Everyone, my name is Dev Prasad. I'm an associate on Senior Analyst Kelly Shi's team here at Jefferies, and thank you for attending our Cell and Gene Medicine Summit in New York. We are very pleased to have Dr. Mark Frattini, CMO from Cellectis, joining us today to share insight on Cellectis. Welcome. Hi. Hi, Dev. Nice to be here. Thank you. Maybe we can start off with the one of the more important debate going on in the industry, which is autologous versus allogeneic CAR-T approaches. If you can provide the opportunity for allo CAR and continue the discussion, and what's the differentiation of TALEN gene editing platform versus the others that are working to bring allogeneic CAR-T to market? Sure. Thanks for the question. So, in terms of allogeneic cell therapy, I guess the obvious major first thing is these are coming from normal, healthy donor T cells. So, these T cells are much more potent. They haven't been exposed to multiple cycles of chemo, immunotherapy, or radiation therapy, et cetera, as a lot of these cancer patients have had prior to proceeding to their autologous CAR-T product. There's obviously no leukapheresis involved from the patient. These cells are immediately available, so basically, from one leukapack from a normal, healthy donor, we can get hundreds of vials of allogeneic product, which are viably frozen and QC'd at that point, so they're immediately available for use. In fact, we, for the centers that are participating in our studies, we actually have the cells on site in their cell therapy lab, so there really is actually no delay from that end. The major delay that happens is they sign consent, and they have to go through screening. So that could be anywhere from a couple of days to 7-10 days, depending on the patient, the center, et cetera. But the cells are immediately available for them. Also, there's the possibility for redosing. That's also involved with allo cells. Since they're immediately available, this can also be done later on. They don't. There's no need to have any further manufacturing. Right. Maybe we can also just touch upon what differentiate TALEN gene editing versus the other platform. So I think, you know, the, there's several different platforms, as you know, for gene editing with, you know, CRISPR being the one that's probably most well known, but TALEN has been around longer. And in fact, TALEN, TALEN is much more specific in its cutting, so there's less off-target effects using TALEN. To date, there's been about 300 patients that have been dosed with TALEN-edited products by patients in our studies and those of our partners. And this, to the best of our knowledge, represents the largest safety data set in this setting. Great, great. So maybe we can move on to various program that Cellectis is running based on TALEN technology. If you can provide brief description of fully owned program as well as those important partnership program that Cellectis has. Sure. So in terms of our partners, I would just start out with saying that in terms, Allogene would be our partner in this regard. As you know, they have a CD19-directed allo CAR-T product in pivotal phase for relapsed refractory non-Hodgkin lymphoma, and this is potentially will be the first allogeneic product approved. In addition, they also have their BCMA and CD70 programs. In terms of our wholly owned products, we have three products currently in escalation in the clinic. So we have a CD22-directed product for relapsed refractory acute lymphoblastic leukemia. We have a CD123 product for acute myeloid leukemia, and we have the first dual allogeneic CAR-T in the relapsed refractory non-Hodgkin lymphoma setting, where that's targeting CD20 and CD22. Right. So before we jump into the specific program, another important aspect of cell therapy is the manufacturing, and Cellectis has intentionally made a big push on manufacturing that they have brought all the manufacturing in-house. Maybe you can allude to that point and maybe some strategic advantage that you see in bringing manufacturing in-house. Yeah, I mean, at Cellectis, I mean, this happened before I joined the company, but in 2018, they really made this key decision to begin the whole procedure of bringing everything in-house in terms of manufacturing. So, and I think this was really important for several reasons, but really, a couple of the main reasons were, one, having everything in-house, you don't have to rely on CDMOs for anything. You don't have to wait in line to get your product done for by CDMOs. And also, in terms of your-- you have control over the quality of the product. And I would say that, we have two GMP facilities at Cellectis. We have a GMP facility in Paris, which makes all of the starting materials for it. So the TALENs, the mRNAs, et cetera, are made there. That's all shipped to our facility in Raleigh, North Carolina, where the cells are manufactured, vialed and viably frozen. ... Right. Great. So, maybe we can jump onto our first program, UCART22. Can you provide an update on UCART22, which you are testing in ALL in terms of study progress? You already dosed a first patient in EU and also in US with in-house manufacturing product. Maybe you can talk about that as well. Sure. And I just want to add on to the previous. We do. In terms of that, we have our products for our 22 study and our 20 by 22 study are now what we're using are all made at Cellectis. So, as you pointed out, for 22, that is one thing we'll get to. At EHA this year, we presented our data for the CD22 study that included mainly, it was data from. Well, it was all data from our CDMO-made product, but it was through dose escalation at dose level III, which is 5 million cells per kilo. And what we showed was that that dose, three out of six or 50% of these patients responded, and I will tell you that these are—I'm a leukemia doctor by training for over 20 years before I went into industry, and these patients are some of the worst in terms of being relapsed, refractory, completely hard to treat. They failed multi-agent chemoimmunotherapy. They failed—All of the responders failed CD, autologous CD19, 1 or 2 infusions of autologous CD19. All three of the responders failed allogeneic stem cell transplant in addition to the chemoimmunotherapy. And then we had 1 of those patients failed both blinatumomab and inotuzumab. And then the other two failed one or two rounds of venetoclax-based salvage therapy. So, a 50% response rate in this patient, patient population with literally no other therapeutic options is, we think, and the investigators think is, is very, very good. To your other point, with P2, we have since brought our pro. We call it Process 2, but that's the product that's made at Raleigh and wholly made within the Cellectis, both, Paris as well as North Carolina. And, we are currently dosing patients with that product. Right. So, you started dosing. Maybe you can talk about the trial design, how it is different than the product that you manufactured, used from CDMO, and a little bit on that aspect. Sure. So, there's no difference in the actual trial design. What we did that was different is because the in vitro comparability tests that were done between the CDMO-made product and the Cellectis-made product showed that the Cellectis-made product was significantly more potent, in the order of logs, more potent than the CDMO product. We did bring the Cellectis-made product into the clinic at a lower dose level. So we started dosing patients at DL2 instead of DL3, so it was 1 million cells per kilo is where we started dosing with the new product. Maybe interestingly, it's more potent. Any insight to why it was more potent than a CDMO product? Well, I think a lot of it's got to do with the process, and I think, like we talked about, the control of the quality, timing, everything, I think is really, really important. And I think one of the other things is, you know, Cellectis has been around for over 23 years, and they're really the pioneers in this area in developing allogeneic cell therapy. And so I think, you know, on the back of all that experience comes what we're seeing in the clinic now. Right. So maybe, if the potency is higher, that can also help reduce the costs and related expenses. What are your views? Well, I think in terms of the, you know, obviously, the expenses for an allogeneic product are going to be significantly less than an autologous product, as you know. Right. But, in terms of the manufacturer, the main difference is that if we use less, instead of two vials, we use one vial type of thing, so- Right. You know? Okay, great. And, maybe you can share, when should we expect the next data update from an in-house manufactured product, and, should we expect it at any medical conference, or it'll be an investor event? Any insight on that? Yeah. So we plan to discuss the first patients treated with the in-house made product later this year at a major medical conference. Okay. All right. So, one more thing, differentiated is that you also included alemtuzumab as an investigational medicinal compound in your trial. Could you discuss the reasoning behind that and, what will be the implication moving ahead? Yes. I think that, the major thing that we, we noted is by deleting CD52 with the TALEN technology, that allowed our CAR T cells to be resistant to alemtuzumab. And one of the things that we did early on, both in our 22 study and in our 123 study for AML, is that we started a cohort, an initial cohort, that just used fludarabine and cyclophosphamide lymphodepletion without alemtuzumab. And what we saw was that, we weren't getting adequate host immune suppression throughout, for instance, like a 28-day DL2 period. And as a result of that, we weren't getting significant enough expansion to give us good clinical activity. So we closed those arms of the study. We opened the arms with, using fludarabine, cyclophosphamide, and alemtuzumab. What we saw in both studies was that we then did achieve adequate host lymphocyte suppression throughout a 28-day DLT period and beyond, number one. Number two, this allowed for a much greater level of UCART expansion, and this translated into a better clinical activity- All right. for that. Right. So, another thing is, can you provide some color on expectation for UCART22 in patient who has progressed on CD19 CAR previously? Sure. So I think what we're seeing a lot of in our study are patients who have failed at least one round of autologous CAR 19. I say that because we have had a few patients that have had two CAR T-cell infusions that have been separated significantly in time and failed both of them. So we are seeing responses in that setting, and in addition, we're seeing responses in setting where they failed allogeneic stem cell transplant as well. Right. So overall, for UCART22, what would you say will be the bar for success for the dose escalation trial? So I mean, I think the bar is going to be obviously lower than what's out there for autologous CD19, mainly because we're going into an additional line of therapy. I mean, in these patients that we have right now, they're so heavily pretreated. I mean, our median number of lines of therapy is four, so far going into these with these patients, with a range that goes up to eight different treatment lines prior to getting our, our therapy. So it will be lower than autologous CD19. Right. Okay. And, moving on to UCART123, maybe you, if you can discuss the progress so far for UCART123 program, and, again, when should we expect some data update for that program? Sure. So, our UCART123 data was, that we've disclosed so far was from last year's ASH, where we had an oral presentation where we showed basically from the beginning through mid-dose escalation, with the UCART123 product using FCA lymphodepletion. We showed initially the difference between plus alemtuzumab, minus alemtuzumab. The other thing I want to point out between those is that we oftentimes get asked questions about increased infectious complications, et cetera. And in both of our studies, both the UCART22 and the UCART123 study, comparing those that received only FC and those that received FCA, there was no significant difference in infectious complications with the alemtuzumab usage. So, we showed that we got better host immune suppression that allowed for more significant UCART123 expansion, and we saw significant responses with using FCA lymphodepletion. So one of the responses was a patient who had failed multiple lines of therapy, including transplant, who then was able to get UCART therapy to reduce their disease burden so that they could get a donor leukocyte infusion from their prior transplant donor that they couldn't have gotten before because they still had such a significant burden. The other was a patient who had failed, again, 5 prior lines, including an allo transplant, who went into the study with multiple grade 4 cytopenias that were at least 2+ months prior to coming into the study. And this patient really had nothing left. I mean, they failed basically everything, and they went on to get an MRD negative CR that lasted over a year. So really an amazing response in somebody that had such a really, refractory disease. Nice. So, maybe if you can set expectation on data update and what should we expect in terms of maybe efficacy bar or number of patients? Sure. So I think that for UCART123, the other thing that we showed last December was that CRS is a, you know, is an expected complication of CAR T-cell therapy, but particularly in targeting AML, and in targeting UCART123, there's a higher risk for CRS. In fact, we had 100% CRS in the study, most of it being low grade, grade I and II, that was easily manageable, but we did have higher CRS in a couple of patients. And as a result of that, we sorta went back and redesigned our treatment strategy to use more of a 2-dose regimen. So by knowing that using alemtuzumab, we can achieve a significant period of host lymphocyte suppression, we're able to give a cell dose at day 0, and then we're giving a second cell dose, you know, between days 11 and 14, so that that second cell dose will still be allowed to expand given the lymphocyte suppression from the alemtuzumab. In addition, we also implemented giving a dose of prophylactic tocilizumab before cell infusion, which has been shown in the NHL setting to help reduce the development of significant CRS, and those complications. And so, likely, you know, we won't be disclosing any more data this year, but early, I mean, some at some point next year, we should be able to disclose data for the patients treated with this 2-dose regimen. and how effective that's been in both mitigating CRS as well as clinical activity. Right. Great. So moving on to dual CAR CD20 and CD22, what's the rationale to pursue if you can elaborate on this dual targeting strategy? And, also, if you can talk about expression level related to CD19 and how widely these two antigens are expressed. Sure. So for 20 and 22, so these are both antigens that aren't CD19, so it provides an alternative for CD19, particularly for those that have failed prior CD19. I think importantly, the dual CAR allows for a tighter synapse and better killing. It also allows for preventing antigen escape. And in terms of expression, 20 and 22 are pretty much universally expressed on all B-cell NHL subtypes, and the expression levels between 20 and 22 are similar to CD19. Right. And continuing the discussion, if you can talk about the progress on this asset, and maybe how many sites are open, and any feedback you received from KOLs on the design, dual CAR design as well as study design. Yeah. So, first off, the investigators are super excited by this because, one, like we say, it's an alternative to CD19. And also, you know, with a significant amount of patients failing CD19, at some point it provides them for the next line of therapy. So they're very excited by the dual nature of it, as well as the fact that it's CD20 and CD22 and not CD19. We have began enrolling patients in the study, and we will disclose some of the first-in-human data later this year. Right. We look forward to that data set later this year. And finally, before closing our conversation, if you can talk about collaborations that you have with the different companies, Allogene, Iovance, any thoughts about those, and should we expect more strategic collaborations? Well, I think, you know, as everybody, we're always looking for strategic collaborations, as opportunities present themselves. So that's the first thing. I think in terms of Allogene, as I discussed before, they're a very strong partner, and we're super excited to see as their CD19-directed product progresses through their pivotal phase study, in addition to what's being done with BCMA and CD70. In terms of Iovance, again, this is something where we're looking forward to as they disclose data from their melanoma and non-small cell lung cancer study, where they're using a TALEN edited PD-1 deleted TILs. So we're looking forward to that data as well. Then for Cytovia, there's been great progress in terms of the preclinical data, and, you know, we look forward to when they get to the point of being able to bring these TALEN-edited iPSC-derived and CAR NK cells into the clinic. Right. And with this, we will wrap up our conversation here. Thanks again for spending time at Jefferies Cell and Gene Medicine Conference. Thank you. Thank you, everyone. Thanks, Prasad.