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spk07: Greetings, and welcome to the Cellulite Oncology Year-End 2020 Earnings Call. At this time, all participants are in a listen-only mode. A question and answer session will follow the formal presentation. If anyone should require operator assistance during the conference, please press star zero on your telephone keypad. As a reminder, this conference is being recorded. I'll now turn the conference over to your host, Filippo Petti, Chief Executive Officer of Cellulite Oncology. Thank you. You may begin.
spk01: Thank you, Operator, and thank you, everyone, for joining us today for our 2020 Financial Results Call. Joining me from the management team is our Chief Scientific Officer, Dr. David Gillum, our Vice President of Global Clinical Development and Medical Affairs, Dr. Frederick Lehman, and our Chief Business Officer, Dr. Stephen Rubino. We will start today's call with an operational and clinical update, followed by an overview of our financials, And then we'll then outline the expected key milestones for the company over the next several months. We'll then open the line for your questions. As we look back over the past 12 months, two key themes shape Cellulite Oncology. On a macro level, there is a COVID-19 pandemic that has impacted everyone within our organization and worldwide to varying degrees. We're thankful for our team's hard work this past year amid challenging times and their overall steadfast dedication to our mission to bring innovative CAR T therapies to cancer patients with unmet medical needs. On a company level, 2020 marked a significant period in our history as we announced a rebrand to reflect our experience and expertise more accurately in the oncology space, along with prioritizing our pipeline to develop our allogeneic CAR T therapies. This streamlined strategy allows us to focus our resources more efficiently and advance our allogeneic portfolio and technology platforms. Today, we are excited to announce preliminary safety clinical data from our lead SHRNA-based allogeneic CAR-T candidate, CIAD211, from the Immunity 1 trial, a Phase 1 study for the treatment of multiple myeloma, in which we initiated late last year. In addition, at the beginning of this year, during ASCO GI, we announced updated data from our CIAT 101 program for the treatment of advanced metastatic colorectal cancer. We believe the progress made over this past year is a strong example of how cellulite oncology is leading the field in CAR-T development and creating novel therapies for cancer patients. The past two years have been one of steady progress, strategically focusing on establishing a foundation for the organization to build upon for future success. One of our key goals has been to highlight our differentiated outlook to allogeneic CAR-T development by showcasing the advantages of our platform, including our non-gene edited technologies and our all-in-one vector approach, as well as to advance our clinical candidates. I feel that we have made great strides in strategically positioning the company for future success within the dynamic CAR-T landscape. Let me stop here and turn the call over to Dr. David Gillen, our Chief Scientific Officer, to provide more detail into our progress. David?
spk03: Thank you, Filippo, and thank you everyone again for joining us today. As Filippo just discussed, in 2020, we have thoroughly evaluated our portfolio and underlying technologies. Now, back in 2017, we started working clinically with the NKG2D receptor as a novel CAR T-cell therapy approach. Our clinical trial activity has definitively demonstrated the safety of this approach with promising evidence of clinical activity in both solid tumor indications and hematological malignancies. It certainly seems to me that the explosion of interest around NKG2D at the moment is in no small part thanks to our groundbreaking clinical work with this receptor. Behind the scenes, cellular oncology has been highly active working on practical solutions and forward-looking programs. The NKG-UD-CAR-T clinical program has been delivered thanks to our pioneering efforts to generate highly robust and reliable clinical cell manufacturing. We have subsequently built our first non-gene-edited allogeneic cell therapy, combining this innovation around clinical cell manufacture with our novel peptide-based technology, referred to as TIM, to produce the highly differentiated CIAD101, our allogeneic NKG2D CAR T-cell therapy. As Frederick will describe, this is now in an expansion cohort in our Phase I allostring trial after initial encouraging results from the dose escalation segment. Given this differentiated, non-gene-edited approach to allogeneic CAR-T, over the last two years or so, we have been working hard using a different technology referred to as short hairpin RNA or SH RNA that we feel brings significant possibilities to the field beyond that offered by other technologies in the CAR-T space and as a platform can be used for any chimeric antigen receptor strategy. Within two years of starting to work on this technology, we have taken CIAD2-11, our first-generation single hairpin BCMA-targeted allogeneic CAR-T, into the clinic. Frederick will discuss this trial in detail momentarily. But to recap, CIAD2-11 has been developed using a single shRNA to target CD3-Zeta, It results in knockdown of cell surface T cell receptor expression with no detectable evidence of graft-versus-host disease in our preclinical models. But, interestingly, leads to increased persistence of T cells as compared to T cells with a comparable gene-edited CD3Z2 knockout. We expect the ImmuneC1 Phase I trial to firmly establish that allogeneic CAR T cells using shRNA technology can generate clinical benefit without inducing graft-versus-host disease. We have not stood still with the development of CIAD211. While we demonstrate the shRNA allogeneic platform at the clinical level, it is important to remember that we have also shown in our autologous CIAD02 candidate that shRNA can be used to refine and enhance the therapeutic activity of clinical candidates. At ASCO last year, we showed that multiplexing shRNA is feasible in the preclinical setting, where multiple shRNA can be expressed from a single vector. Over the last year, we have worked further on our second generation multiplexed shRNA platform, which we believe has advantages when using our first generation multiplexing system. Going forward, we will leverage our multiplexed shRNA platform with our all-in-one vector-based approach, to underpin our future allogeneic CAR-T candidates, including several programs which are in a discovery phase of development. We are very excited about these latest advancements and look forward to providing more details on the platform and these new candidates in the future. With that, I now turn over the call to Frederick Lehmer, Cellular Oncology's Vice President of Clinical Development. Frederick?
spk02: Thank you, David. It's great to have this opportunity to speak with everyone today about the progress we have made in our pipeline over the past year. As David and Philippo have discussed, we are very excited by the data we have generated and potential from our ongoing studies, which support our decisions to focus our future R&D program through the prioritization of our allogeneic assets. Let me start by providing you an update on our clinical activities with CA-211. As just mentioned by David, CA-211 is a first-in-class allogeneic CAR-T candidate engineered to co-express a BCV-targeting CAR and a single SSH-RNA, which interferes with the expression of the CD3-Z, a component of the TCR complex. In December last year, we announced the start of the EEC-1 trial, which is the first human open-label dose escalation study evaluating the safety and the anti-tumor activity of a single infusion of CI311 following a cycle of phosphomide and tridirabine preconditioning tumor trapping in patients with refractory and relapsed multiple myeloma. This trial seeks to determine the recommended dose of CI311 for future development as well as to establish proof of concept that single estrogen-immediate knockdown can generate allogeneic T cells in humans without inducing graft-resistant disease. To note, by health authority requests for this first-in-class allogeneic RT candidate, and similar to other allogeneic RT candidates in early-stage developments, The enrollment of each patient is staggered with a period of 28 days between patients. To date, four sites, including two in Europe and two in the United States, have been activated for the trial. Today, we are pleased to announce that no safety concerns No evidence of graft-versus-host disease or immune effector cell-associated neurotoxicity syndrome have been reported in the three first patient trips at the dose level 1 of CI-211 at 13 million cells per infusion. Accordingly, enrolling in the dose level 2 of the immune C1 study is now underway, and is evaluating the CI-211 at the dose of 100 million of C per infusion. We continue to expect to announce additional proof-of-concept data from the initial dose cohort of the study by the end of the second quarter of 2021. Let me now turn to the CIAT-101 program. Again, as mentioned by David, CIAT-101, the oncology first-in-class non-gene-addicted clinical candidate that co-expressed the NKG2D receptor and the novel TCR-inhibitory molecule, or TIN, which is literate with the native CD3-β, reducing the thinning of the TCR complex, protecting from risk of episodes. Our current clinical program, which we refer to as the allosterone phase 1 study, is focused on the treatment of advanced metastatic colorectal cancer, a difficult indication for immunotherapies. At the recent ascogastrointestinal symposium, we present additional positive data from this phase 1 study, including a median overall survival of 10.6 months for the dose escalation segment, as well as tumor burden decreased according to the standard 3D criteria observed in 8 of the 50 patients enrolled, including 2 patients with a confirmed partial rest. We also presented preliminary data showing that out of four patients analyzed at the recommend dose level 3 of 1 billion of cells per infusion, three patients with evidence of clinical benefit demonstrated an increase in the T cell repertoire, whereas the patients with a progressive disease did not show such an increase, suggesting that the patient's immune system may well be activated and participate in the anti-tumor activity observed with Fiat 101. To our knowledge, Fiat 101 is the first investigational allogeneic CAR T candidate to generate evidence of clinical activity for the treatment of a solid tumor indication, which is a major challenge in the CAR T industry and one we are working diligently to overcome. In terms of progress with the allo-shrink study, we set the patient enrollment for an expansion segment, which is evaluated in SET 101 following false theory, chemotherapy as the preconditioning for setting, in refractory late-stage metastatic colorectal cancer patients at the recommend dose of 1 billion of cells per infusion. We expect to report the preliminary data from this segment of the allo-shrink study in the second quarter, As we plan out further, we are on track to initiate the Phase I Keynote B79 trial by mid-2021. This study will evaluate SIAT-101 following fall theory pre-conditioning chemotherapy with Merck's K-TRUDA in refractory metastatic colorectal cancer space with microcephalite-stable proficient mismatch recurrence. We strongly believe that our SIAT-101 core team have the potential for both direct anti-tumor activity as well as the ability to relieve the endogenous of the patients in response that may further enhance the clinical benefit following treatment with the anti-PD-1 treatment they took. Lastly, let's talk about our progress with the Seattle Blue Party, our next generation of Congress candidates. that incorporates the SSUNA technology to target the MTG2D ligands A and with B. CITO2 is being evaluated for safety and activity. The dose escalation phase one cycle one trial for the treatment of relapsed refractory AML and MDS patients following the five flu preconditions. Just a few months ago at the annual ASH conference, We announced the initial clinical data from the study that showed encouraging clinical signals. As an update today, currently, nine patients have received treatment in this trial at Seattle 2, which has been generally very well tolerated. Of the 70 patients evaluated for clinical activity, five patients demonstrate anti-leukemic activity. We find at least 15% bone marrow blast treat. including a very high-risk MDS patient treated at the dose level 3, who achieved a marrow complete remission, which is still ongoing today. Enrollment in dose level 3, evaluating 1 billion of cells of several tools, is currently ongoing. While we are prioritizing our allogeneic programs, we continue to believe there is a high unmet need for patients with relapsed refractory, EML and MDS, And we plan to further assess the O2 differentiated profile and potentially see collaborative partnerships that could assist in driving the clinical development of autologous cancer. With that, let me turn the call back to Filippo. Filippo?
spk01: Thank you, Frederick. Turning to our financials. I'd just like to remind you all that our full financial details are available on the Cellulite Oncology website in both French and English languages. For the full year 2020, our research and development expenses were 21.5 million euros compared to 25.2 million euros for the full year 2019. The 3.7 million euro decrease was primarily driven by the decrease in preclinical activities, including process development, as well as clinical development of our autologous AML and MDS programs. In 2020, general administration expenses were 9.3 million euros as compared to 9.1 million euros in 2019, an increase of 0.2 million euros. Our net other income for the full year 2020 is associated with other grants received from the Walloon region, mainly in the form of recoverable cash advances, the change in fair value of contingent liabilities, and R&D tax credit income. Net loss for the year ended December 31, 2020, with 17.2 million euros, or 1.23 euros per share, compared to a net loss of 28.6 million euros, or 2.29 euros per share, the same period of 2019. The decrease in net loss between periods was primarily due to the increased change in fair value of contingent considerations combined with the decrease on our R&D expenses. Net cash used in the operations for the year ended December 31, 2020, which excludes non-cash effects, amounted to 27.7 million euros. as compared with 28.2 million euros for the year ended December 31, 2019. As of December 31, 2020, the company had a treasury position of approximately 17.2 million euros, or $21.2 million. Subsequent to the end of the fiscal 2020, we entered into a committed equity purchase agreement for up to $40 million with Linkin Park Capital. Over the 24-month term of the agreement, we will have the right to direct Lincoln Park to purchase up to an aggregate amount of 40 million American depository shares, or ADSs, each of which represents one of our ordinary shares. The equity facility is expected to strengthen our current financial position while also providing us with access to future capital on an as-needed basis. Based on our current scope of activities, we estimate our cash and cash equivalents as of December 31, 2020, combined with the $40 million equity purchase agreement the company has access to, should be sufficient to fund operations until mid-2022. In closing, Cellulite Oncology is more focused than ever before on our mission and our path forward. We have several key clinical milestones expected to be announced in 2020. including, one, the additional proof-of-concept data from the initial dose cohorts of the Phase I Immune C1 trial of CIAD-211 for the treatment of relapsed refractory multiple myeloma, which are expected by the end of second quarter 2021, preliminary data from the expansion segment of the AlloShrink trial evaluating CIAD-101 follicle theory preconditioned chemotherapy in refractory metastatic colorectal cancer patients, which are expected in second quarter of 2021. The initiation of the Phase I, the keynote B79 trial, which will evaluate CIAD-101 with Keytruda in metastatic colorectal cancer patients with microsatellite-stable disease, which is expected to begin during the first half of 2021. And lastly, additional data from the dose level 3 cohort of the Phase I cycle 1 file of CIAD-101 for the treatment of relapsed refractory acute myeloid leukemia and myelodysplastic syndromes, which are expected in the first half of 2021. And with that, I'll now turn the call over to the operator for your questions. Operator?
spk07: Thank you. At this time, we'll be conducting a question and answer session. If you'd like to ask a question, please press star 1 on your telephone keypad. A confirmation tone will indicate your line is in the question queue. You may press star 2 if you'd like to remove your question from the queue. For participants using speaker equipment, it may be necessary to pick up your handset before pressing the star keys. Our first question comes from the line of Olga Smolenceva with Brian Gardner.
spk06: Please proceed with your question. Good afternoon, guys. Can you hear me well?
spk01: Yes. Good afternoon, Olga. How are you? Great.
spk06: Thank you. Good. Thanks, and congratulations on the ongoing progress. And just a few questions on CI101. Firstly, and I'm sorry if I missed it, but I'm just curious about the timing of the safety follow-up for the first three patients and basically how long has it been since the infusion and maybe if we could get some flavor on CRS profile as well.
spk01: So with regards to the 101 program and the allo shrink expansion cohort, as you know, we announced that we had dosed the first patient in December of last year. What we can say today, I think, is enrollment continues. As you may recall, we're looking to enroll somewhere between 12 and 15 patients within the cohort. We currently have multiple clinical trial sites that are up and running within Belgium. We also are moving diligently to open up a clinical site in the U.S. as well. And essentially, I think, you know, it's, in general, enrollment, I think, has been good and healthy. And, you know, we're excited to see some of the initial data towards the end of the first half year for us to get a better sense of how the program continues to develop. And a big part of that is also how we will feed into the keynote B79 study, and being able to initiate that with our partners at Merck.
spk06: And basically on 211 as well, I'm just curious if you get any flavor on the initial safety on those cases.
spk01: Yeah, maybe I'll turn it over to Frederick to provide some additional thoughts. But what we've seen so far in the first dose level is, as Frederick highlighted, no graft-versus-host disease. I think we're very happy this is a first-in-human study where we're using the shRNA technology to really drive an allogeneic CAR-T. So I think we're encouraged. It is still early days here, so as we dose escalate up into the program and you see one trial, we'll learn more. But what we can say is, you know, I think we're comforted in the first initial readout on safety, and we'll look for the program to progress. But let me turn it over to Frederick for some additional thoughts there.
spk02: Yes, thank you, Philippe. No, really nothing to add on that point of view. Indeed, the dose level one, which I remember you, it's 13 million doses. There are infusions strictly no type of toxicity like CRS, GRAS, and other, and obviously, Granville's disease. Three patients means that we have any dose-limited toxicity. That's the reason why we directly enter to the dose level 2, which is now at 100 million of health. I'm not being ready to add on the top. I'm sorry. Go ahead, Aldo.
spk06: And maybe just a last question, if I may. Please. Would we maybe expect any update in terms of self-expansion and persistence in the near term as well?
spk01: Yeah, I think those are certainly things that we're keeping an eye on. We'd like to provide, as you know, some additional data here as we continue to move through the program. I think today's update for us is certainly encouraging, right? It helps us what we were trying to establish in terms of proof of concept and And that will come from multiple things, right, as an initial kind of clinical safety readout. And right now I think we're very encouraged with the lack of graft-versus-host disease that we've seen so far. As we continue to progress, I think we're really focused on the ability to continue enrollment. The other parts of proof of concept for us is it can obviously be, Can we begin to see some hints of clinical activity within the program? And then how does that match up to cell kinetics is certainly a question we're looking to answer here in the upcoming months.
spk06: Thanks a lot.
spk01: Thank you for your questions.
spk07: Thank you. Our next question comes from the line of Raju Prasad with William Blair. Please proceed with your question.
spk08: Thanks for taking the question. Congrats on the progress. Can you maybe just discuss a little bit about your dosing strategy for 211, you know, given what we know about kind of the dose response with ECMA and CAR-T? Are you thinking about, you know, doing the kind of necessary safety hurdles at 100 and kind of dose escalating to 300? Or will you be guided by potential efficacy there? Maybe just a little insight there would be great.
spk01: Yeah, thanks for the question, Raju. So we will be evaluating dose levels currently within the 211 program. As we've reported today, the first three patients in the 30 million dose level one, we are now moving into the 100 million dose level. We'll look to then go to a 300 million dose level. So it's a three plus three design. We're currently, you know, I think what's important here is also we're infusing the cells, cytoplasma and fludarabine, in really 300 mg per meter squared and 30 mg per meter squared, respectively. I think one thing that we have at the top of our head, you know, top of mind for us is to get through these next couple cohorts. Then do we think about perhaps maybe altering the preconditioning But I think what's key for us is to get to those higher levels. I think what we've seen from the BCMA landscape is kind of a dose escalation. There seems to be improvement in the responses, and I think overall, we anticipate that we'll begin to maybe see some initial clinical activity at the middle dose. And as we begin to, you know, dose escalate up, it's that higher 300 million dose level that we really will provide, you know, the greatest insight into how the program could potentially move forward. And from that perspective, how we may think about perhaps altering the preconditioning if necessary.
spk08: Great. And maybe just a question on the SSRNA platform. You know, clearly the first group of concepts is favorable on the GDHD. But maybe some discussion on the modularity of the platform. Obviously, there's discussion on how much B2M should be knocked out. Obviously, and track, I think, obviously, is something that you want to knock out completely or the T cell receptor. But maybe a little bit of discussion on the difficulty of kind of giving a modular response and the manufacturing associated with that. I'm curious to hear your thoughts, maybe David, on variability of cell products when you're looking for, you know, a 70% knockdown versus a complete knockout. Thanks.
spk01: Yeah, thanks for the question. David, I think it might be a great question for you to answer that.
spk03: Yeah, sure. Hello, Raj, and hi, everyone else as well. Yeah, so good question. One of the key advantages that the SHRNA approach gives us is that we can actually look to target a specific level. One of the advances we highlight is that this isn't an all or nothing. Exactly what the level of expression is of HLA or B2M knockdown is still something up for debate. So we're looking to try and understand this in our preclinical models to determine is there a sweet spot that we can identify protection against both natural killer cell and B-cell mediated rejection. That's very much on the activity. But I will highlight that we've really, behind the scenes, been working ever more on the platform, really with a view of having a multiplex platform that allows us to express these SHRNA with even more control than our first-generation option has allowed us. So that's very much in development. We're going to talk a little bit more about this later in the year. about those but what I can say is that the next generation multiplex approach we're using does give us a high degree of control in terms of the level of expression of the shRNA and actually the specific shRNA that's chosen does tend to show consistency in terms of the knockdown so really the choice of the shRNA really determines the level of knockdown that can be achieved and so we're using that within the basis of our new and improving framework regions So altogether, it's a work in progress in terms of understanding whether a near-complete knockdown is required or a flavor or reduced level of knockdown, Raj. We want to really have some robust preclinical assays that can answer that question. But the technology we're using at the moment, I think, gives us confidence that we can achieve whichever level of knockdown that we're really aiming to want to achieve for those products.
spk08: Great. Thanks for the question.
spk01: Thank you, Raj.
spk07: Thank you. Our next question comes from the line of Nick Abbott with Wells Fargo. Please proceed with your question.
spk09: Good morning, everyone, and thanks for taking our questions. David, I think this one's for you. You know, obviously it's very intriguing that a knockdown of TCR seems to improve persistence versus knockout. how do you think about the bar in order to declare that you can demonstrate increased persistence in the clinic?
spk03: Hi, Nick, and a good very early morning to you. That's a really good question insofar as the fact that engraftment in the patients will be determined by the level of pre-conditioning chemotherapy. So we're using I mean, if there is a standard level of chemotherapy, 30 and 300 is probably it, certainly compared to the autologous situation. We'll, of course, be looking to see what our peers and colleagues in the space are achieving with their gene-edited approaches in terms of looking at the expansion of persistence there. The question really will be that we need to be able to compare apples against apples and understand what the the impact of preconditioning chemotherapy, understand the engraftment, and then the persistence of those cells over time, because clearly the persistence of those cells will be determined by the returning patient's immune response. So all of that says it's not going to be so easy and straightforward to understand in patients, Nick, but we'll certainly, of course, be looking at the absolute levels of those cells and how they persist, certainly after a short-term engraftment and then a persistence after that. But we will have to... there in mind, you know, and try to understand how the different preconditioning regimens that are currently being used, how those impact on the different cellular therapies. That's not a great difference, but we really have to ensure that we compare, you know, life against life.
spk09: And do you think that SHRNA, you know, platform can be used to help defend against this recovering host immune response, I guess there's probably not too much you can do if perforin blasts a big hole in the cell, but if there are apoptotic pathways or something, is that something you think is within the remit of the RNA platform?
spk03: Right, absolutely. I mean, so one of the reasons why we're discussing now looking up to controlling the expression of up to six different hairpins is the fact that we want that modularity in that function. So not only can we use this to generate a platform, which, for instance, would be a TCR knockdown, can we look to, as Raj was just mentioning, can we impact on HLA, which allows us to try and defend against NK cell and T cell mediating rejection of another product. But then impacting, yeah, on apoptosis, on intracellular signaling pathways, which really is, I think, the big advantage to the SHRNA approach, that we, because we're using a single vector, we can select those cells easily, and because we can also tighter down the level of expression of some of those key proteins and enzymes and kinase targets. Yes, we certainly can, and we're certainly looking at how we can impact on the survival of those cells as well when they go into particularly harsh conditions. So that really is one of the big advantages of the SHRNA approach, certainly, Nick. understanding the contribution of each of those hairpins is going to be very key for us in terms of thinking about what the final products would look like.
spk09: Great, thanks. And then last one from me. We noticed there was a recent cancer immunology immunotherapy publication suggesting that targeting of NKG2D ligands on myeloma stem cells could be an attractive option. So, David, have you made a dual NKG2D BCMA CAR yet?
spk03: so it's certainly top of our mind Nick in terms of using NKG2D we certainly think that NKG2D not only as a front line single chimeric antigen receptor approach gives us certainly benefits but combining with other targets as well where we could imagine that not only potentially dealing with say for example as you say ligands expressed on myeloma stem cells but also more broadly than that using these stress ligands which are expressed across a wide range of tumours whether we can combine our NKGCD car with other types and approaches to try and help eliminate and reduce escape is clearly top of mind at the moment and something that we are working on in the background.
spk09: Great. Thank you very much. Great. Thank you, Nick.
spk07: Thank you. Ladies and gentlemen, as a reminder, if you'd like to join the question queue, please press star 1 on your telephone keypad. Our next question comes from the line of Smith Roy with Jones Trading. Please proceed with your question.
spk10: Hi. Good morning, everyone, and congratulations on all the progress. A question on the – probably another way of asking the prior question. Are you measuring the CAR T expansion, at least in the first dose, up to 211? And what could be a trigger to change the preconditioning regimen prior to completion of all the dose cohort up to 300 million? Like, second dose CAR, if you see the CAR T's are not expanding, would that push you to change the conditioning ahead of schedule? Just trying to get your process here.
spk01: Yeah, sure. Thanks for the question. It's a good one. Look, we are certainly going to be looking at the data here and processing that still and, you know, going through analysis on cell kinetics and we plan to have an update and really having us to try to triangulate as to what's going on. I think, you know, a couple of things here for us as we think about the manufacturing perhaps. If we take a step back, because we have an all-in-one vector process, because we do a transduction, because we are using an enrichment process with allogeneic cells, we have more of an autologous-like manufacturing process for us. So now we're currently evaluating this as a first-in-human study. As David pointed out, we're looking at more of a standard preconditioning in the context of B-cell malignancies and hematological malignancies, let's say. of 330 for cycloplasmal and flutherabine for a few days. For us, I think because we have picked up this hint that there may be a better persistence, we want to see, I guess, how that all ends up with kind of a standard preconditioning approach because we are, you know, I think it's a more robust, from our perspective, more robust manufacturing process. Does that translate using a standard approach and a standard chemotherapy that, you know, similar to, you know, I think some of the great data we've seen around BCMA and the autologous side of CAR-T? Does that translate? And then I think we want to get through the 3 plus 3 design and get through, you know, the first nine to 12 patients, let's say, and then really kind of have a sense of how we would think about maybe altering the preconditioning. So I think it's premature right now. I think that, you know, it's something we recognize the landscape within the context of allogeneic CAR T. Some of our peers are using preconditioning doses that are certainly higher and maybe longer in duration as compared to what we're starting off with. But I think, you know, one of the things we're trying to test out is capture kind of lightning in a bottle here and having an allogeneic CAR T, but because it's more autologous-like and we get more autologous-like data. So that's the premise. That's what the hypothesis will, you know, we'll run the study, collect our facts, and then see how we need to pivot from there. I don't know. I've got David. If you'd like to add anything there as well.
spk03: Yeah, I appreciate it. Thank you, Philippe. And Shumit, hi. Nice to speak to you. Actually, perhaps this relates to some of the other questions, but Raj and Nick asked and they'll go ask in particular. So the reason why Felicio says about an autologous light process, this is really around the duration of time in culture. Because we're not carrying out multiple edits and then having to really extensively select the cells and then look to really expand them to a very high level. We culture our cells for around about 12 days and so pretty similar to many autologous approaches. So the reason why we feel But we were interested to see what happens when we infuse these cells into the patient. Does that shorter term of culture, that culture time that's very similar to an autologous product, does that correlate with the levels of engraftment that we can see with the autologous BCMA product in particular, again, using the same preconditioning chemotherapy of 13300? So that's really an underpinning to the process where we've tried not to grow the cells for an extended period of time. I'm sure you're aware there's a lot of knowledge out there that the shorter the culture period, then generally the better in vivo effect. And so we've looked at the compromise over around 12 days to really ask the question of whether that shorter culture as well, which the FHRNA approach gives us and the single vector approach, whether those factors combined to generate the projects we can see enhance the engraftment of those cells. And we're following, of course, by standard PCR-based technologies to understand the relative engraftment of those cells. So that's really... Just to capture Felice's comment there around the autologous life, is this really based on the duration of culture that we maintain ourselves for before they're banked?
spk10: Got it. That was really helpful. The second question is, you know, the access of, despite there are several allergenic approaches coming up, is still the big access to the technology is a big draw here. And are you thinking of any way to monetize and capitalizing on on your technology. It looks like it's heading in the right direction and where you can actually claim in the next six months that you are there and this is a valid allogeneic approach.
spk01: I think that's a great question, Shobin. Maybe I'll turn to Stephen to let him answer as well. But I think for us, I think it's key. This data set that we'll be generating for 2.11, I think, is going to be crucial for us to really put a flag in the ground around the capabilities, the flexibility around this HRNA, and thinking about this as a very novel approach to allogeneic CAR-T. But let me hand it over to Stephen as well to have him provide some thoughts.
spk05: Yeah, and let me build on what Filippo offered as well as what David mentioned and highlighted in some of his answers as well around the SHRNA platform. We clearly believe that we've got our proprietary products and secondarily what we have with the SHRNA platform, the power, the flexibility to really be able to build enhanced CAR T-cell that's foundational to us and we are you know, looking to build on that through pipeline expansion as well in terms of opportunities of building allogeneic CAR T cells on this first generation that you've seen with 211, but also the second generation that David talked about. in terms of increased flexibility and power there. And we're looking to see how we can create value for our own pipeline and for others in terms of collaborations, partnerships, co-development opportunities down the road with this platform, because we do think it really is best in class. We think it's a much better platform than the gene editing platforms simply because, you know, we're not changing the underlying genome, but more importantly, we have the ability to tighter things up and down as opposed to an on-off that you get with gene editing. So all of those things are really front and center when we think about how we're building pipeline for ourselves and looking for partnering opportunities with other players who have a similar interest in building next-generation CAR-T therapies. Thank you so much, and congrats on the program.
spk10: Yeah, thank you for the question, Sherman.
spk07: Thank you. Our next question comes from the line of Ed White with HC Wainwright. Please proceed with your question.
spk04: Thanks. Just two quick questions for me. First, on the 211, from what I could surmise from what you said before, investors should not be expecting clinical efficacy at the at the first dose level. Is that correct? And then we'll look more to the second dose level.
spk01: Yeah, look, I think we chose the doses we've put into place here. It's a first in human study. I think we wanted to make sure we looked at doses that we could scale up to, I think, in speaking with the health authorities. And then also looking across, you know, from similar programs in BCMA, both autologous and allogeneic, I think those were, you know, really the guiding presence in some of the data we had in-house that we wanted to kind of, you know, sort of lower dose and get our arms around what the safety profile may look like and really, you know, specifically around the SHRNA and graft-versus-host disease, et cetera. So I think kind of a you know, a lower dose level and having us think about scaling up. And I think as what we've seen, if you look at the BCMA landscape, as you scale up in dose, typically you've seen improvement in response rates and you've seen improvement within the context of duration of response. So overall, our belief is that we'll need to get to that middle dose level before we begin to see some initial activity. But, you know, we may be – you know, happy to see something in an earlier at the first cohort, but at this point, you know, I think we're looking into the higher dose bubbles, but let's see where the cards fall.
spk04: Great. Thanks, Filippo. And then the second question, when talking about the future allogeneic candidates with the SHRNA, Will you be looking at solid tumors as well?
spk01: Yeah, that's certainly a great question, and it's a key focus for us. I mean, we're looking to really establish the proof of concept with 211 in the context of SHRNA and with a well-understood target and well-understood indication. But I think one of our key focuses is obviously the 101 program. in the context of solid tumors, we do believe there's a tremendous potential for NKGTD, in particular around solid tumors, because of not only the ability of the receptor to target stress ligands on the tumors themselves, but also within the tumor microenvironment. I think we talked a little bit about this last year at our R&D day. You know, the ability of the NKGTD receptor to target myelodepressor cells, Tregs, cells that are undergoing neovascularization. And so really a holistic approach to solid tumors. Now, I think, you know, one of the key, at least from my perspective, one of the key aspects of the CAR-T landscape is I think folks are looking for solutions for solid tumors with this modality. and we are obviously looking at potential other targets that could maybe complement what we have with NKGTT as well. So overall, I think it is certainly a clear focus of the organization, but I think we'll be balanced in terms of thinking about not only solitumas but hematological malignancies that we could target and indications that would be applicable there.
spk10: Great. Thanks for taking my question.
spk01: Great. Thank you, Ed.
spk07: Thank you. Ladies and gentlemen, this concludes our question and answer session. I'll turn the floor back to Mr. Petty for any final comments.
spk01: Great. Thank you, operator. Well, with that, we'll bring the call to a close. I'd like to thank everyone for joining us today and your continued interest in cellulite oncology. And we look forward to speaking with everyone soon and to a very catalyst-rich 2021 for us. Thank you.
spk07: Thank you. This concludes today's conference. You may disconnect your lines at this time. Thank you for your participation.
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