MiNK Therapeutics, Inc. (INKT) Earnings Call Transcript & Summary

All right. Good morning, everyone. Our next fireside chat for today is MiNK Therapeutics. With me, I have the company CEO, Jennifer Buell. If you have any questions for us, please e-mail them to me at [email protected]. Jennifer, welcome. Thanks for joining us today. Let's maybe start off by learning about recent developments at MiNK, and let's also help our audience by laying out what's next or what's in store for the next 6 to 12 months in terms of R&D updates and clinical developments.

Kalpit, thank you very much. We're so glad to be here at your conference. And I'll tell you, over the next 6 to 12 months, we will be reading out a mature data set on our solid tumor clinical trial. This is a big deal for us. You may recall that just last November at SITC, we had presented some early signals of our cohort, which actually opened in May of last year, and enrolled 40 patients in a very short period of time. At the time of SITC, we actually presented some early observations, and these observations showed some biomarker activity of the cells, which actually -- in patients with solid tumor cancers. And these biomarkers address some common limitations that we see with currently available therapy and the most commonly used like anti-PD-1. And these include drivers of immune exhaustion and -- that allow tumors to escape. And what we were able to demonstrate both preclinically and then clinically is that invariant natural killer T cells, or iNKT cells, which are a subset of T cells that actually have the capability of both T and NK cell, which is very important. And we've shown that these cells actually address the limitations of the most commonly used cancer therapies biologically. That includes taking a profile in which patients are treated with chronic antigens or exposure to their tumor. They're treated with PD-1. We see sometimes some benefit there, but yet we also see a signature of exhaustion, which starts to be exacerbated over time, and continued exposure. What we were able to show is that we could take these cells and they actually reverse that exhaustion, and they reinvigorate T cells and allow them to be tumor-killing again. It's really important. They also traffic the T cells to where they need to be within the tumor. So that's one important update that we will be reporting out on as -- maturity of our clinical cohort in solid tumor cancers of the cells dosed as a monotherapy as well as in combination with KEYTRUDA or OPDIVO. You could expect those data in the beginning of this year, which we're quite excited about. In addition to the solid tumor data, we also will announce some important updates on our armored-CAR-iNKT programs. Now we've shown that we have an IL-15 armored-FAP-CAR-iNKT that appears to show some benefits that could be potential first-in-class, first-of-its-kind with addressing FAP in solid tumors. We've also armored our BCMA-CAR-iNKT program, which addresses many of the limitations of BCMA, which is an active target in hematologic malignancies, but limited by some of the cost and logistic feasibility. So we've been able to now demonstrate that we can armor BCMA for enhanced longevity and engineer it into an iNKT, which allows us to address the logistic feasibility, showing efficacy with the speed and cost of biologic therapeutics. So it's really exciting advancements for all of our programs, the cells in their native form in solid tumor cancers and our engineering capabilities in very novel CAR-iNKT approaches.

Okay. Fantastic. And Jen, one of the most, I guess, common questions we get, there's obviously a ton of cell therapy players out there with different cell types, auto versus allo, gammadelta versus iNKTs. I guess, if you were to highlight a few differentiating features with yourself, what would they be? And have you -- do you have clinical evidence in your data set with agenT-797 that suggests that those outline benefits have somewhat translated into the clinic?

Thank you for asking this question. I have to tell you, one really important piece is after our presentation at SITC, we presented in 5 programs, clinical and preclinical. And we then later hosted an R&D Day, and all of this in its full form and abbreviated form are on our website. I'd really encourage you -- we had some independent thinkers who are experts in cell therapy, specifically in the cell types that you're talking about, T, NK, gammadelta, MAIT, iNKTs, what are the strengths and limitations of these approaches? What we were presented with, which I thought was really extraordinary, is that our team -- there have been long-sought mechanisms of these novel cell types, moving away from conventional T cells and the limitations of conventional T or the limitations of NK cells and durability. What our team was able to demonstrate in multiple different forums, solid tumor cancers in the clinic as well as in preclinical data sets very thoughtfully done, were that the characteristics of iNKT cells compared to other cell types that have been hypothesized but never demonstrated. And we actually demonstrated some important features that are differentiated in invariant natural killer T cells. Those include that iNKT cells, they are a rare and potent class of T cells. They're a subclass of T cells. They have been challenging for the field to bring forward because of their rarity. They're very difficult to access in circulation. They're less than 0.1 -- 0.01% of circulating T cells. Our team has been able to address this through a very thoughtful manufacturing process that allows us from a single donor to generate essentially 5,000 doses per year. This gets us to a point where we could address all of the logistical challenges that have faced the industry but also give us an opportunity to test this much more broadly. Because of the scalability, we've been able to demonstrate some important features of these cells. That includes that the cells actually have the killing power of NK cells and the memory potential of T cells. We've shown this visually. We've shown this with immunohistochemistry. We've shown it in clinical samples, and we've done it preclinically that these cells can actually take and chaperone exhausted CD8 T cells into the tumor and reinvigorate these exhausted T cells to killing again. Incredible. So those elements we do -- we cannot show with some of the conventional cell approaches that are being used widely today. We've also shown some novel and differentiating features in that these cells can activate dendritic cells. Dendritic cells are signalers that actually help the immune system recognize cancer tumor cells specifically. And importantly, and I believe this is a very novel finding that we've shown that iNKT cells can actually kill M2 macrophages. This is a long-sought feature. M2 macrophages are immunosuppressive cells that constrain the body's ability to fight tumors. And we have been able to demonstrate that iNKT cells actually can kill M2 macrophages, very important feature. And I mentioned already restoring the tumor-killing capacity of exhausted T cells. Those data taken together and the signals that we shared in our solid tumor protocol are now coming together with synergy. What we had shown publicly during SITC is in a very early data set. We were seeing some interesting signals of disease stabilization in tumors that were refractory to all available standard of care. In our updated data set, we will present data showing maturity of the data set and some very interesting signals where we believe these cells are showing quite a bit of benefit in solid tumor cancers.

Okay. And maybe -- I want to ask a question on the efforts in multiple myeloma first. You've shown data that patients can tolerate doses up to, I think, 1 billion cells, at least so far. Are you planning any further exploration of additional doses? Or I guess, is dose escalation still ongoing for that trial?

So we have -- now there are some important components here. We have tested the cells at multiple doses, and we designed our trial to do so to address the FDA requirements on dose optimization early in clinical trials. This allows us to set a randomized Phase II dose very quickly and develop in a more expeditious way. So not only did we start at a very low dose, essentially at 100 million cells, we went up to 1 billion cells. And we've demonstrated that these cells can be administered tolerably, no cytokine release, no neurotoxicity. These cells can also be administered in combination with the most commonly used therapies, including anti-PD-1 therapy. We also conducted dose escalation in that combination. We'll continue to do expansion cohorts so that our data set in safety at multiple doses is really quite robust. But we believe we have a dose that we've selected that is biologically active, tolerable and can be dosed in combination with important checkpoint-modulating antibodies as well as other standard-of-care chemotherapeutics.

Okay. And do you expect the dose for agenT-797 to be different for solid tumors versus liquid tumors? I mean, is there a different right dose in solid tumors?

I would say, at this point, what we and others have shown that the cells can be dosed to about 1 billion. It seems to be somewhat of a sweet spot in solid tumors as well as in heme malignancies. We have some more work to do in heme malignancies to be able to demonstrate that we have a deeper data set in solid tumor cancers to feel more confident about the dose. But I would say that based on where we are, generally, I think that getting to that 300 million to 1 billion cells is a sweet spot. The difference with the iNKT cells is we could get there without cytotoxic lymphodepletion, which is very favorable, particularly in the setting of heme malignancies, where cytotoxic lymphodepletion is still required and really is difficult many patients to tolerate. We don't appear to need any lymphodepletion in our studies, both in the solid tumors nor in hematologic malignancies, which we think will be a major differentiating going forward.

Okay. And based on the properties and underlying biology of iNKT cells, are there certain types of solid tumors that you think might be more susceptible to agenT-797 at -- perhaps at higher doses?

I'll tell you, Kalpit, I'm glad that you're bringing this up. So MiNK was born really just about 14 months ago given the value that we believe that these cells can present and what we as a company can bring to the science and technology through our manufacturing background and prowess in the space. The data that we were really building on was generated independently of MiNK initially in the autologous setting. So the clinical benefit of iNKTs has been demonstrated and a number of independent clinical studies that have been driving our opportunities for development as well. And what we've been able to show is in certain tumors that have previously responded to the autologous iNKT cells, we've been able to create an off-the-shelf approach much more feasible and demonstrate activity in these tumor types. And these tumor types also represent favorable areas for development. So historically, independent of MiNK, there are data that have demonstrated an overall response rate of greater than 50% in head and neck cancers with autologous cells. And that compares to about 20% -- just over 20% with standard-of-care therapies, a long-term durable disease stabilization in refractory non-small cell lung cancer. And that's a major opportunity for MiNK. Because with cells right now, what we've been able to demonstrate is in non-small cell cancer, when patients are refractory to KEYTRUDA or OPDIVO, there's really nothing for them. The bar is about 10% with docetaxel. So we have patients with lung cancer being treated with our invariant natural killer T cells allogeneic, both alone and in combination with these major checkpoint-modulating antibodies. And that's an area of opportunistic development where standard of care after PD-1 is very limited, very low bar. And in addition, what we've also seen with the cells in the autologous setting is long-term survival in liver cancer, and this is also a big opportunity. What we see mechanistically is that these cells can actually home to the liver and modulate disease in the liver. This is very unique, I believe, to iNKT cells. We know as a field that our liver exists to tolerate us to things, food, the environment, toxicities. And it -- the liver also tolerates us to cancer. That's a major limitation. And when patients have disease in the liver, our available therapies are actually not helpful. So if these cells can do what we believe they can, and with the autologous iNKT cells showing not only disease modulation in the liver and in liver lesions but also clinical benefit of long-term survival and in our clinical data set that we'll be presenting publicly in the very near term, we are seeing some disease modulation in the liver, which is not only very important for the cells today for patients, but also from some combination approaches that we are contemplating with very novel checkpoint-modulating antibodies, including Agenus' botensilimab, which is taking center stage at ASCO GI on Saturday. That is an Fc-engineered CTLA-4, which we have previously presented at AACR. The complementarity of botensilimab that can address cold tumors -- multiple cold tumors, including MSS CRC and lung lesions -- and in preclinical models, when you take that benefit, 30%, 40% in those disease settings and you add the iNKT cells to botensilimab, you can get complete tumor elimination. So we will be looking for opportunities to start to expand benefit of botensilimab, of KEYTRUDA, of OPDIVO in these disease settings by adding native iNKTs. And the data that we'll be generating in solid tumor cancers will actually lay the foundation and demonstrate where we believe these cells can be most opportunistic and expanding benefit of these well-known agents today.

Okay. And you bring up combination-based approaches here. I guess, how are you thinking about the potential safety and tolerability? I think you have some safety data with the combination with PD-1 inhibitors. So curious to hear your thoughts on safety as you sort of expand combination-based approaches.

I'll tell you, we've been very enthusiastic about the tolerability, particularly to the doses that we've been able to test. We are going to be pushing the limits beyond where we're seeing tolerability in order to ensure and secure the data sets and the observations that we've seen so far. But what we have observed is in preclinical models as well as in the clinical setting, there's no question we could dose the cells tolerably in combination with widely used therapies, including KEYTRUDA and OPDIVO. Those are the most widely used cancer therapies in solid tumors right now. We've also shown preclinically in important IND-enabling studies that we could dose the cells tolerably in combination with agonists, in combination with iNKT cells and some of the therapies that I mentioned, like botensilimab. We will, of course, be thoughtful and conservative in our dose setting, and we'll start lower and ensure safety for patients. It's our highest priority. But right now, based on the preclinical data set that we've generated, the clinical data set of over 300 patients now dosed with botensilimab in tens of thousands, if not close to a few million patients dosed with anti-PD-1 therapies, we have a very sound data set to build from, and we can monitor tolerability very carefully and closely. But we're confident today that the cells can be dosed in solid tumors, multiple dose levels, alone and in combination with the most widely used therapies.

Okay. And one intriguing aspect of using agenT-797 or iNKT cells in general is that you're administering -- or you can administer these therapies without lymphodepletion, which some may argue that, that might impact the persistence of the cells and thus limit durability efforts. I guess, what have you seen so far in terms of persistence for 797 that -- does it indicate that these cells have the power to remain active for the right amount of time in the body?

Thank you. And Kalpit, we'll be presenting a pretty deep data set at an upcoming conference early this year that actually supports some of the questions that you have on persistence. What we had previously presented is that these cells appear to not only -- when we administer them, they are accessible in the periphery for about 7 days. We then see that they somewhat immediately traffic to very important tissues. And that includes the lung, the liver, the bone, spleen, et cetera. And we've been able to demonstrate that the cells actually persist in those locations. They're tissue-homing and dominant, and they persist beyond 30 days in those settings. We've also been exploring this deeply in the setting of multiple myeloma and solid tumor cancers, and we're going to be providing an update. I'll tell you from what we could say just briefly is that we believe that currently, we can administer the cells without lymphodepletion and maintain the persistence that is necessary. The other important piece is the data that we've observed is that the patients don't generate alloantibodies to these cells. And actually, the alloantibodies that are generated very early appear to be quite transient and are absent soon after dosing. We believe we can redose, and we're going to be exploring that very quickly and announcing that in some upcoming clinical trials that we could actually redose these cells and they can be redosed tolerably and also without lymphodepletion. These cells have an important feature and that they actually are -- they not only prevent or do not induce graft-versus-host, but they actually prevent graft-versus-host disease. And those are some of the findings that we've been able to lean on that show that these cells actually have the kinds of persistence and beneficial immune-modulatory activity that will not induce rejection. Now we're going to take those findings and apply them certainly in the settings that we're talking about, but we will also be advancing these cells in the disease settings where we believe that their natural biology can also address a major unmet need, including engraftment success and in GVHD, which we haven't spoken too much about as of yet because we've been prioritizing our solid tumor trials. But we will be announcing this more clearly in the upcoming weeks.

Okay. That's great. Maybe shifting focus to some of your earlier-stage programs that you're planning to advance in the clinic here shortly. You have 2 IL-15 armored-CAR-iNKT cells. There's MiNK-215 that's targeting FAP, F-A-P. And then you have MiNK-413 that's targeting BCMA. Maybe starting with 215. Can you talk about this target? I've not heard about fibroblast activating protein (sic) [ fibroblast activation therapy ] very frequently in the cell therapy landscape. What antitumor enhancements that you can expect with 215 over native, just made of iNKT cells or agenT-797?

Absolutely. Happy to do that, Kalpit. Now FAP-expressing and CAF-expressing immune-modulatory activities is actually a major driver of tumor escape. And we've known this from interrogating tumor biology for some time, but there have been no effective therapeutic approaches that could address this biology in effective ways. So it is a known target that actually is a driver for tumor regression or progression and escape. What we've been able to demonstrate is -- now I'll tell you something -- some very important synergies that we have, particularly given our background in the antibody space. Our Chief Scientific Officer, of course, led the antibody and was our Chief Technology Officer at Agenus. And prior to that, he was the platform developer and engineer at Medarex and Genmab, et cetera, a deeply experienced individual in leveraging platforms and biology in order to find ways of optimally addressing biology. So we have the luxury of interrogating multiple approaches to address biology. And what we landed on here, because of the paucity of approaches to address that effectively, we've been able to take advantage of our CAR-iNKT and we can generate a FAP-CAR-iNKT armored. And we've been able to demonstrate that not only does this approach increase T cell activities towards the tumor, but it also shows important tumor control. We've presented that now at SITC in important preclinical models. We're, of course, continuing to expand this model with additional parameters to deepen the mechanistic benefit. But we believe that actually not only has -- can a FAP-CAR-iNKT eliminate tumor burden but also promote survival. And these are in models that are in exhausted settings. So they were not only able to address the biology but also the immune-modulatory cells that are necessary to potentiate tumor-killing. And that includes reinvigorating CD8-exhausted T cells as -- and trafficking natural killer cells for rapid cytolytic activity. So this is an important advancement in addressing a very important unmet need right now in tumor biology and one that is currently in IND-enabling studies. And the other that you've mentioned, of course, is our BCMA program. Now I mentioned a bit about BCMA. It's an important target. They're addressing this target, has shown great benefit on response rates. But we also see that more than 2/3 of patients progress. And those patients, 65%, 66% of those patients, are still expressing BCMA antigen, which not only demonstrates that the current approaches are limited, they're also really short term. So while the benefit is pronounced and profound in the short term, it's actually not durable. It's also not logistically feasible. It takes a long time to get these products to patients. We could overcome that with a product that we believe not only will -- and we've demonstrated preclinically that we can slow tumor growth, but we appear to expand beyond the benefit with our BCMA-CAR-iNKT than what's available with any of the BCMA approaches, commercially approaches and those in development today. And I think that that's a really important feature that we need to be thoughtful about. There are current approaches that are short term, high impact, effective but don't eliminate the disease. And so there's still a major unmet need. We are exploring opportunities in which we can leverage partnerships in order to accelerate our development capacity because our innovation and our speed of innovation is outpacing our ability independently as a small company to bring these forward. So these approaches give us an opportunity to explore opportunities to accelerate development through strategic partnerships and collaborations, which allow us to retain control of the assets, but also to speed them up so that we can bring multiple products and innovation forward to patients quickly.

Okay. Great. That's fascinating material, Jen. It's always great to learn about ongoing developments at MiNK, but I think we're out of time. Thank you very much for joining our fireside chat today. I look forward to the many updates from MiNK over the next 6 to 12 months. And thanks, everyone, to the audience for tuning in.

Thank you very much, Kalpit. Great to be here.