Hello. Thank you for joining this HOOKIPA webinar, Advancing Novel Immunotherapies. In a moment, you will hear a presentation from HOOKIPA CEO, Jörn Aldag, and Translational Research Director in Gynecologic Medical Oncology at Memorial Sloan Kettering Cancer Center, and co-investigator in the HOOKIPA study, Dmitriy Zamarin, and CMO and Global Head of R&D, Igor Matushansky. Following the presentation, there will be an opportunity for you to ask questions, and we'll provide details on how you can do that at the end of the prepared remarks. Now to the presentation. Jörn. Welcome, everyone. We are excited to update you on our great progress in our efforts to advance novel arenavirus-based immunotherapies in cancer. We show early proof of concept of our HPV cancer program, based on which we believe to have opened the door for many more cancer therapies to come. I'm incredibly proud to be here today to report on our first immuno- oncology trial of HB-200 for patients with HPV16-positive cancers, with a focus on data from head and neck patients. This is a moment to say thank you to all those patients who've been cohort trial therapy, clinical investigators who helped advance the trial, and all my collaborators at HOOKIPA who have been working with much enthusiasm to reach this point. This is also a moment to remember that just five years ago, in 2016, we set a bold vision to develop our novel arenavirus technology to create a new approach to cancer immunotherapy. Cancer researchers have established that a significant quantity of potent, non-exhausted CD8 T cells in and around tumors were paramount to control or shrink tumors. Many cancers cannot be cured due to a lack of tumor antigen-specific killer T cells. Many therapies do not work effectively in patients who lack such T cells. This is the area of our strength. Arenavirus, known for their ability to supercharge the natural immune defense mechanisms by activating large numbers of incredibly potent target-specific T cells, seems to be the ideal tool to overcome the challenge of too few potent and specific T cells. We committed our company to address this urgent need for people fighting cancer. Data from our ongoing phase I study was selected for an oral presentation at ASCO. This is great recognition by the oncology community of HOOKIPA's still nascent approach to treat cancers. We believe we are at the beginning of establishing the potential for HOOKIPA's unique platform to redefine success in effective cancer treatments. Next slide, please. Please read our safe harbor statement. Today, Dr. Ho from the Memorial Sloan Kettering Cancer Center delivered at ASCO the first report of the safety tolerability and preliminary anti-tumor activity of HB-201 and HB-202, an arenavirus-based cancer immunotherapy in patients with HPV16-positive cancers. In this talk, I will use HB-200 to refer to 201 or 202 separately or together. Next slide. The ASCO oral presentation is based on data from our ongoing phase I trial. We're in early stages, and we see great potential given the results reported to date and that we'll review further today. We were bold in our design of this trial. While many new compounds are investigated in combination, we intentionally started the HB-200 program evaluating our therapy as a single-agent monotherapy, so no combination with another immune therapy or a co-stimulatory agent, and we did this in heavily pre-treated patients who have progressed on standard of care, including checkpoint inhibitors, the most difficult of all situations which we tackled here. HB-200 is a phase I trial still in dose escalation. We expect to define our phase II dose by year-end 2021. We'll start phase II studies with and without checkpoint inhibitor in Q1 of 2022 and intend to file for BLA on the basis phase II data. Next slide. The HB-200 trials has shown great early results. Here is some perspective. HB-200 induces an unprecedented number of circulating T cells to become target-specific to seek their enemy cell. Notably, up to 40% of all these T cells become antigen-specific. Historically, objective response rates to single-agent active immunization therapies in third-plus line head and neck cancer patients have been zero. HB-201 shows an encouraging preliminary overall response rate of 18% as a single agent. Still ongoing median progression-free survival of 3.5 months is longer than progression-free survival of CPIs, checkpoint inhibitors in second line head and neck cancer. Next slide. Let me summarize our three most important takeaways. HOOKIPA's killer T cell platform generates unprecedented T cell responses, at times converting almost half of the CD8 T cell pool to be specific for the desired cancer target. Second, HB-200 is the only systemic and intravenous active immunization treatment with clinical efficacy as a monotherapy in cancer patients who progress on standard of care, including checkpoint inhibitors. Thirdly, based on the translational safety and efficacy results seen to date, we believe our versatile platform has the potential to address the major challenge of cancer immunotherapy, which is a lack of T cells at the tumor site and inability to turn a cold tumor hot. There is a myriad of applications where this capability of generating these kinds of T cells can be really useful across a broad range of tumor types. Next slide. Dr. Dmitriy Zamarin, Translational Research Director in Gynecologic Medical Oncology at Memorial Sloan Kettering Cancer Center and co-investigator on our ongoing phase I study, will talk to you about why T cells matter and how they should be seen in historical and comparative context. Igor Matushansky, HOOKIPA's Chief Medical Officer and Global Head of R&D, will offer additional insights into the data presented at the ASCO oral and will provide more important translational data, including early biopsy results. I will briefly discuss the path forward. Dmitriy, please take over here. Next slide, please. All right. Well, thank you, Jörn, for the kind introduction. As Jörn has mentioned, my name is Dmitriy Zamarin. I'm a Translational Research Director in Gynecologic Medical Oncology at Memorial Sloan Kettering Cancer Center, and my clinical and preclinical research actually focused on cancer vaccines and viruses. I'm also a co-investigator on this ongoing phase I HB-200 study. Over the next several minutes, I'm going to provide a framework in which to evaluate the T cell immunogenicity data as well as the clinical data that were presented earlier today at the ASCO presentation by my colleague, Dr. Alan Ho. Next slide, please. Recognition of cancer by the immune system is dependent on activation of a specialized immune cell called a T cell, but CD8 T cell, is also known as killer T cell, playing a central role. These T cells normally recognize foreign antigens that are associated with viral and bacterial infections or abnormal and mutated proteins that can be associated with cancer cells. These proteins are collectively known as antigens, and relevant to today's talk is actually viral proteins that are associated with cancer cells that serve as antigens that we're trying to target. Activation of CD8 T cells requires recognition of the specific tumor antigen that's presented on another specialized immune cell called antigen-presenting cells, shown in blue here. These activated T cells then proliferate or expand and then migrate to the site of the tumor through the peripheral vasculature, and it's at the site of tumor, obviously, where they mediate killing of the cancer cells. Also, upon infiltration of the tumor, they become called tumor-infiltrating lymphocytes or TILs, which is a term that you commonly hear. Next slide, please. Mechanisms of immune resistance can be present at multiple levels. Cancers are smart. They have found ways to evade the immune response, which allows them to grow. This immune resistance can actually start with the lack of the ability of the immune system to recognize these tumor antigens. Downstream, it may also include multiple other mechanisms of resistance even to the established immune response. This includes inactivation of T cells through a number of mechanisms that lead to T cell inactivity or exhaustion, and also through generation of a very immunosuppressive microenvironment. This can decrease the effectiveness of the T cells that can actually penetrate the tumors. Clinically, once the cancers are able to evade the immune response, they grow and they metastasize and spread to other areas. Next slide, please. The solution to this evasion of the T cell control is really the basis of active immunization therapies, also known as cancer vaccines. Active immunization therapies are designed to wake up the immune system by either boosting the pre-existing responses to the cancer antigens that these patients may already have or by development of new CD8 T cell responses to the cancer antigens. These responses are then mediated through CD8-dependent killing mechanism that I have described several minutes ago. Next slide, please. Given that HPV-associated cancers such as cervical and head and neck cancers, as well some others, express these foreign viral antigens, there's a high rationale for targeting of these antigens using active immunization. We have recently summarized the progress of immunotherapy for HPV-related cancers in this review that was published in "Cancer Discovery" several weeks ago. In general, while the strategy has been shown to be effective in elimination or control of pre-cancerous lesions, also known as pre-neoplastic or pre-invasive disease, the successes in the advanced or established cancer setting has unfortunately been relatively marginal, specifically for the single-agent vaccines. However, there is some positive data that are emerging for these active immunization strategies against cancers when these vaccines are used in combination with other agents, most frequently immune checkpoint inhibitors. Next slide, please. Let us now consider the process of how this type of active immunization therapy can work to create a highly specialized killer T cell army that can control cancer. There are three key steps to generation of tumor-specific T cells, as I have highlighted before. First, the T cells need to recognize and become activated in response to the specific tumor antigen, which is expressed by the cancer. Next, these antigen-specific T cells need to expand or proliferate, shown as multiply on this slide. Finally, these tumor antigen-specific T cells need to travel or migrate to the site of the tumor, where they need to infiltrate the tumor in order to mediate their killing. I want to cover how these three critical steps apply to the HB-200 data that we'll see in the ASCO presentation today and that Igor will go over later. Next slide, please. How do we know whether a vaccine is generating a cancer-specific T cell response and whether these T cells are capable of killing? There are a number of assays that have been developed to assess the T cells functionality, and most of these assays involve taking the T cells out of the patients, usually out of peripheral blood, and then assessing, first of all, the overall percentage of the T cells that react to the antigen, but also their overall functional status or fitness. The way that the T cells fitness for killing is measured is by assessing T cells for specific markers. The two most common markers that are frequently used are cytokines called interferon gamma and tumor necrosis alpha. Those are proteins that are secreted by activated T cells. T cells, which become positive for these markers in response to the antigen, are very fit for killing, and the more markers they express in general, the better. This is called polyfunctionality. On the right side of the slide, you see these pie charts that are summarizing the assessment of these markers in the patients who received a single dose of HB-201 or HB-202 vaccine. They do show that these vaccines are capable in generating high-quality CD8 positive T cells, which are fit for killing. You can see that the number of these are double or even triple positive T cells. We know that they're good T cells, and they should be able to kill cancer cells. Next slide, please. Aside from the functionality of the T cells, the number is actually very important. What is the overall number or quantity of the antigen-specific T cells that could be generated by such an approach? This number, as I mentioned, is a key determinant of efficacy and is frequently used in vaccine studies as a measure of immunogenicity. We express the quantity as a% of killer T cells, which are specific for the tumor antigen relative to the entire population of the killer T cells in the patient's blood. How many is sufficient? We don't really know the number precisely. We know that the more, the better. In most of the vaccine studies, if you can achieve a level of 3%-5%, the vaccine is considered to be a good vaccine and capable of generating enough T cells to mediate the killing. Another important note to highlight is that when we measure these T cells, we need to measure them directly from peripheral blood rather than just taking them out of the patient, expanding them, and then seeing whether we can identify them. Obviously, the latter strategy can identify the T cells that are specific for the antigen, but it tells us nothing about their relative predominance in peripheral blood. The direct measurement directly from the peripheral blood is more important. On the right side of the slide, these HB-200 phase I immunogenicity data show that as a single vector, HB-201 can indeed generate HPV-specific CD8 T cell responses, and these T cells represent approximately 4% of the total CD8 positive T cell pool. That's great. As I highlighted before, 4% is great. Not as exciting. What was more impressive is this T cell response generated when the two-vector approach was used, using the HB-202 and HB-201. This resulted in antigen-specific T cells representing 40% of the total CD8 positive T cell pool. In other words, 40% of all peripheral blood CD8 positive T cells are now recognizing vaccine antigens. This level of reactivity is really unprecedented, I mean, larger than anything that has been previously reported for active immunization types of strategies. If this level of HPV reactivity does not generate tumor killing, then there's probably no future for HPV targeting. Hopefully, that's not the case. Next slide, please. The generation of these HPV-targeted T cells in blood is certainly a good thing, but the T cells are useless unless they actually can make it into the tumor where they mediate the killing. This is a very important last step. It has been demonstrated that presence of the CD8 T cells in the tumor can correlate directly with survival for multiple solid tumors, including HPV-positive head and neck cancers. It has also been associated with response to immunotherapy. To assess whether the T cells actually make it into the tumors are typically stained for the presence of CD3, which is a general T cell marker, and also CD8, which is a marker of these cytotoxic T cells. Here, the HB-200 biopsy data from a single patient for the biopsy obtained pretreatment and post-treatment clearly demonstrate that in this patient that had cold tumor that had absolutely no T cells, therapy with HB-200 has led to tumor infiltration with T cells. Next slide, please. To sum up the phase I data that have been generated so far. They do demonstrate that these HB-200 arenaviral therapies are capable of two major things. First of all, the antigen-specific T cells that can be achieved with this type of vaccination are historically unprecedented. Secondly, there's actually evidence of tumor shrinkage that has been observed with the vaccine as a single agent, something that has not really been seen with the prior vaccine studies. Although the data are early, I believe that there's probably a causal relationship between the T cell levels that we're observing with this vaccination strategy as well as the efficacy that we have seen to date. Furthermore, given just my general involvement in the vaccine field, if this level of systemic response to HPV active immunization therapy does not result in clinical efficacy, as I mentioned before, there's probably no HPV vaccine will result in clinical efficacy. From scientific perspective, this will be a very important answer for us to get. Although I do certainly hope that this strategy will be effective and will open up the doors for more studies and combinations, and early data so far seem to be suggestive that's going to be the case. I'm going to stop here. I'm going to turn the presentation over to Igor now, but we'll be happy to answer any questions later. Great. Well, thank you, Dmitriy, for putting some of our data in a broader perspective. Allow me to further expand on the next slide with additional detail on some of the themes that both Igor and Dmitriy introduced. I'd like to speak to you about the following three points. One, does our clinical data confirm the arenavirus mode of action of driving unprecedented antigen-specific T cells as the preclinical data suggests? Two, do we have evidence that HB-200 is an immunotherapy agent effective in controlling cancer as a monotherapy without other agents in the post-checkpoint inhibitor setting? Three, what evidence do we see to date for a relationship between the mode of action and the biological activity seen in the trial? Focusing first on driving unprecedented antigen-specific T cells. Next slide. Go back one. Thank you. First, let me quickly remind you, our arenaviral vectors are non-lytic, function via a systemic intravenous dosing, naturally target antigen-presenting cells, and allow for full antigen incorporation. As a result, preclinically, as we have seen here, we have demonstrated significant induction of antigen-specific CD8 T cells in multiple tumor models, T cell tumor infiltration, and an associated dose-dependent efficacy. Based on this preclinical data and benchmarking ourselves to the field as a whole, we felt confident that if we could induce such potent and specific immune responses in people, we should see efficacy even as monotherapy and even in advanced cancer patients. Albeit, we are well aware, as Dmitriy has pointed out, that this has never been done before. Next slide. In April, at AACR, we showed immunogenicity from our patients demonstrating that HB-200 was able to induce mid-single digit level antigen-specific CD8 T cells following just one administration of our vectors. Just with one dose, this means that up to 8% of all of the CD8 T cells in the body have been focused exclusively on a cancer antigen of our interest. This is already, as you heard Dmitriy say, an enormous accomplishment. Furthermore, these several hundred-fold increases were measured via a direct assay without any kind of artificial expansion. Next slide. At ASCO, we have shown what happens when we follow up with additional administrations. As can be seen, all patients undergo significant antigen-specific CD8 T cell reduction. In many of our patients, we are coming close to, if not exceeding, the upper limit of quantification for these assays. Reported at ASCO, the data here shown as a direct ELISpot measurement corresponds to about an average of 6% and range as high as 40%. This means that at this extreme range, almost half of all of this patient's CD8 T cells have been refocused on HPV16-positive cancer. Later in the presentation, I will review the impact of these T cells on tumor shrinkage. Finally, to note, these CD8 T cells response occur very quickly, often just within two weeks. As we know, these patients have advanced cancers, and we as treating physicians know that speed is critical. The therapy must work fast, within weeks. Otherwise, the battle is already lost. Next slide. This is why all of this is so exciting, because everything we have seen preclinically, from the magnitude of induction to the pace of induction, is being perfectly recapitulated with the clinical data. Next slide. Summarizing this block, early clinical data confirm the arenavirus mode of action, specifically being able to drive unprecedented antigen-specific CD8 T cell levels. All patients do indeed show increased CD8 T cell levels following our treatment, at times reaching as high as up to 40%, and completely recapitulating the data that we have previously shown preclinically, confirming it in the clinic. Next slide. I hope you can tell that the PhD biologist in me finds this translational data extremely exciting and validating from a technology proof of mechanism point of view. As Dmitriy has said, a paraphrase, if this level of immunogenicity does not result in efficacy, we kind of need to question our biology a little bit. The M.D. clinical oncologist in me asks, this is all nice, but what about the patients? What about efficacy? Next slide, please. I remind you that we began this trial exploring many facets of our technology. We explored not only three-week but every two-week dosing schedules. We explored not only intravenous continuous administrations but also one dose of intratumoral followed by intravenous continuous administration. We also explored HB-201 and HB-202/HB-201 alternating therapies. Just to remind you that HB-202 and HB-201 are two different arenaviral backbones but having the same HPV cancer target in common. As Alan Ho showed in ASCO, our best data has come from the every three-week intravenous dosing schedules. During this talk, I will therefore focus on patients with head and neck cancers who received HB-200 every three weeks via intravenous administrations to explore in more detail the relationship between dose and efficacy seen to date. Next slide. To remind you, as of March 31st data cutoff, we had 38 patients dosed. 14 received HB-201 intravenous every three weeks, eight received HB-202/201 intravenous every three weeks. The remainder received either intratumoral and/or every two-week dosing. The number of evaluable patients with efficacy scans are shown below as the 14 and four, 11 and four, respectively. Next slide. The demographics of the 22 patients who received intravenous therapy every three weeks, as seen here, were not different from the demographic profile of the 38 patients as a whole. Notably, patients had advanced disease and were heavily pretreated, with an average of three prior treatments. 82% of all patients had prior checkpoint inhibitors. Specifically, excluding patients with nasopharyngeal head and neck cancer for which checkpoint inhibitors are not standard of care, all head and neck squamous cell carcinoma patients had prior checkpoint inhibitors. Further, 90% had prior platinum and 80% had distant metastatic disease. Next slide. Before we stating our ASCO data, it is important to put efficacy data into perspective. As disease progresses, it becomes more and more difficult to treat. As a rule, patients with metastatic solid tumors are not curable. As patients progress in treatment, their response to the next treatment becomes less and less. Why? Well, multifactorial. However, more advanced patients are sicker, can tolerate less of the toxicity associated with most cancer therapies, and unfortunately, as Dmitriy has said, cancer evolves. You're better at either fighting or evading the therapy itself. Focusing on HPV-positive head and neck squamous cell carcinoma, we see that in the first-line advanced metastatic setting, that is the first therapy patients who present with advanced and/or metastatic disease, the response rate as a% is at best in the mid-30s, as you can see in the gray pie chart. Our first-line is our best therapy. As oncologists, we are not saving our last for best. Our best must be our first, or patients will die. Here, our best unfortunately means that 70% will not respond at all to our best therapy. In this case, it's some combination of checkpoint inhibitor and chemotherapy. Once patients progress from first-line therapy options into second-line treatment or for even less, response rates are usually less than 20% as shown on the orange pie chart, which means that over 80% of patients are not even expected to respond. As Dmitriy already mentioned, response rates to active immunization at third-line is, well, marginal at best. You can see if you look at either overall survival or median progression-free survival rates, a similar trend is observed, with median progression-free survival already in the second line dropping more than 50% from the first line. Although extrapolations are completely linear, it is obvious to conclude that third-line survival rates are to be expected to be even less than those in the second line. Next slide. This is what makes our data for me as an M.D. clinical oncologist so exciting. Except for the one nasopharyngeal patient we had, all of our head and neck squamous cell patients are third-line or more, having seen chemotherapy and checkpoint inhibitors previously. We are seeing both early responses and a prolonged progression-free survival with further dose escalation ongoing. Putting our data on top of the data shown earlier in the first- and second-line setting, we see that the expectation for the third-line response rate was about 0%. We are actually seeing an 18% rate. Progression-free survival was expected to be worse than second-line, worse than two months, just like second-line seemed to be worse than the first. Yet our data shows quite the opposite. This is what gets me so excited. Patients are living longer without our therapy, which they could not have done otherwise. Next slide. Seen here in the swimmer plots, it becomes obvious that many of these third-line advanced patients are not only responding but staying on HB-200 therapy for a period of time that is much longer than one would have thought possible so late in this disease. Next slide. Focusing on HB-201 and comparing dose Level 1 light blue and dose Level 2 dark blue, we are clearly seeing that patients on dose Level 2 are staying on therapy even longer than dose Level 1. Next slide. For HB-202/HB-201, while it's still too early to make comparisons to HB-201 alone from a time on therapy analysis, as they were started later than HB-201, it is notable that nearly all the HB-202/HB-201 patients are still on therapy as of the data cutoff. Next slide. Looking at this data as at a waterfall plot, it is easy to see that more than half of our patients show evidence of tumor regression. While we could not compare HB-202/HB-201 to HB-201 alone on the tumor plot shown before, on this waterfall plot, it appears that many more of the HB-202/HB-201 patients, as seen by the red color, are showing regression than progression. In other words, there are more reds to the right than to the left of the slide. Next slide. Looking at this data on a spider curve plot, in fact, we see quite clearly only one patient who is truly rapidly progressing. All other patients either had prolonged stable disease or had rapid responses. We could see some patients that we presented back in December, and we have seen additional patients showing response in the lower part of the curve. Next slide. Putting it all together, I've shown you that for HB-201, we have an overall response rate of 18% for head and neck squamous cell carcinoma, a disease control rate of 73%, and a median progression-free survival of 3.5 months. For our initial cohort of patients of HB-202/HB-201, although we have not seen any form of PRs or CRs, our disease control rate is 100%, with three of the four patients showing evidence of tumor shrinkage following just one cycle and a median progression-free survival that is already 3.5 months and ongoing, exceeding the progression-free survival of checkpoint inhibitors even in earlier settings. Next slide. The clinical efficacy as monotherapy in the advanced setting comes with minimal safety concerns. Specifically, no Grade 3 or higher, no one has continued due to adverse events. While tolerability of therapy is almost always an issue in late disease, it is not an issue here. Combinations with other agents are clearly great to consider at this point, not only by this very favorable tolerability profile, but also by the fact that we were already combined with pembrolizumab in three separate patients without any additional toxicity observed. An example of this was shown back in December for combining with HB-201. Another example will be shown shortly for combining the HB-202/HB-201. Next slide. Summarizing here, we see early signs that HB-200 is effective in controlling cancer as a monotherapy in the post-checkpoint inhibitor setting. Specifically, monotherapy with HB-200, unlike other monotherapy activation therapies, provides clinical responses in third-line post-CPI patients where historically none have been seen. We have seen two objective responses and a disease control rate that goes as high as 73% for HB-202/HB-201 and so far 100% for HB-202/HB-201 in advanced patients as monotherapy. As well, we have seen additional benefit when combined with checkpoint inhibitors. Finally, HB-200 has a benign safety profile, supportive of combinations with many different therapies. Next slide. So far, we have spoken quite a bit about immunogenicity and efficacy separately. However, is there a relationship between the two? I would say on a high level that a relationship is in its early stages of being defined. But what we do know so far is indeed support of a relationship between the two. Let me show you some data. Slide 39. Regarding dose response, data on the various efficacy plots I've shown you before have already suggested the emergence of a dose response. Here it is presented directly. On the left, comparing response rates, target lesion shrinkage, as measured at the first scan for HB-201 dose Level 1, HB-201 dose Level 2, and HB-202/HB-201 dose Level 1, we see that as either dose increases or we switch from a single vector to a dual vector approach, both modifications geared to give us greater immunogenicity, we see an increase in response rates. This was also seen when compared the progression-free survival of dose Level 1 to dose Level 2. Remember, median progression-free survival for HB-202/HB-201 combination is still unknown. Next slide. Additionally, Dmitriy has shown you this. We have begun to examine whether our peripheral blood antigen-specific CD8 T cells penetrate the tumor. Here we see an example of a paired biopsy showing the absence of CD8 T cells before and the obvious presence thereafter. These data are very reminiscent of the blood immunogenicity shown earlier. Next slide. Finally, a picture is worth a 1000 words. This is our first patient to have received HB-202/HB-201, the alternating two-vector therapy. This patient had an oropharyngeal HPV16-positive head and neck cancer that was treated with radiation therapy in 2018. The patient had developed metastases in the lymph nodes and the lungs and was subsequently treated with cisplatin with some improvement. The patient subsequently progressed and entered a clinical trial with an investigational triple therapy of monalizumab, durvalumab, and cetuximab. There was some improvement with this triple therapy and then again, progression, this time mainly in the soft tissue surrounding the thyroid gland. In the top picture, you can see the baseline situation and entering to our clinical trial with a CAT scan here, and more easily in the zoomed-in picture, showing the soft tissue mass kind of surrounding the trachea in the place of the thyroid. The patient received one cycle of HB-201, HB-202, then HB-201, and has a rapid induction of antigen-specific CD8 T cells, reaching 35% by direct measurement. The CT scan, this initial six-week evaluation, shows a 20% reduction in the parathyroid soft tissue target lesion. Shortly after scan, the patient complained of difficulty swallowing. The investigator, who was at that time concerned about possible esophageal obstruction from involved lymph nodes, decided to add pembrolizumab. No additional safety signals were noted. The repeat CT scan six weeks later, right around the time of the data cutoff, shows further reduction in the thyroid soft tissue mass to a 40% reduction and an increase in antigen-specific CD8 T cells to similarly 40%. Next slide. Summarizing. Early data does indeed suggest a relation between T cells and clinical efficacy. To come back to Dmitriy's point that if we don't see clinical efficacy into these kinds of T cells, not sure what we're doing. We are seeing efficacy, which is a good sign. Efficacy measures do indeed improve with higher dose and with alternating single vectors. HB-200 therapy causes a similar increase in CD8 T cells in blood and tissue biopsies. In these tissue biopsies, there is further early evidence that HB-200 decreases the immune suppression in the tumor microenvironment. At this point, I'm going to hand it over back to Jörn, who can tell us what comes next. Slide 43, the bright future for the T cell re-education platform in oncology. Next slide. Our phase I data on HB-201 monotherapy are exciting, and we haven't yet reached optimal dosing. Furthermore, we're only starting to see the data on our alternating two-vector therapy, yet we are confident that we have at least three avenues to obtain accelerated approvals in HPV-positive indications. With its notable single-agent activity, its compelling T cell based mechanism of action, and its benign safety profile, HB-200 is likely to be a strong match for combinations with checkpoint inhibitors. In Q1 of 2022, we will start a phase II in combination with a PD-1 inhibitor. In addition, provided our data continues to support it, we will start two second-line trials in advanced metastatic HPV16-positive cancers. The first will be in monotherapy in late-stage head and neck cancers. The latter in combination with CPI, checkpoint inhibitors for anal cancer, where there is no current standard of care. Next slide. Our HB-200 was the first study ever where we put an arenavirus therapeutic into humans. While to date, this established proof of concept successfully, there was a lot of learning with this new modality which took time. Now that we have designed and tested arenavirus constructs in humans and have set up our manufacturing processes, other programs can build on this expertise and potentially move significantly more quickly towards the clinic. The arenavirus approach is now becoming a platform. Our ability to drive the antigen-specific T cells can be leveraged to produce best-in-class therapies in multiple indications, potentially as monotherapy and/or in combination with other immune modulatory agents whose potential is often limited due to a lack of T cells at the tumor site. We have demonstrated pre-clinically that we're able to break tolerance in animal models. We believe we can translate this to humans just like we did in the HB-200 program. Our first program targeting self-antigens will be in the prostate cancer space. Mutated oncogenes such as KRAS could be very interesting targets for our therapy. There's a myriad of other diseases which would greatly benefit from our approach. Next slide. To wrap up, here are our key milestones. The next comprehensive data update will be no later than 4Q 2021 and entail more patients from the HB-201, HB-202 combination. We expect to define or select phase II dose in 4Q 2021, which then leads to the start of the three avenues, the three trials that I mentioned before. The start of phase II HB-200 second-line expansion cohorts in the first quarter of 2022. The start of checkpoint inhibitor combination study in first line head and neck squamous cell carcinomas in the first half of 2022. Our prostate cancer program, named HB-300, is expected to have an IND in the third quarter of 2022 and then move on to the clinic. Looking at the ability to drive novel programs forward, we would expect to be able to deliver one additional IND per annum starting in 2023. This concludes our presentation, and I'm very happy to open up for Q&A at this point. Thank you very much. We now turn to the Q&A, and the panel has been joined by HOOKIPA CFO Reinhard Kandera and Chief Business Officer Christine Baker. If you'd like to ask a question, then please click the raise hand icon on Zoom and we will come to each of you in turn. If you're dialing in on the phone, then you'll need to dial star nine to indicate that you would like to ask a question. The first question. There we go. The first question comes from Asthika Goonewardene. Asthika, if you would like to unmute your microphone and please go ahead. Hi, guys. Can you hear me okay? Yes. Hi, Asthika. Hello, and thanks for taking the time to do this update and Jörn for staying up quite late on your side of the world there. First up, really interesting to see the kind of T cell response that you guys produced here and as they have produced and that kind of data. I want to get some ideas. Of the eight patients that you kind of treated with the HB-202/HB-201, about how many of these actually got into that close to a 40% antigen-specific CD8 positive T cell compartment range? Just curious because maybe give us an idea about that. I know it's about the 40%, but how many of them went around there? That patient who got into the 40% was kind of an extreme outlier. I would say what we are currently seeing for the HB-202/HB-201 for the moment, as we can extrapolate, is probably in the double digits. That patient is kind of at the extreme range of what we observed. Got it. Guys, just look at the spider and you have some patients who are in the stable disease category, including some who are getting the heterologous prime boost. I'm just wondering, have you looked at extensively at biopsies in these patients to see if there's maybe some sort of inflammation that may be offsetting tumor volume reduction, kind of like almost like a pseudo progression happening? We haven't seen any, I would say, inflammation in any of the tumor biopsies that we do that. We really haven't seen any. I mean, I resist, it's what the following patients worth exists so we can rule out pseudo tumor progression from initial inflammation. We haven't seen evidence of that. Got it. Last one from me is the focus, much of focus today was on the Q3W dosing. I am just wondering, are you suggesting that with the Q2W maybe the T cell response is not as great? I am just wondering why is it that the Q3W looks so much better then? Not only clinically did those patients not do as well, but also from a CD8 T cell levels, we did not quite observe upon boosting that their levels were as high either. There are a couple of independent factors that are both pointing to the fact that is not the best schedule. Excellent. Thanks for taking my questions, guys. The next question comes from Andrew Berens. Andrew, if you would like to unmute your microphone, please go ahead. Thanks. Can you hear me? Mm-hmm. We can. Great. A couple of questions from me on the regulatory pathway based on what we've seen today. You mentioned accelerated approval as a pathway, and I was wondering what you think the bar is for approval. I assume it's based on ORR, and you're citing an 18% ORR, but your confirmed ORR rate is not really 18%. It's half of that since that one patient didn't confirm. When I look at the spider plots and the swimmer plots, it doesn't appear that some of the actual response, those two responses are durable. What type of durability do you think you need to show for accelerated approval? Lastly, it seems like most of the efficacy that you're seeing is stable disease, which could lead to a PFS benefit eventually. Do you think a randomized trial might be a better strategy with PFS versus going for accelerated approval on response rates? Yeah, those are all good questions. I think our plan for the moment is to, A, progress our data as we continue to our phase II dose. I think what the points you raise are exactly the way I'm seeing the situation. I think we'd like to both get the response rate, as well as the, I would say, the durability up to where it's solidly in the three- to four-month range with a response rate that I would say is a solid 18%, fully objective, to really get where we want to go. We can think about it as a phase II. we are, I would say, optimistic that, as we're seeing with our data's increasing the dose escalation, that we will have those kinds of numbers in the near future. We'll be discussing that path with the FDA probably in the Q4 of this year as we think about monotherapy in the advanced settings. Okay. What do you think the bar is that you need to show in terms of the ORR and the durability for an accelerated approval? Historically, the accelerated approval has usually have had, in first line, has been quite high. I think, in general, if we can show in these advanced treated patients that we can have a 20% or higher bar, considering that the historical response rate has been dramatically less, and the second line is only 13%-18%, that would be sufficient. That can be discussed with the FDA. Okay. I guess we haven't seen any responses with the combination therapy yet, or the alternating therapy yet. Where are you on the dose escalation part? How much higher do you plan to go? When should we expect to see some formal responses? I can't say when you expect to see formal responses. The phase II dose for the program will be defined by year-end. We have currently just dosed second dose Level 2 of the HB-202/HB-201, and are dosing dose Level 3 as well. The question is, can we go higher? Will depend on the data. Okay. What type of T cell response are you seeing with the alternating therapy now, relative to the 40% that you've seen? Yeah, we haven't updated this holds any information out past our data cut-off, and we'll probably be saving that for our next formal update. Okay. Thank you. Thank you, Andrew. The next question comes from Brian Abrahams. Brian, if you would like to unmute your microphone and please go ahead. Thanks. Can you guys hear me okay? Yeah. Yeah, we can. Great. All right. Well, thank you so much for taking the questions and for the presentation. I guess the first question would be following up on the patients who received alternating HB-201/HB-202. When we look at the swimmer plot, it looks like the patients who responded to monotherapy, HB-201, seemed to respond relatively early in the course of treatment. Whereas for HB-201/HB-202, it is still relatively early, but you have not yet observed responses, and you have described that you are seeing pretty robust double-digit antigen-specific T cell levels. Can you maybe, I guess, square those and help us understand what would be the outlook then for those patients, at least on the first dose? Are there preclinical or other mechanistic data such that the speed of response, despite the higher initial T cell levels, might differ for this alternating regimen versus the monotherapy? Yeah. I think the spider curve plot is really not the best place to look at. There are a lot of lines there. I think the lines overlap in that early left side of the bar. I think if you look at the waterfall plot, I think that might be an easier place to look at in the slide deck that we just showed. Is there any way I can have my slides back? Yes, we can. Which slide would you like? Well, the waterfall plot. Can you fast-forward? Yeah. Give it a go. If you look at the waterfall plot. 33. Thank you. You can see there that the red guys are HB-202/HB-201s. They are showing responses early. I think they're a little bit probably overtaken by the many more blue bars in the spider plot. I would say you're looking at the first scans, and we'll see what happens with further treatment. Okay, fair enough. Sounds like it's still early in it. Are there any data on how chemotherapy might affect T cells? I guess what the time between systemic therapy and starting on HB-201 or the combo would be? I guess I'm just curious if there's any influence on T cell levels or activity, and what the implications for that might be for exploration in an earlier line setting, including front-line setting. We haven't seen any relationship between previous chemotherapy usage, and how it affects our CD8 T cell inductions. If that's the question you're asking, I would say, we haven't seen any evidence of that. All of our patients have, I would say, respond very nicely to our therapy. They all get significant expansions. We haven't seen, I would say, any relationship between the two. We are actually in the middle of starting an investigator-initiated trial, looking at kind of an early setting of a direct combination with chemotherapy and HB-200 to see how the concurrent use of chemotherapy may affect our viral vectors. Chemotherapy has been known to both promote active immunization, so we'll see how that goes. We have not seen any evidence to date regarding this. Got it. One more quick one if I could squeeze it in. Are you guys planning to explore any additional dosing intervals, perhaps just given what you've seen with the wider space intervals leading to more robust clinical and immunological responses? Thanks. Our protocol, I would say, is open to allowing us to explore different dose schedules. The protocol as written is flexible, and we have the option to explore a four-week dosing schedule as well. For the moment, we are still discussing with the investigators whether this is worth pursuing or not. Part of the problem with extending the dose intervals is, of course, you're running against the timeframe that you have to get in therapy into relatively quickly before the tumor progresses. You can imagine dosing once every three months if it won't work for this patient population unless you're one dosing control the disease. A, we have the option. B, we are currently discussing with investigators whether this is an option we want to execute on or not. Great. Thanks so much. Thank you, Brian. Thank you, Brian. The next question comes from Alec Stranahan. Alec, if you would like to unmute your microphone, please go ahead. All right. Perfect. Can you guys hear me? We can. Perfect. Hey, guys. Thanks for taking my questions, congrats on the update. Wondering if there's any demographic differences you'd point to in the 4 FX patients in the two-vector arms that can maybe explain the lack of objective responses, or do you think it's really more driven by a shorter duration of follow-up? Additionally, whether you think the one patient that received KEYTRUDA, which is now in the PR, will you continue to follow this patient and provide updates maybe later this year? As far as we can tell, there's no difference in demographics of any of the patients at all. They're all, I would say, fairly homogeneous. They all have been treated, all progressive CPIs. As to the patient in question, we will of course update on all patients as we do at all of our updates. We either show waterfall plots and swimmer plots for, and there were spider plots for all of our patients to show that, absolutely. Okay. Just one point of clarification on your registration plans. Do you expect that you'll take forward the two-vector approach, or will the studies that you've highlighted be just the HB-201 monotherapy with or without PD-1? Will this really depend on the data update later this year? Well, I think our general philosophy at HOOKIPA has always been and remains the same. We will take the HB-200-forward as monotherapy, and by monotherapy we mean either HB-201 or HB-202/HB-201 into the post CPI space. We believe the fact that no active immunization has ever worked in that space, and the fact there's no standard of care in that space really gives us a shot in terms of getting our drug approved in that setting. At the same time, we believe that our clean safety profile, the synergy already shown with CPIs, and the fact that we're the only active immunization therapy to show monotherapy efficacy makes us the ideal partner for CPIs in situations where CPIs are approved. Now, we're going to go both CPI and then CPI-approved indications with CPI. The only question that we need to hold on resolve is the HB-201 alone or HB-202/HB-201. I think we will make that decision and recommendation as part of our phase II dose guidance, which we'll have by the end of this year. Okay. That's helpful. One final question, if I may. It's more of a science-y question, I guess. I thought it was interesting that in the FACS plots, you showed that the two-vector therapy generated a much higher level of TNF alpha T cells. Wondering what in the HB-202 vector you think may be driving this? Well, for the record, what we're showing is in the upper right corner of the FACS plots, a TNF alpha interferon gamma double. The double vector is generating in general just more polyfunctional CD8 T cells. In other words, that HB-201 homologous versus HB-202/HB-201, critical heterologous. The heterologous gives us simply many more polyfunctional antigen-specific CD8 T cells. This has to do with the fact that when you have different vector backbones, they minimize competition against the same backbone when you reintroduce, therefore allowing expansion of the target antigen in common. That's the entire theory behind the heterologous or the alternating dual vector approach. I think what I was pointing to is the single application of HB-201 versus HB-202 on one of the slides. I was thinking more about the two-vector strategy. I would be interested to hear what you've observed with just HB-202 alone, in terms of the polyfunctional T cells as well. Well, in AACR, Alec, we show what happened after one dose of HB-201 versus one dose of HB-202. Okay. Thank you. There you saw they were both mid-single digits. One was three, one was eight. I would not necessarily put too much stock in those two numbers. I would say pre-clinically, we both saw they both gave us about 4%-5%. Clinically, we saw one gave three, one gave eight, but they both gave in the same range. I would not say there's a difference shot for shot. I'd say the real difference comes in when you actually boost with a different vector versus the first. Okay. All right. That's very helpful. Thanks again for taking our question. Thank you, Alec. The next question comes from Roy Buchanan. Roy, if you'd like to unmute your microphone and please go ahead. Okay, great. Thanks for taking my questions. Really impressive T cell results. It's good to see. I guess I had a question, maybe I missed it, but the patient with the 40% induction of directed T cells, that patient's not considered a partial response because of the lymph node progression or why is that? No, the patient had a 20% response to HB-202/HB-201, they investigated added pembrolizumab because the patient was complaining of some kind of esophageal difficulty swallowing. There was some concern about esophageal lymph node inflammation, they investigated, actually added pembrolizumab. On a subsequent scan, we finally crossed the 30% threshold for a partial response, that was with pembrolizumab added after the first scan. As monotherapy, it doesn't count as a PR. Got it. Okay. That makes sense. I guess, do you guys have any data or information on vector-directed T cells for the combo, the HB-201/HB-202 alternating sequential? I mean, how many T cells? I know you're trying T cells against HPV, but do you know how many are against the arenavirus? We do know how much is against the arenavirus, but we haven't formally compiled that information. What I can tell you is basically for the heterologous combination, it is less than for the antigen itself as our desired result. Okay, great. I guess you guys have any early data on durability of the T cell responses? Some of the patients that we talked, we showed data showing you the max responses. That is actually up to 84 days. We know that the CD8 T cells, once induced, actually stay quite up there with some of our, up to at least four treatment cycles. Okay, perfect. I had one last one for Dr. Zamarin. I'm not sure if maybe this was in his review or not, but I'd say there is some validation for the T cell theory for HPV, right? In the cell therapy. There's some early data with some good response rates. I think they also used interleukin-2. Just wonder if you could maybe comment more broadly on the cell therapy approach. If you think maybe that was potentially due to the antibody too, or just your thoughts there. Thanks. Yeah, no, absolutely. Adoptive T cell approach. They infuse a relatively smaller population of T cells into the patient. In fact, the patient needs to be lymphodepleted to make room for the T cells to expand, and IL-2 is applied specifically to allow for expansion of these T cells. In this case, I guess the question does come, Well, what if we actually add some IL-2 to boost up the efficacy of this current agent? It seems like the expansion is quite high. It's actually, if we do talk about 40% of the peripheral blood T cells being specific for the antigen, that's higher than you would achieve with an adoptive cell therapy approach. I think the T cells, granted that it's only been seen, that 40% is an outlier, but even if we're talking about the teens, it's still much higher than what we typically observe for the cancer vaccine studies. I don't think a cytokine that would necessarily stimulate the response would help here with the peripheral blood, at least T cell proliferation. The question is whether it would help with the effect or function of the T cells once they actually make it into a tumor. That's a good one. Certainly something to think about if the current strategy of combination with perhaps immune checkpoint inhibitor doesn't pan out. Okay. Thank you. Thank you, Roy Buchanan. The next question comes from Vikram Purohit. Vikram, I believe you're dialing in on the phone. You should be able to speak now. Give it a go. Hi, Vikram. You may have to unmute, Vikram. There you go. Great. Can you hear me? Yes. Great. Thanks for taking my question. A couple from my side. First, you mentioned that of the 38 patients that were dosed, there were 20 discontinuation. I just wanted to get a sense of how the discontinuation rate compared to what you would have initially expected or modeled when you were starting up the study. Well, the patients discontinued usually for progression. There are no surprises. They're all kind of end-stage, third line, more advanced cancer patients. I'm actually surprised that patients are staying on therapy and responding to drug as long as they are, given the advanced nature of these patients. Okay. All right. Understood. Now that you've had a couple of months since the last update in December, to presumably learn more about the two patients who did have responses for HB-201 monotherapy, have you come across any patient-specific factors that might explain or that may have played into these patients' responses? Especially the partial response for the patient that did not pass away. Yeah, no, it's a great question. Clearly, we've scrutinized those patients in every way we can. The short answer is no. We do not yet see a predictor marker, either from a clinical perspective, from a treatment history or by any kind of tissue or biology or any other kind of marker that actually explains why those particular patients responded better. What I can tell you is, the message that I tried to send along the way is that the patients where we have higher CD8 T cells tend to show some better signs of response. That is not a completely linear relationship either. Okay. That's helpful. Maybe one last question from my side. For the T cell responses you're seeing, are there any migration markers that you've been tracking to help to get a sense of whether these CD8 T cells have been traveling through the tumor sites or anything of that sort that you've been tracking that you could do some color on? No, we have not been tracking the CD8 T cells. We've been measuring either directly from the blood and trying to look at TILs in the tissue biopsies, but we have not been measuring, or we're not been trying to track them in any way, answer is no. Okay. Understood. Maybe if I could squeeze in one last question. Thinking about the update that we're supposed to get in about the fourth quarter, I think you mentioned, both for HB-201 and HB-201/HB-202. Based on your sense of how the studies are enrolling and based on how high you think you can dose the HB-201 monotherapy, how many patients and how many dose levels worth of data do you think would be reasonable to expect by that time? I think we should be able to get through three dose levels for both programs at minimum. Okay. That's helpful. That's it from me. Thank you. Vikram, thank you very much. The final question comes from Swayampakula Ramakanth. If you would like to unmute your microphone, and please go ahead. Thank you very much, gentlemen, for doing this. Really appreciate it, and thanks for taking my questions. Most of them have been answered. I have a couple of quick ones. I'm just trying to follow up on the migration question. How many patients had the data? For antigen-specific CD8 positive T cells in the tumor biopsies, and do these correlate with the T cell response that we saw in the PBMCs? We only have two sets of paired tissue biopsies that correlate to the peripheral CD8 T cells. For those two where we have correlates between both blood and tissue, they do correlate. Okay. Thank you for that. The last question from me is on the dose level that was used in the HB-201/HB-202 combination, how does that correspond with the monotherapy? The dose is a little confusing. Dose Level 1 for HB-202/HB-201 is the second dose level of HB-201 monotherapy. In other words, for HB-201, we used the highest dose we cleared from the monotherapy at the time we started the combination. At that time, that dose was dose Level 2. Numbers help. For HB-201 monotherapy, the first dose was 5x1 0 to the fifth. The second dose was 5x 10 to the sixth. However, for dose Level 1, for the HB-202/HB-201, the HB-202 is dosed at 1x 10 to the sixth, and the HB-201 is dosed at 5x 10 to the sixth. Okay. That's helpful. Thank you. Thank you very much for doing this for us. Thanks. Thank you very much. We have one more question, one final question. That's from Asthika Goonewardene. Asthika, if you would like to unmute your microphone and go ahead. Hi, guys. Thanks for letting me in. Just another quick one here. Igor, I'd like to look ahead to the next update. What are you planning on including in that next update? In terms of, I'm really curious to compare some of the translational data, in terms of the tissue numbers. What should we look forward to in that? Thank you. In a way, I've been thinking about this. I think, at AACR, we, I would say, gave out some initial immunogenicity data in the blood. We followed up on ASCO, I would say, with a lot more. I would say here we're presenting some early tissue. We're going to present, I would say, similar amount more at the next update. For translational, I would like to be able to push the story a little bit further in terms of this relationship between what we're seeing in the blood and what we're seeing in the tissue. I'd like to push that a little bit more. I think if we could assume the same kind of incremental update that we saw with the blood, going from AACR to ASCO, I think you'll see the same kind of incremental update as we see in tissue of going from where we are today to where we'll be by the next update. The second thing at the next update I think will be important will be the phase II dose. I've already commented on the fact that I'd like to do a formal update on three dose levels of HB-201 and likely three dose levels of HB-202/HB-201 and contrast and compare those two in order to make some final recommendations. I'd like to at the next update also talk a little bit more about how we're seeing our CPIs combinations. I would say we've alluded to the fact we've had several patients on CPIs. We haven't really discussed it. We're going to put on a fair amount of more before we conclude dose escalation, and I'd like to have an update on that at the next update. Got it. Thank you very much. That was the final question. If I could perhaps hand back to you, Igor, just for your final remark. Yeah. I would like to thank everyone for participating in this meeting. We believe that we've made great progress, and we will continue to push hard to develop our immunotherapies to change the lives of patients. Stay tuned. There's a lot more to come for our next data update in the fourth quarter. Stay with us, and stay safe and healthy. Thanks a lot. Bye-bye.