor microenvironment. So I'm going to stop there and just to reiterate that we think we know now how to exploit the different areas of that need to be exploited in -- for an effective cancer therapy and NHS-IL12 or PDS0301 appears to be an integral component of that strategy. Thank you.

Great. Thank you so much, Dr. Schlom. James, we'll turn it back to you.

Yes. So thank you so much, Dr. Schlom. That was really wonderful. And so I just want to go through some of the clinical data now that we have with NHS-IL12. This was the first in human study that was published in clinical cancer research, and we did come up with a maximally tolerated dose. This was a study that was designed as initially a Phase I dose escalation study, we did have single ascending dose as well as multiple ascending dose. So basically, only 1 injection given for the single ascending dose study in a 3 plus 3 dose escalation. And then eventually, the FDA allowed us to do a multiple drug -- multiple ascending dose so you could give multiple injections over time so long as the patient remains stable or better. And the dosing schedule is given at every 4 weeks. We'll come back and talk about that in a little bit, too. And it was given subcutaneously, and there was a 6-week dose-limiting toxicity period. The primary objective was safety where we were looking at the maximally tolerated dose and secondary objectives that we'll talk about included in the pharmacokinetics and pharmacodynamics. So you can see here in this panel that there were 22 patients total treated with a single ascending dose that only got 1 dose of agent. And then you can see there's 37 treated in the multiple ascending dose. The maximally tolerated dose was 16.8, as you can see here, micrograms per kilogram. With the dose-limiting toxicities largely being liver enzyme abnormalities, but patients were also in the upper dose levels were starting to have the systemic side effects of IL-12 such as low-grade fevers, they're transient and the liver transaminases were also transient. So here is the pharmacokinetics. So unlike the recombinant IL-12 where the half-life is measured in minutes, you can see an improved pharmacokinetic profile here. And you can see that it was similar both after just 1 dose as well as on subsequent dosing, and there is intrapatient variability. And you can see that there was a trend for increased exposure with increasing dose, as indicated here. Interestingly, the pharmacodynamic study showed that there was a substantial increase in gamma interferon, the type 1 cytokine that's involved with activation of immune cells, especially at the higher dose levels. And just like in the previous studies, this was followed by an increase in IL-10. What's also interesting is that by day 14, these would come down to baseline. And you can see that this pharmaco -- in the left, you're seeing just after 1 single dose and in the right, you're seeing with multiple doses. And you can see that you're getting similar types of increases in the cytokines in -- with multiple doses as you did with the first dose. So we also then said, well, if everything is back down to baseline by day 14, can we give this safely every 2 weeks instead of every 4 weeks, and that could open up safety data for us to give this every 2 weeks, every 3 weeks or every 4 weeks. And so we did a small addition to the study, where we enrolled another 13 patients, and we found that you could treat at both 12 micrograms per kilogram as well as 16.8, and there was no -- the maximally tolerated dose was not exceeded. And I'm going to share with you some of the data from that study. So what you're seeing here is the data from the patients that were evaluable. And the patients are listed in the rows and in the top 6 rows, you -- 5 rows rather, you have those patients that had progressive disease. And in the bottom 7 rows, you have those patients with stable disease. What I want to draw your attention to is that those patients that had low baseline IL-12 were the higher levels of the nonclassical myeloid cells that are more immunosuppressive. Those patients actually didn't -- those were the patients that had the progressive disease, whereas those patients that didn't have that had better outcome -- clinical outcomes. In addition, those patients who had increased -- those patients with progressive disease had decreases in their NK cells or activated NK cells and decreases in their CD8 central memory and effector memory cells. Whereas, those patients who had a better clinical outcomes had increases in both NK and CD8 cells. So this is a study that I just want to mention to you also where we looked at the immune correlates. And what you can see here is that there is a difference in the dose. So if you come in with a lower dose, you don't get as much activation of the NK T cells or the NK cells, you don't get as much activation of the of the CD8 cells. And this was data done by Dr. Donahue and Dr. Schlom. I want to switch gears and talk briefly about 2 different agents because I'm going to be talking about a combination clinical trial. And so you heard both Dr. Schlom and Dr. Wood talk about the Versamune PDS vaccine that targets HPV. The idea here is you give the vaccine as an injection subcutaneously and you can get the vaccine either going to the draining lymph nodes or being picked up by the antigen presenting cells, such as the dendritic cells and then traveling to the draining lymph nodes where they interact with the T cells, can cause activation of CD8 T cells as well as CD4 helper T cells. And these activated T cells can go travel anywhere in the body, recognize the tumor and attack the tumor. In addition, here is data from that vaccine, this PDS0101 that shows that you can get really good immune responses. And what you're seeing pretreatment in the dark bars compared with post vaccine. And you can see there's a big increase in all of these patients following vaccination in their HPV-specific T cells as measured by the gamma interferon ELISpot assay. Similar data we've seen with Granzyme B and really like many other vaccines, there is only mild transient injection site reactions without systemic toxicity. One other agent that I want to mention to you is the agent that Dr. Schlom mentioned briefly, bintrafusp alfa. We did the first in-human study of this agent at the NCI. And what it does is it targets PD-L1, like many other immune checkpoint inhibitors. However, what's unique about this one is that on the Fc portion of the antibody that has 2 TGF-beta receptor 2 molecules that serve as a trap for TGF beta. So it can sequester the TGF beta decreasing its immunoregulatory influence within the tumor microenvironment. So what we did was we looked at this, and you saw this data really similar data from what Dr. Schlom showed, same experiment. You can see that in the panel in the upper left in the triplet where you have the PDS0101 and the NHS-IL12 and the bintrafusp alfa, you can see the best outcomes in terms of tumor weight per mouse. And as Dr. Schlom already shown you, those mice with a tumor volume of less than 300 millimeters cubed, you can see that by far, the best group was the triplet. And below, you can see that also in the individual plots of over time, you can see that was the best outcome, too. So this triplet appeared to be quite active in preclinical models. And so we designed a clinical trial to mirror that. And in this trial, we gave the bintrafusp alfa every 2 weeks. The NHS-IL12, we gave it 2 different doses, either 16.8 or the 8 micrograms per kilogram. And the PDS0101 vaccine was given every 4 weeks also. The primary endpoint was objective response rate, and secondary endpoint was safety. I just want to share with you the top line results from this study. So what we saw was that you can get good responses as shown in the waterfall plot despite the type of HPV-associated malignancy. So we saw responses in cervical cancer, vaginal vulvar cancer, anal cancer and head and neck cancer. In addition, what's interesting about what we're seeing here is that those patients that got the higher dose of the NHS-IL12, that seems to be -- they seem to be more of those patients having responses than patients with a lower dose of NHS-IL12. So that may be critical moving forward. In addition, we saw patients that had responses, whether they were immune checkpoint inhibitor naive, as you can see in the blue, and virtually all of those patients had responses, all but one. And you can see even in the immune checkpoint inhibitor refractory setting, where we would expect about 5% or less response rate to immune checkpoint inhibitor -- subsequent immune checkpoint inhibitor, you're seeing good reactivity and response rates in those patients that -- in this high unmet clinical need population. I'd just like to end with one thing, and that is the NCI publications involving NHS-IL12, you can see here. In addition, there are other ongoing clinical trials of NHS-IL12 at the NIH clinical center and there are 8 of those studies that are currently ongoing. So more to be seen with this agent as we move forward. And with that, I'll turn this back over to Dr. Wood.

Thank you again, James, as well as Jeff, for those excellent overviews, both preclinically and clinically. Before we get to our question-and-answer opportunities. I just want to highlight, I love your description, James, of NHS-IL12, PDS0301 as the Swiss Army knife cytokine. I think that is really an apt and appropriate discussion given the fact that it's a cytokine that can bridge both innate and adaptive immune responses by engaging antigen-presenting cells, NK cells, NK T cells as well as T cells, including both CD4s and CD8s. So that's something to keep in mind. The other thing that I would like to highlight from Jeff's presentation is the fact that in the combination studies, I was really impressed with the fact that we see activity of PDS0301 in combination with some standard-of-care agents as well as investigational epigenetic agents, but we know some of them have been approved. And I think that kind of highlights the potential outside of just giving PDS0301 in combination with other immune-based agents because of its specific ability to target tumors because it is targeting DNA histones and necrosis within the tumors, which we see in association with radiation therapy, chemotherapy or even immune-directed therapies that results in cytolytic killing. So what I'll do is I will now open the question-and-answer session. And okay, I don't see any in the bottom of my screen. Hold on, let me look and see.

[Operator Instructions] Back over to you, Dr. Wood.

Okay. One of the questions that has come in is, again, several companies have recently halted their IL-12 programs due to disappointing results. And why do we anticipate that PDS0301/NHS-IL12 is going to be successful where others have failed? So Dr. Gulley has given us great insight in terms of the early limitations of the first-generation recombinant IL-12 products. The very short half-life, the very high peak intensity levels that were associated with the very significant adverse effects. I think what's important to highlight and what's already been reinforced by Dr. Gulley's presentation is that this NHS-IL12 is distinctively different from the early generations of IL-12. It specifically is a fully humanized immunocytokine. It has on it an antibody that again, as he demonstrated both visually in the preclinical studies as well as in some human imaging that the antibody attached to the NHS-IL12 specifically binds to DNA that's been exposed through breakdown of cellular membranes, which happens with tumor necrosis. So as a consequence of that, we see lower peak systemic levels of cytokines. It's delivered subcutaneously. So we have a much more prolonged half-life of days, an average of approximately 8 days for the 16.8 microgram per kilogram dose. And then we also know that because of its innate activity as an IL-12 immunocytokine that it activates circulating NK T cells and T cells not only in the circulation, but has been demonstrated in the local tumor microenvironment. And those are the issues that we are really trying to address and move to the next level with immune-based therapies. As Dr. Schlom highlighted, we know that immune checkpoint inhibitors only work in about 20% of patients. So what we've got to do is be able to get to more potent and direct antitumor activity at the site. And that's one of the possibilities, I think, that has clearly been demonstrated with IL-12. James or Jeff, would you like to comment?

I would like to add to your comments, which I agree with, that the use of these cytokines may be -- there may be monotherapy activity in some tumors, but they're also are great opportunities as we tried to show here with combination approaches. And I think that, that could be a really a key differentiator for this agent and the potential -- obviously, I wasn't involved in the other studies with NHS -- sorry, with IL-12. But I think that IL-12 can really prime the immune system to do the right thing, but you still need to guide it and direct it. And I think that with adding in a vaccine to guide the immune system, adding in an immune checkpoint inhibitor to allow those immune cells to be functional in the tumor microenvironment really sets us up for a good combination approach. In addition, it can be combined with standard of care. And we have ongoing studies looking at that, and Dr. Schlom showed some beautiful preclinical data showing the power of those types of combinations.

Great. I understand that we do have a few questions on the phone. So let's move there because we want to give our viewers the opportunity to ask their questions. So Kevin, I'll let you control the questions, and please.

Our first question today is coming from Louise Chen from Cantor Fitzgerald.

So I had a question for the panel here. I wanted to understand what you think is the best development path forward for your triple combo product? And how do you want to design that to show a competitive product in the space? And the second question I wanted to ask you was you did make some interesting points on the HDAC and solid tumors. And I'm curious if we'll see more data over the next 12 to 18 months to support those hypothesis?

So Louise, I'll start off, and then I'll let James and Jeff weigh in, in terms of moving forward with the development of the triple combination. I think from the data that's presented been presented here today, I think we clearly want to move forward with a triple combination in the ICI immune checkpoint inhibitor refractory population. We know that's where there's a huge unmet medical need. We've gotten excellent scientific insights in terms of why that's a very rational combination in this group. From the NCI's preliminary studies, we clearly see that we can see induction when we deliver PDS0101, PDS0301 as well as a checkpoint inhibitor. Even in these refractory patients, we are seeing induction of HPV-16 specific responses despite heavy prior treatment. And in addition to objective responses with the combination, we are also seeing differentiating survival. And maybe I'll let James speak to that as well.

Yes. So Louise, thank you so much for the question. And I think that -- and we can talk also about the HDAC. Let me just mention your question about the HDAC inhibition. We do have an ongoing clinical trial looking at the combination of an immune checkpoint inhibitor plus entinostat, which is the HDAC inhibitor that Dr. Schlom showed you as well as NHS-IL12 and that study is ongoing, and we hope to be able to present data in a future meeting. I'm not sure exactly when we're going to have our full data set, but that could be within the 18 months that you talked about. I think that, that particular combination is quite interesting, and there may be opportunities there, as Dr. Schlom mentioned, for other epigenetic modulators to combine with immunocytokines and really take advantage of the genes that are repressed in tumors that may include mutated antigens as well as antigen-processing machinery that could make the tumors much more immunogenic and much more visible to the immune system.

[Operator Instructions] Our next question is coming from Kalpit Patel from B. Riley Securities.

This is Andy Fleszar on for Kalpit Patel. Given the unique TGF beta tracking attribute of bintrafusp alfa, how is switching to a commercially available checkpoint inhibitor impact the activity of the triple combination? And any potential synergies with NHS-IL12?

Great. Thank you for that question, Andy. That's an excellent question. And what I'm going to do is I'm going to turn this over to Dr. Schlom, who has done additional preclinical studies substituting other checkpoint inhibitors other than bintrafusp alfa in the combination and maybe you can comment on that?

Yes. We started off with bintrafusp alfa. But subsequently, it appears that a PD-1 and anti-PD-1 will work just as well with the combination of NHS-IL12 and the HPV therapeutic vaccine. So that's just evolved.

I think that also is an important testament to really doing excellent preclinical scientific vetting as thoroughly as possible in replete models, in ICI refractory models, understanding combination specific agents as well as with other multiple agents within a class to really bet the activity of these combinations. So we really do appreciate that work that you've done, Dr. Schlom. And thank you for that question, Andy.

There are no further questions over the phone. I'll turn the floor now over to you, Dr. Wood.

Okay. Great. We still have a few minutes. I do want to highlight just a few more things that were presented by Dr. Schlom, specifically the fact that when you see NHS-IL12 co-delivered, one of the transformations that you see in the tumor microenvironment is this real increase in CD8 T cells, an impressive increase in the ratio of CD8 T cells to T regulatory cells. That's been observed with NHS IL-12, but it's actually also been observed with PDS0101 in our preclinical studies in the TC-1 tumor model where there was also increased activation of CD8 T cells and an increase in this CD8 to T reg ratio. So I think that also might help contribute to the fact that we see enhanced antitumor activity where we see replication of the same kind of activities within the tumor microenvironment with each component of a combination regimen contributing. I think it's critically important, and maybe James could comment again in terms of the potential, since PDS0301 is a tumor-targeting cytokine, this potential to transform cold tumors and make them hot, because -- maybe you can speak to some of the cold tumors that are out there because there's a fair number of them. And what we really desire to do in the field is move the needle so that we can get to more than 20% of patients responding. We'd really like to see at least 50% of patients respond to our immune-based therapy.

Yes. So great point. And that's why having the tumor targeting ability for this NHS-IL12 is really important. So just as a refresher, not only do you get these dendritic cells activated in the tumor microenvironment, which are really important as there's always dead and dying tumor cells there even as new ones are growing, these can be -- these dead and dying cells can be taken up by these antigen-presenting cells. It causes activation of the CD8 cells and NK cells. It also takes those naive CD4 cells and makes them a TH1 driven so that they can be good helper cells and really drive this immune response. In addition, because of the activation of the NK cells and the T cells, you're going to get more gamma interferon there, which is going to cause upregulation or your antigen processing machinery or MHC. So all of this really sets up the tumor microenvironment for a wonderful immune response that you can then potentially augment by blocking these negative checkpoints like PD-1 or PD-L1.

Great. We've had another question come in, and I'll direct this to you, James. Can we expect further data update on the triple combination at ASCO or another conference in 2023?

There will likely be a publication that will be put together this summer. I'm hoping that it will be put together this summer, and that will be hopefully out before the end of the year. Absolutely.

Great. That's wonderful. Are there any other questions, Kevin, I just want to check with you, in case someone has come on the line and might have an additional question.

Sure. Not this time, Dr. Wood.

Okay. Well, again, I want to thank everyone who has dialed in this early morning. I especially want to thank my esteemed colleagues and collaborators, Dr. James Gulley and Dr. Jeffrey Schlom of the National Cancer Institute for joining us today. I hope that we've been able to provide you some of the insights in terms of the long-standing efforts to really get to a better immunocytokine through excellent science, both preclinical and clinical that is resulting in better outcomes for patients. That concludes our program today. Again, thank you both for your insights today, PDS Biotech is committed to advancing the study of Interleukin-12 and specifically PDS0301 to provide physicians and patients with a potentially effective treatment as quickly as possible. An audio recording of today's session will be available on the PDS Biotech website for 90 days. You can access that recording at www.pdsbiotech.com. Again, thank you for your interest and participation in today's session. Thank you, everyone, and have a great day and a great weekend.

Thank you. That does conclude today's teleconference and webcast. You may now disconnect, and have a wonderful day. We thank you for your participation today.