Session I

Toxicity prophylaxis and treatment 

Right? I mean, I think, I think it was interesting, we, we talked a lot about really the idea that ICANS neurotoxicity is a cytokine-driven process. And obviously the first logical thing to block was IL-6. And the early prophylactic interventions using Tocilizumab, the IL-6 receptor blocker really didn’t lead to decreased risk rates of ICANS, but really to decrease CRS. And then obviously IL-1 was the next cytokine that was, you know, attempts for me to block that. But that doesn’t seem to be the be-all and end-all either.

Yeah. No. And I think the other important thing that came up in the session was that, you know, despite all these attempts at blocking, inhibiting, the early days of CAR T, everyone was very afraid to even give any steroids, even steroids around collection, people were very afraid to do that. There are some data that look at the risk of steroids, long courses of steroids. And I think there’s definitely an infection risk in terms of treatment-related mortality. Whether those steroid durations are more of a surrogate for high-risk patients who would otherwise have high toxicities, I think is unclear. But we really haven’t had a study that impacted the efficacy of the CAR Ts in a negative fashion. So, I think, just all the more reason to continue to investigate these individual pathways, especially since we’re starting to really understand what the avalanche is that leads to some of these clinical presentations, right?

But I think at most centers, I mean, certainly at my center and probably yours as well, I think we have moved steroid use earlier, just based on some of the prophylactic or at least early intervention steroid arm, the SMS cohort for data. I think typically we’re intervening at grade 1 to 2. Whereas I think historically, everyone intervened at grade three. But by then, I think then you’re, you’re really stuck with perhaps not reversing the symptoms for many days.

I think you made a fantastic point of a little bit of steroids up front can potentially prevent a whole lot of steroids on the back end, right? And overall, with infectious complications and what not, be better for clinical management.

Right.

And I was also very intrigued by the data you presented about, and I guess, you know, we still await a clinical trial on this, but the potential for blockade of interferon gamma. Yeah, I know there’s a lot of, you know, serendipitously the new approval for Emapalumab and HLH within the last year or so, gave us a potential tool now to use in the clinical setting. University of Pennsylvania and some other institutions have started to play with this and use it in highly refractory patients who failed other management. But I think we definitely need good prospective studies. We’ll get this, try to understand again, more mechanisms and see how we can impact it but you know, the dosing, the tumor-burden impact, all of the various factors. I think you’re going to be hard to necessarily control for, right. And I think you bring up the great point of really doing for these prophylactic interventions, prospective studies. I think a lot of what we have are these piecemeal retrospective, selected patients, small numbers.  And again, we don’t have then the correlative data that will really help us move forward because as we saw with some of the, you know, Anakinra, maybe it helps decrease the toxicity somewhat, but it’s not really going to allow us to completely move to patient administration.

Right? But, you know, I think it was a great session. Great questions. Yes, lots of good questions. You know, probably more questions when we get back downstairs. Yes. Look forward to having more of a discussion on this.

Updates in multiple myeloma

Hi, I’m Rafael Fonseca from Mayo Clinic in Arizona. And we are today at the International Workshop for CAR-T Cell Therapy. I’m joined here by three esteemed colleagues and would like to do a summary of what we just discussed for the treatment of multiple myeloma. Doctor Bahlis, would you mind introducing yourself?

Sure, I am Nizar Bahlis from University of Calgary.

Dr Yi Lin?

Hi, Yi Lin. I’m from Mayo Clinic in Rochester, Minnesota.

Doctor Mailankody?

Sham Mailankody from MSKCC in New York.

Well, thank you. Thank you for joining us. We had an extensive discussion, we could go on for hours, but if you were to put a brief synopsis, why don’t we start first with you  Dr Lin, talking about BCMA-targeting, both CAR-T cells and bispecific antibodies. Lots of excitement there.

Absolutely. These are the new kid on the block in the recent years. We have FDA approved BCMA CAR-T, two BCMA CAR-Ts in the US. And most recently a BCMA-targeting bispecific antibody also approved. So we heard from Doris Hansen on real-world experience with ide-cel. So we see that even though in the real-world, close to 70% of those patients’ wouldn’t have qualified for the registration study. Overall, the outcome has been very good.

I presented an overview of these BCMA CAR-T in earlier lines setting. The randomized control study for Ide-Cel versus standard of care has been recently published. So FDA is currently looking at this in terms of how this might move Ide-Cel into earlier treatment landscape. And we will hear coming up, Cilta-Cel versus standard of care in early line of therapy this year. In addition, there are studies in the frontline setting. So Krina Patel also then presented looking specifically at myeloma, high-risk myeloma, both how we think about functional high-risk and cytogenetically defined high-risk. What have been some of the activities of CAR-T in that space and how to think about the use of CAR-T. And then of course, Rafael, you presented on the bispecifics. We’re seeing not only now Teclistamab in

real-world practice, but a number of BCMA-targeting bispecifics in clinical trial setting. What’s really exciting with this being off-the-shelf, we’re seeing fairly comparable PFS compared to patients who would have received CAR-T. One of the questions with this being a continuous therapy is understanding some of the toxicities and how to potentially optimize its use in practice.

Excellent summary. Thank you. And it’s just such you know, a wonderful set of examples of how can we can extend the lives of patients and hopefully they’ll move earlier in lines as you just described, perhaps even with better activity. But the good news is we have more than one target. So Sham, what do we know about the other targets that are, you know, being used for development of these agents?

Yes. Although the BCMA therapies are great and we see deep responses, I think one of the challenges, as we’ve discussed at this meeting, is that many patients unfortunately eventually relapse and need additional treatment options, which is where these other antigens come. And in our field, I think now there are two non-BCMA targets for immunotherapies. One – GPRC5D, two – FcRH5, both of which have clinical trial data now suggesting good efficacy. For GPRC5D, if CAR-T cells targeting GPRC5D, there’s at least three that have been published, including one from our group looking at using CAR-T Cells to target GPRC5D. And all of these products show good responses in the order of +70% of patients responding, including many patients with previous BCMA therapies suggesting that you can get more than one immune modulating treatments sequentially and have good responses. There’s also bispecific antibody. So Talquetamab, which is a GPRC5D bispecific antibody was also presented, published and we discussed some of those data at this meeting as well. Looking at, again, the response rate in the order of 65 or so percent of patients with the response and it’s likely that Talquetamab that may very well be the first non-BCMA immunotherapy to become readily available in the near future based on these results. And then there’s FcRH5 for which currently there is a bispecific antibody, cevostamab. Again, in phase I-II studies we’re seeing responses in upwards of +60% of patients and including patients with previous BCMA-directed therapies, etcetera. So I think we have BCMA-directed therapies which are already available more readily. And then GPRC5D and FcRH5 targeting treatments. So, one of the big challenges we spend a lot of time discussing is what is the optimal sequence of these different agents, can we combined them? Does one come before the other? Do we use a bispecific before CAR-T cells? Vice versa – how do we move this up? So those are some of the challenges, but they’re good challenges to have because it means our patients have many more options to treat their disease and hopefully live longer with better quality of life.

Thank you. Thank you. That’s excellent. And Dr Bahlis, your group has been, you know, thought leaders on understanding the biology and mechanisms of resistance and perhaps prediction of those spaces that are better treated with one of these agents versus another. Uh Could you expand a little bit on, on what was discussed and your thoughts on that particularly? Sure if I let this meeting discussed with my colleagues, the mechanism resistance to BCMA bispecific antibody mostly. And there’s been a lot of work done in this context and also resistance to BCMA CAR-T cells. What the studies show right now for CAR-T cells that biallelic loss of BCMA post-CAR-T cell is a rare event, less than 6% of the patients seem to have this event happening post-CAR-T cells, their limiting resistance has to do more with the CAR-T cell product itself. Meaning is it rich more for memory like T cells CD4/CD8 ratio and the presence of regular T-cells in this kind of product. This seems to be the predominant mechanism from a CAR-T cell product itself. There is some clinical factors as well that seemed to predict lower outcome or lesser survival in these patients has to do with a high disease burden in the these patients and the presence of extra artery disease. And as stage three, for bispecific antibody, the story seemed a bit reversed. There, the loss of BCMA at progression seemed to be a more prevalent event. Any small cohort we studied this seemed to be over 50% of the patients have either bad like loss of BCMA or a functional loss. Meaning they have a mutation, the BCMA your domain that alters the binding of bispecific antibody. The good news that these bispecific antibodies have different activity against this mutation, meaning they can be resistant to one BCMA-tageting bispecific antibody, but sensitive to the other one. But we still need to better understand this mechanism. And this one, I was to hopefully better design better CAR-T cells in the future and better second generation bispecific antibodies as well.

Thank you. Thank you. That’s remarkable. I’m going to ask each one of you to give me a take-home, like very practical clinical pearl for people that are seeing us out there who may be in clinical practice. And maybe I’ll let you think about that, I’m gonna start with mine. But I think one of the key aspects is going to be to understand which patient is better treated by one of those agents, right? We’re now totally (inaudible). We’re thinking: should we measure for BCMA or not? Which in fact, we can spend a few minutes discussing how that could be helpful or not, but there might be a future where specific antibodies might detect truncated protein, right? And by many histochemistry, you know, this patient should go with this or this other, right? But the bottom line is: we don’t have those biomarkers yet. So that’s my take-home message. Maybe, Sham, let me start with you. So I think for me, I think one of the teams is toxicity management. So as we develop these treatments, the big focus with CRS and neurologic toxicities, and don’t get me wrong, those are still very important toxicities managed. But we’ve learned more about how to watch for them, and these happen typically when patients are admitted and monitored very closely. I think what worries me a little bit is more longer-term toxicities like infections. You know, how do we recognize infections early? There are some unusual infections we see with these treatments, how do we manage and work these patients up appropriately and treat appropriately. So I think managing long-term toxicities, infections such that that is not a challenge for our patients is probably an important consideration.

Very important, you know, patients will be seen by community practitioners. So we need to keep that in mind right, as well too. Yi?

My practical pearl, which could change by next year, hopefully. But as of today is very much, you know, if you are in practicing, treating patients with myeloma, please, and you’re not a CAR-T treatment center, please engage with these centers. Teclistamab was just approved by December of last year. And at least in my practice, I’m still seeing a relative slow rollout to broader community, even though it is an off-the-shelf drug because of the rams required with step-up dosing. And so, we really encourage that communication about the patient because the manufacturing slots for CAR-T is getting better. And so it’s important that we have that dialogue to understand for each specific patient. In my mind, a patient who is fit enough for CAR-T should be considered to see if we can get them to CAR-T because they could potentially have a treatment free period with benefit of remission from myeloma. And then, you know, we would love to learn together how to roll out better access for Teclistamab for everyone. Thank you. Thank you very much. Nizar?

I agree with everything you guys said. I’ll stress the infection and the use of IVIG for prophylaxis for infection is extremely important because the last thing I want to do is provide the benefit as far as myeloma but lose a patient infection. And also I agree with you, Yi, about the importance of using these agents early, because we clearly heard from elevated a high disease burden results and lower this response. So don’t wait to the patient has dramatic expansion in their disease burden, treat them earlier. The early relapse and it will yield better results and outcomes. Thank you. Well, I’m going to thank you for your thoughts and your engagement and again, thank you to the audience for, for your interest.

Updates in CLL

I’m John Gribben from Barts in London. And we’re here at the fifth iwCAR-T meeting in Scottsdale, Arizona and we’ve just completed the CLL session. I’m joined here by Joe Melenhorst, who’s now at Cleveland, of course, previously at Penn, Tanya Siddiqi at City of Hope, who’s, of course led the Transcend studies. We’re going to talk about just a moment. Now, of course, we’ve talked about that CLL was the very first disease in adults that we saw successes from CAR-T. You were probably at Penn at the time, right? And the success and that some of the things we’ve seen. But yet, despite that, we still don’t have an approved product and having seen some of the data we’re going to go through in just a moment, does seem almost surprising that we haven’t been able to do it. But there are some intrinsic issues related to CLL and most of us of course know, and of course, it’s been a big focus of my lab for many years. A large problem has been the intrinsic T cell defects that occur within CLL and Joe, you started to really talk in your talk about how we can start thinking about that challenge in terms of how we can look to overcome it.

Right. That’s absolutely true. So the T cells in most patients, as you say, it’s dysfunctional, it might be a subset that’s specific for say (inaudible) virus that has retained some of the functionality. But that’s a really big challenge. So how do you figure out how to do the next better therapies? We, we’ve discovered the subset that we think is most important precursor cells, we can augment that, we can select it. There’s ways of doing that, but those are combination therapies that could actually help us and enhance the overall therapeutic advocacy of CAR 19 therapies.

We heard from some of the audience in some of the terms of the questions, even this almost intrinsic bias in the old T cells don’t work in CLL. But of course, we just had a whole session where people are so excited about CAR-Ts and myeloma where the results in CLL look just every bit as good, if not better. So why are we not as excited in CLL as the myeloma field? I guess because they’ve got approved products and we don’t. But why do you think there is this inbuilt bias in terms of, I guess you could say that the field did go backwards a little bit in the middle. 

Yeah, I mean, I think in lymphoma because there’s so many different types of lymphomas. And we have the more aggressive, more immediately life-threatening lymphomas compared to CLL, which is considered to be the cure, chronic incurable disease, people can stay on pills forever. Whereas the need to kind of come up with the CAR-T, etcetera, etcetera, except now we’re starting to see those patients who are progressing on BTK inhibitors and Venetoclax and we really have nothing to offer them in the real world. So CAR-T cells are now emerging as okay, more exciting again. And can we offer patients a time off treatment with this one time sort of bolus of CAR-T cells? And can they go many years without needing to be on continuous pills and things like that? So I think it’s the nature of the disease. Myeloma is also more aggressive in a sense, you can’t just leave it alone forever where and same as DLBCL and mantle cell lymphoma, etcetera where CLL is sort of okay. Some people need treatment sometimes and sometimes they don’t. So I think that’s why it’s taken a bit of a back seat CAR-T cells have in CLL so far. Now, of course, I mean, they’re two big groups who’ve been continued the focus on, you know, there’s the group at Penn with a modified product, not the Kymriah product as we heard Saar present. And of course, also the work usually from Seattle and now through Juno, and then on to BMS with liso-cel, which of course is what you’ve been presenting. I’ll give you a big plug because I know you can’t talk about some of the data because it’s embargoed because you’re going to be presenting it at ASCO on the Monday. So those of you who are interested in hearing much more about this tune in to ASCO to hear Tanya present the update on Transcend, which you could only kind of allude to today. But two arms in Transcend, I just want to kind of take apart a little bit one without the Ibrutinib.

Although nowadays, of course, saying without Ibrutinib and a lot of the patients are getting Ibrutinib anyway, up until they’re collecting the cells. And then the other arm where the Ibrutinib was overlapping the collection and the process you want to just tell us a little bit about where you are with those. Sure. So the monotherapy arm has obviously completed accrual and that’s the one I’ll be discussing at ASCO in great detail. The Phase II portion it’s over 100 patients. And you know, we already published the Phase I portion, which was the 1st 23 patients that shows very high MRD rates, very high remission rates. And in a large majority of patients long duration of responses as well, especially in people who have achieved undetectable, minimal residual disease, whether they’re CR or PR doesn’t seem to matter. The other cohort is the combination cohort where we think that combining with Ibrutinib, starting two weeks prior to leukopheresis during manufacturing during CAR-T infusion. And then for up to 90 days after CAR-T cells, we’ve preliminarily seen less CRS without affecting expansion and actual outcomes and, and whether or not that will now become more of a standard. If we continue to show that the responses are good beyond the initial 20 patients that have been reported on the Phase II portion of that cohort is also completed. We haven’t analyzed the results yet. I think there’s 70 plus outpatients. I can’t remember exactly. I mean, we haven’t seen how many total patients there are yet, but that’s also coming. And with these two items from this Transcend CLL study, I think we’ll be able to

make a big difference in these patients.

Do you know if the plan from BMS is to file for registration on the basis of that? So do you think they’re going to want to do a Phase III trial?

I think they’ll have to do a Phase III trial for the FDA regardless, right? I mean, that’s just the nature of the beast. But, well, except that which CAR-T was not first approved on the basis of Phase II. 

No, no, no. I mean, ultimately is what I meant. Yeah. Ultimately, I think the FDA will demand that. But my sense is that they are going to go to the FDA this year with the monotherapy data. Yeah.

And of course, the third talk we had in that session was from Saar Gill who unfortunately can’t be with us here. But I just kind of summarize what he was doing again from the U Penn experience again using Ibrutinib. And I thought the really intriguing things that Saar was showing was a) the persistence of the CAR-T. I mean, I think you know that from your studies, but he showed it very, very well studied there. But also these very deep remissions and in particular, very small cohort, but a very important cohort of the frontline treated Ibrutinib patients only where 100% of those patients were alive, MRD-negative with kind of prolonged follow-up, suggesting that if we get the right patient at the right time with the right

combination of agents. Then this combination of a BTK inhibitor plus a CAR-T could really be transformational in this disease. And perhaps the one setting where you believe that being able to get somebody off lifelong BTK inhibitors suddenly makes economic sense to do the CAR-T cells right up front. But there are some ethical questions that have to be thought about in terms of how do we select which patients to do that in, right?

And so my ideas always are like, I would like to test it earlier in the earlier lines of therapy once we have FDA approval for later lines of therapy, I guess. But picking only initially the patients who have high risk disease, people who have 17p deletion, TP53 mutation, unmutated IGHV, complex karyotype. There are a subset of those patients right up front and we have seen those patients who then progress very quickly on BTK inhibitors and venetoclax, you know, within one year each. So I think those are the types of patients I’d like to treat earlier and see if we can get them into a deep remission for a long period of time and give them sort of a new lease on life if you will or whatever.

Now, in CLL, I mean, we no longer use chemoimmunotherapy in the treatment of CLL, but the fact remains is that a large number of the patients we’re going to be seeing in the near future who are coming to CAR-T, our patients who went through the era of received it.

We know of course, that treatments particularly FCR can be very immunosuppressive for very long periods of time. You’ve done a lot of work looking to try to understand what’s the right T cell makeup that’s going to be a good patient. The impact that, you know, even long ago FCR had, have you had a chance to kind of look at that and how in any way that kind of helps us if you, like, think about a patient who’s potentially not going to do as well or, or do you think we’re, um, you’re focusing much more on what we have to do to get there rather than trying to identify who we should not be getting there?

That’s a great question. Well, we haven’t addressed that part yet. I think the initial challenge for me was to figure out why patient did or did not respond. We uncovered some of that. We also showed some of the resistance that actually is mediated by the tumor cells themselves. I think Saar Gill also showed some really interesting data on another subset that contributes to CAR-T therapy. So that’s sort of looking forward at Cleveland Clinic. That’s what I’m doing now, building a cohort, building a biobank to address exactly those questions that are really important for this field, but also in other human solid tumors.

The other interesting thing, of course, in terms of your thinking about Ibrutinib is we’ve certainly seen patients who are no longer, no, their CLL is no longer responding to ibrutinib, yet it can still maintain that immunomodulatory activity because of course, the resistance has appeared within the CLL clone, but it still can have this effect on the T cells.

I guess lots of us had thought that if you, if it was a lot, a lot of it was just removing the immune inhibitory effect of the CLL. But it seems much more complex than that, doesn’t it,

it seems that way. I think CLL is very complex disease where the clone that circulates not exactly the same biologically as the one that sits in what’s called the cradle of the CLL, the lymph nodes and possibly the spleen also. And also when you’re looking in lymph nodes by variability, heterogeneity, if you will of the tumor cells themselves. So and also we don’t really understand what sustains the CLL cells in the lymph node has been talked about these nurse like cells that probably are the myeloid-derived suppressor cells. But how it’s all happened plays out in lymph node in the architecture. That’s some of the questions that we’re hoping to address in the next few years in this disease.

And I wonder if that’s why Richter’s emerges in these patients in the lymph nodes and not in the arising in uh hectic environment. Exactly. Then let me know exactly because we were talking about that in the panel discussion, weren’t we about how you do see some Richter’s emerging? And yet we see persistence of the CAR-T. So there must be some way that those Richter precursor cells are in some way protected from those CAR-T that we know do retain the ability to kill the Richter cells. Although not in every case.

Well, there you have it. We’ve discussed what we talked about in the CLL session today. What we’re looking forward to is hopefully by next year’s meeting, we’ll have further progress in knowing where we are with the registrational process for hopefully being able to see the real advance outside the setting of clinical trials by being able to have CAR-T available for our patients with CLL. Thank you.

Updates in ALL

​​Hi, my name is Bijal Shah from the Moffitt Cancer Center. I’m joined today by Rebecca Gardner from Seattle Children’s, Claire Roddie, from University College of London and Nirav Shah from the Medical College of Wisconsin here at the iwCAR-T meeting in Scottsdale, Arizona. Thank you guys for joining me.

What a fascinating session. So we spent a lot of time today talking about dual specific and even trispecific CAR-Ts. So I’m just going to throw a question out to the three of you: What do you see as the biggest challenge moving forward as we try to integrate these novel CARs into clinical practice?

I think the biggest challenge is clinically improving outcomes, right? So we now have really mature long-term data, especially in pediatric ALL where, despite getting the vast majority of patients into remission, the large number of them continue to have events after treatment and how can we make a product that’s better than what we came out with initially? I think that’s where we really started to stumble. We manipulate things, we change CAR constructs and turns out we were really lucky in the beginning and this is very complicated. So I think there’s a lot of challenges to make a product that can get patients into remission, can keep patients into remission and kind of prevent the antigen escape that we’ve seen.

Claire, as we start to think about some of the data that have come from AUTO3, and again,

these novel designs for making [CD] 19/22 CARs for ALL

I want you to project forward for me. We have one that looks like it’s working. Is the answer then going to be a randomization, is the answer going to be: we’re going to target post auto CAR failures? How do we begin that process of moving it now into the clinic where it’s an FDA approved product? Or EMA approved product or NICE approved product. MHRA approved product. It could be anything… approved at some level. And so in terms of the,

I guess the space for dual targeting CAR, I mean, I think we can acknowledge there is a space because you know your experience with the Kite product and our own experience with AUTO1 is that a proportion of patients do get CD19 negative relapse. I’m not sure that at the current time, we’ve definitively proven that targeting more than one antigen actually prevents that from happening. I’m not sure that we’re quite at that point. So I do, I think in terms of the dual targeting CAR-T space that we would would be looking to accelerate the progress to randomized studies. I think we really need to find the sweet spot between all of these. So many permutations: delivery, manufacturer methodology, dual targeting, bicistronic constructs versus cocktail CARs versus two separate manufacturers. You know, I don’t think we really the jury’s out as to which is going to be the winning formula.

And I think that’s probably one of the biggest challenges going back to your previous question is how do we sort of unify and homogenize the kind of the data so that we can really sort of, I guess, do those direct comparisons. And I think Saar Gill touched upon that during the the question session, you know, really, we should, we should focus on that as a group, and try to really drill down on those important points, our definitions to be able to make those comparisons.

Absolutely. You know, as we start thinking about our antigens, we’ve got 19, 20, 22. We also heard a lot about targeting in T cell ALL, CD5, CD7.

You know, we’re stuck with our murine model systems. Is there a better way for antigen optimization to say, hey, this is the next best target to think about? So, you know, I joked around in the session about a quattro-cistronic or even a Septo-cistronic CAR. But is there some way to optimize that process? And then thinking downstream of those antigen-targeted approaches, we talked about ICOS CD28, 4-1BB and so on

Nirav, thoughts?

Yeah, I think that as we move forward, we want to personalize these treatments even better. You know, when CD19 CAR came around, it was such a remarkable technology. We sort of said “one size fits all”. And I think we’re gonna see, we’ve seen it already throughout today. We’re going to see in other talks. Probably biologically, these diseases are all a little bit different. And so there may be a disease such as mantle cell, which is a CD20 bright disease where a 19, 20 might be an optimal way, there might be ALL where CD22/CD19 might be the optimal way.

So I think we need to move away from saying one size fits all for all B-cell malignancies. But start thinking about these diseases biologically, what is the expression of these different molecules, which actually for 19, 20 and 22 is variable across these B-cell malignancies and then start priming our treatments to the specific disease. I hope that’s what we sort of get to as we move forward. So we’re sort of giving each patient their best chance, which I still believe their first CAR is their best chance, and not to say that future CARs and human CARs and things can’t overcome some of those intrinsic issues with T-cell based immunotherapy. But I’d like to give each patient the best possible CAR for their disease.

Great answer. And I think, continuing to have this idea of reverse translation. When we started, we came up with what we thought were the ideal criteria for a CAR-T cell product. And so we developed products, tested them and said this is the one we’re going to take forward. We now have so much patient experience interrogating: What’s a good product? What does it mean to have a good product?

If you produce interferon gamma, is that actually bad? Does that lead to M2 macrophages which cause toxicity and decreased efficacy? So maybe we’re thinking about this all wrong. So I think to think about the ideal product, it’s going to be a lot of different things. What are the targets? What are the CAR constructs? You know, the CAT CAR that Claire talks about, this idea that it’s fast on, fast off and it doesn’t have all of that extra continued stimulation against its target. It’s probably a really good thing.

And now we probably have much more capability to predict what are the good attributes of a CAR construct, of a target, of a product, to be more rational before we take it forward into trials.

Fantastic and to build on that as well. I mean, you know, because we’re focusing sort of on the design of the, the molecule that we’re putting into the T cell and then we can’t ignore the T cell attributes as well. I mean, I think, was it Evan Weber, gave the talk earlier on? And, you know, I mean, there’s some really fundamental lessons being learned about how we can modulate the fitness of the T cell before we even go ahead and do the infusions. And then there’s that whole piece about the tumor, because it’s the elephant in the room. But we’re talking about the things that we can modulate, which is the construct and the and then the T cell and so on. But actually, if you think back to the talk from yesterday about imaging the vasculature of the solid tumors, and I mean, you know, some leukemias are lymphomatous. No, I mean, in the sense, we, we’ve got that whole sort of brave new world of um just sort of challenge and combat to, to, to build into our strategies that may be that the CARs aren’t even getting into the tumor in the first place. So I think sort of, there has to be a sort of a parallel strand of design and technology and engineering and sort of cell fitness endeavor. But there also needs to be a parallel strand of interrogation of the tumor micro environment in addition to antigenicity and, you know, up and down regulation of antigenicity. But I think there’s a whole, these two things really need to go hand in hand.

Absolutely. I think we’re still learning how to optimize a patient for CAR-T cell immunotherapy. A lot of that has come down to tumor cell burden. But you know, what else can we do to address some of those, those specific factors? Um Rebecca, I want to come back to you because you gave a really nice talk about how to, how, what happens when we deliver these products? What we see in terms of selective expansion of one product versus another. One of the things that struck me in your presentation was that with your modified CD19/22 CAR platform, a lot of the patient’s had had prior CD19-directed therapy, how might that have influenced this sort of selective expansion or is there any way for us to even meaningful measure that?

I think it’s a great question. Um And one that we were actually really interested in, are we seeing decreased expansion of the 19 CAR? Because all these patients have already gotten a 19 CAR. And so what I didn’t have time to show and kind of fast forwarded through was when you interrogate just the subset of patients that’s not having a previous CD 19 CAR, they replicate the findings where the 19 CAR doesn’t expand as well.

So I think it’s more nuanced. It would be great if we could say it was because they had previously gotten it. But it doesn’t seem to be that way. That being said, I think we’re all like as Nirav said, your first shot is your best shot. And so how can we develop a product that’s better and get that to patients first rather than trying to come in after they failed all the other therapies. A pre clinical platform is the key to this and that does not exist to date. And so I think there would be a lot of um you know, man, I guess it’s a lot of sort of biotech companies and so on that propose, you know, measures of the T cell function with sort of solid phase antigen. So for instance, like an avidity measurement of avidity using your sort of [inaudible] technology or perhaps using your [inaudible] sort of poly-functionality secretome analysis. And you can look at all your different sort of CAR constructs and in parallel with doing your murine models, your then applying them into these sort of systems to get readouts that I mean, we’ll have to do this really in retrospect with clinical trial, treated patients and then try and make those, I guess those connections sort of post talk.

I’m going to paraphrase Dave Maloney and Cam Turtle just just about for just a moment here. You never know until you put it in a person. Yes, that’s I think the challenge is that, you know, we’re in an era where we have approved CAR products. And so like, you know, yes, we want to give the best CAR possible to the patient. But the counter to that is giving experimental CARs as a frontline therapy when you have an approved CAR available also becomes a question about what is the best thing to do? Now, we know that CAR is not curing 100% of patients.

And so we want to offer people something better, but we don’t know if it’s better, you know, and we do these preclinical studies that show again in mice that everything looks beautiful and it can kill all these cells. Um but, but I find that to be a challenge. So I do think at some point, you know, one of these bispecific, you know, dual targeted CARs probably doesn’t go head to head against the 19 and say look, is this actually doing anything better because otherwise, are we just, you know, adding all these modifications without actual clinical benefit?

Yeah, that’s one of the problems with our sort of more recent study led by [inaudiable] and Sara Ghorashian and it’s looking at these two sort of optimized kind of CAR constructs and they’ve got the cocktail CAR approach, the kind of patient that being referred in for that study. These are all patients who are ineligible for Kymriah. So these are all patients with extramedullary disease, isolated extramedullary disease where they’ve already failed CAR-T or they’re CD19 negative already. These are not the patients that were being recruited into ELIANA. And so, you know, the outcomes that we’re looking at are clearly going to be challenged by that patient population. So we’re really climbing uphill all the time or so it’s difficult, isn’t it? 

Yeah, I find that to be the hardest part of what all three of us are doing is to create new CARs in an era where CAR is sort of more available than it was previously. And, you know, I think it comes down to obviously talking with the patient, informed consent, you know, explaining the current limitations of our technology and what we’re trying to improve on. But also the reality that with any clinical trial, we don’t know. And my biggest question still is, does dual targeting, does triple, does that actually mitigate the problem? You know, like when I look at our small series of patients, it seems like it does like we’re seeing lower rates. But again, the number of patients is very small compared to the thousands of patients that have now been treated with CD19-based approaches. So I think that, you know, hopefully we can find, you know, sort of the best model and then eventually, as a group, we all commit to doing a trial of comparing that product to a CD19-based CAR and actually seeing, can we do better? Because we really, again, I believe, give the best CAR first, to give them the chance for a one and done cure. And with all the caveats right, of minimizing FluCy exposure and toxicity, cytopenia, as you know, if we can avoid B-cell aplasia, right? You know, that would be lovely without them relapsing. So, you know, obviously there’s a lot of progress to be made. But love being at this meeting, it’s exciting, it’s, you know, it’s motivating, right? Like giving me ideas and things I should do, allowing collaborations to happen.

Uh So really uh really excited to be here at this meeting in Scottsdale. Perfect way to, to wrap this up. Thanks all three of you guys for talking to me today about novel ways of targeting ALL.

CAR and bispecific updates in lymphoma

Hi, I’m Loretta Nastoupil from the Department of Lymphoma at MD Anderson. And we had a great session here at the iwCAR-T cell therapy program in Scottsdale, Arizona 2023. It’s my pleasure to be joined by my colleagues to cover the lymphoma session. To join me today is Dr Tycel Phillips from City of Hope, Doctor Mazyar Shadman from Fred Hutch in Seattle.

So I asked both of you to kind of give me a summary. Tycel, we’ll start with you. Can you kick us off and describe the sessions that we started off today talking about with CAR-T in lymphoma? 

Yeah, we had a great CAR-T session. Some of the things we discussed are some of the newer CAR-T products that will come. And so I think Dr Miklos discussed the CD22 CAR product in diffuse large B-cell lymphoma that show great efficacy and similar safety profile and even those who have been prior exposed to CD19 CAR products.

So you have a fantastic study looking at CD20 CAR in Lymphoma. Can you give us an overview of what you just you covered today?

Of course. So we talked about the third generation CD20 CAR product that we have two studies ongoing. One at Fred Hutch and the Multi Center study that’s currently ongoing in the US and showed some preliminary data on Waldenström and follicular lymphoma from the Fred Hutch study and also some initial results from the Multi Center study. And in general, there seems to be the same efficacy and safety profile that we saw with the Fred Hutch study with the Multi Center study. So excited to have more patients on the study. These are two studies looking at different targets. We’ve been talking about CD19 targeting CARs for some time. Jeremy Abramson gave us an update on liso-cel and second line large cell lymphoma. We also heard Caron Jacobson kind of cover an interesting application of axi-cel in secondary CNS lymphoma. If you want to kind of highlight what she covered today.

Yeah. So again, she looked at axi-cel in patients with CNS lymphoma. I believe they originally had planned a study to have a primary CNS lymphoma and also include with secondary CNS lymphoma. But the data was encouraging early on showing efficacy of CAR-T products, showing that the CAR-T cells are actually able to take care of CNS lymphoma. I think as the study matures, we’ll get more data and see about durability of response. And CNS lymphoma is given the time of relapse is a bit different than what we see with triple-hit diffuse large B-cell lymphoma. And I think it’s really encouraging that we don’t see worsening safety because these are patients that we get a little bit nervous about in terms of getting them through something where it’s CNS directed therapy.

We also heard Michael Jane give us an update on their experience with brexu-cel and mantle cell lymphoma. Another CD19-directed CAR. What’s your takeaway from that session? I think it was a very important presentation, a very nice summary on what we know from the clinical trials with brexu-cel but also more importantly, recent publication in the Real world Experience with brexu-cel. We know that when we gain experience from the clinical trials, it’s also important to see what exactly happens in practice. And the study showed that mantle cell lymphoma remains an unmet need. Brexu-cel is effective for a number of patients and is currently standard of care. But for example, a report of 9% mortality in the first year after treatment with Brexu-cel with high percentage of those being related to infections, basically tells us that we need to do more and come up with CAR-T products that are better tolerated, while the efficacy remains the same. also some very important practical points from that presentation about the timing of using drugs like bendamustine which is commonly used in mantle cell lymphoma and some important prognostic markers that were described in this study that we’ve not necessarily reported in the clinical trial. So again, highlights the importance of continuing to follow the data even after approvals and generate these important real world experiences. I think the sort of next wave per se in terms of drug development is looking at how can we overcome some of the limitations of the AUTO CARs and one way is to use healthy donor T cells. So I covered preliminary findings from a first-in-human Phase I study where we’re looking at using healthy donor T cells with CRISPR gene editing, knocking out the native T cell receptor putting in the CD19 directed CAR. But also interestingly with CRISPR that gives you the opportunity to do some more creatively gene editing per se. And so also knocking out the gene that codes for PD-1. So again, very early findings, but efficacy looks pretty interesting, safety also is quite intriguing with only one Grade 3 ICANS that was short in duration, no Grade 2 or higher serous. So that study now is finished escalation and the expansion is now launching. 

That raises now some interesting sort of dilemmas per se now that we have these early phase studies that look promising, where do we go next? And how do you prioritise pursuing an investigational agent versus an approved standard of care, AUTO CD19 CAR. So, how do you know that? 

Yeah, I think that’s a very good question. I think in this situation, especially when we talk about large cell lymphoma, which today we mean, we know it’s curative with AUTO CAR-T therapy. in that situation, it’s kind of hard to the private patient of a curative treatment if one is available. But the study that you mentioned and again is quite encouraging. And because it’s of very shortened time since it’s basically an off the shelf CAR-T product versus a typical vein-vein delay we have with AUTO CAR-T obviously does improve the access to these patients because again, access to getting CAR-T on a timely basis is a problem all still suffer with the manufacturing issue. So I think as we get more experience with these drugs and as obviously, the study presented matures out and we can see some long term remissions, we may make it a more palpable debate to actually go to an AlloCAR which is an off-the-shelf product versus waiting for the manufacturing for AUTO CAR. But as of right now, I would still say I would try to prioritize an AUTO CAR at all possible. Yeah. And I think when I think about drug development with cell therapy, either autologous products, targeting different antigens or bispecifics, for example, for CARs or allogeneic products and they’re probably in general three categories that we can think about the space after CD19 CARs. So there are unfortunately, patients who either don’t respond to autologous CD19 CARs or have disease progression. So that is an unmet need. So any new product could be tested and should be tested at some point at that space. The second category or diseases are not covered by the current labels. For example, we had a presentation from a retrospective study looking at basically a case series of patients who received commercial CD19 targeted CARs for Burkitt lymphoma. And unfortunately, results did not look good. I mean their rate of complete remissions were low and they were not very lasting. So the second category really is going for those diseases. For example, your study is a good example of having an allogeneic product, aiming it for a disease for which patients may not have the time for waiting for cell production. And Waldenström is another example that was covered with the CD20. And the third, when we see high efficacy, let’s say in the post CD19 setting. And maybe at some point, we think about maybe competing with CD19 AUTO CARs and that would be probably the next step. But definitely there is room for the new products in the cell therapy world.

So again to kind of summarize what we talked about with CAR-T today. We did highlight some of the big changes of moving CD19 in the second line with Liso-cel, we talked about new antigen targets with CD20, CD22. We looked at those less common lymphoma subtypes like is secondary CNS lymphoma, mantle cell lymphoma. So that now sets the stage for the other sort of competition with T cell engaging therapy. So where did the bispecific antibodies kind of factor into this equation of engaging T cells for our therapeutic purposes?

Yeah, I mean, I think it’s a very interesting question that we’re all struggling with at this point. Now, I mean, I think that we have to be a bit more nuanced and we look at the diseases we’re treating and sort of what we have currently available. Again, with large cell lymphoma cure with AUTO CAR, the bispecific data with Glofitamab and epcoritamab, is very encouraging, but it’s still again immature. Even though some of the more recent data showing some plateaus to the curve suggest that there is some curative intent there. So very excited to see where those go in the future. And if those plateaus are real, then again, we have two curative options and then that gives us more options for this patient population. But we also know that access issues, the CAR-T, an issue and referral and then bispecifics do make it to the community. They will likely be the first choice in those situations. Follicular, mantle cell, I think a bit more nuanced. We’re not curing these patients likely with CAR-T. In that situation bispecifics, I mean the data we have is also very impressive, specifically with MCO patients, the AE profile for at least Glofitamab Uh compares very favorably to what we see with brexucabtagene. So, I mean, these are discussions we’re going to have to have about the durability if they are equivalent, how do we manage the toxicity profile and sort of what’s the best first drug to give first? And what do we give there after, sort of the sequencing discussion?

Yeah, I mean, you did a nice discussion of that of sort of showing where we stand currently with the single arm phase two studies. And what information can you sort of garner to try and help you navigate that expanding treatment landscape? But some the practical aspect is how do you choose, what are the patient specific characteristics when you may have more than one option again, assuming that they’re all going to be shuffling around in terms of as these studies emerge. But currently, how would you navigate that CAR versus bispecific in that third line space? 

I think I echo what Doctor Phillips mentioned, you know that the disease matters. So for large cell lymphoma, assuming that in an ideal world, we have access to CAR-T immediately

that the data is more solid and the long term follow-up and real world evidence is really in favor of using CAR-T. However, we know that not everyone can get to CAR-T immediately, even within academic centers. So I think it is true that the first indication for bispecifics will be a monotherapy indication. But I think very soon we’ll have a data showing efficacy and safety of combination therapy with bispecifics. So I think once that’s available, we can use bispecifics in sequence of CAR-T either before or after. But at the moment, I think there are patients who are not able to, for example, be away from their home and for a few months being in a major center to receive CAR-T. So definitely for those patients bispecifics are a very important treatment option. And patients who may have low disease burden in large cell lymphoma and those who need to wait to be able to, for example, travel to those major centers. And of course, in the post CAR-T space, that’s another unmet need that bispecifics could be used. CAR-T is now approving the second line and bispecifics will be available in the third line. So you know that that would be another distinction between the agents. But I think soon we will have a lot of experience combining bispecifics and they may even move to the earlier lines of therapy and we’ll just have many options and that makes us very busy to study these combinations to see what’s the best treatment for patients. And one interesting sort of thing to postulate is as we have a lot more emerging CD20 bispecifics that are going to move into earlier lines of therapy. Is there going to be more selective pressure to essentially lose that antigen? So there might be a natural progression to then have the CD19 come in at that second line space for patients who are exposed to CD20 bispecifics in frontline. But what do we know currently about sort of mechanisms of failure? And no, there’s a lack of data right now. But can you speculate, Tycel? So how that may impact efficacy?

I mean, I think as you said, we’re in the data void era right now. Um just anecdotally from our own experience. I mean, we have seen loss of CD20 as an escape mechanism. Some of these other patients where they haven’t lost CD20. I mean, some of these patients were patients who did not have very good responses to CAR-T. So they probably have cold tumors and that these immunotherapies are not very effective but agree. Unlike CAR-T, we don’t really know other than what we’ve already tested our own individual institutions about loss of certain antigens. What to drive in the resistance to these bispecific antibodies?

I mean, how do you approach a patient who’s failed a CD19 AUTO CAR right now? I think that’s the question we’re all struggling a little bit with. 

Yeah. So unfortunately, these patients commonly are unfit for clinical trials. I think the priority should still be enrollment in clinical trials for these patients. But we know that these patients suffer from many adverse events like cytopenias and sometimes infections, not being fit enough or just being tired of staying in a major academic center and not being ready for another maybe cell therapy approach. So again, after clinical trial, I think now when bispecifics become available, I think that would be a very important class to consider. I think the challenge is if we are lucky enough to get a remission and the studies that with both Epcoritamab and Glofitamab, you see that the CR rates are pretty similar in patients who are pre proposed CAR-T versus CAR-T naive patients. But the question is do, what do we do with those remissions? I mean, do we continue therapy and hope that those remissions are lasting or maybe selected patients who are good candidates for treatments like allogeneic transplant. Make that referral. I think at least having that conversation is important. But that would be a very difficult decision to make for somebody who’s responding to subcutaneous or even intravenous therapy to stop that treatment and move them to allogeneic transplant. So there’s a lot to learn the upcoming months and years. I think we get to benefit from our patients generally doing quite well with just about any therapies. We have the pleasure of testing, but it does make it a little bit more challenging as the single arm phase two studies lead to accelerated approval. Again, how do we navigate this quickly evolving treatment landscape?

It was a nice summary of the lymphoma session at the iwCAR-T meeting here in Scottsdale this month in April 2023. And I really appreciate you sharing your thoughts and insights. Thank you for having us.

Current challenges

Good morning. My name is Marco Davila. We are at iwCAR-T 2023 in Scottsdale, Arizona. We’ve just had a fantastic session this morning about resistance or why CAR-T cells don’t work in patients. I gave a talk on how myeloid cells in patients and in animal models can lead to the suppression of CAR-T cells. We have Doctor Evan Weber who also had a great session. So give us a recap of your talk. Yeah.

So today I spoke really about some of the limitations for CAR-T cells in patients, mainly poor persistence. And so my group basically embarked on a project to try to identify transcription factors that are responsible for promoting that phenotype. And we figured out ways to enforce that memory, persistence-associated phenotype as a way to enhance CAR-T cell efficacy and function.

Doctor Michael Green from MD Anderson.

Yes. So I spoke about our application of single cell genomics to address critical questions in CAR-T cell therapy, focused mostly on mechanisms of failure and mechanisms of toxicity. From a failure perspective, we’ve looked at both infusion products and the tumor micro-environment at the time of progression.

And these have a lot of similarities, primarily that there tends to be an enrichment of exhausted CD8 T cells in the patients that don’t tend to do so well. From a toxicity perspective, I focused mostly on prolonged cytopenias and again, CD8 T cells came up as being of major interest because in the patients with prolonged cytopenia, we saw an enrichment of specific subset of CD8 T cells within the bone marrow that produced a lot of interferon gamma that could be associated with HSC dysfunction.

All right, Dr Filip Ionescu, from Moffitt.

I spoke today about our experience using an alternative lympho-depleting regimen. We know lympho-depletion is important for CAR-T cell efficacy, and in the setting of fludarabine shortage, we use an alternate agent called cladribine. And we really observed similar clinical efficacy at short term follow-up and similar correlative analyses as well. So it’s an encouraging area of research, right.

So I think, really one of the things I enjoyed most about this session is how we are focusing on how CAR-T cells don’t work or mechanisms of resistance to be able to improve outcomes for patients. So to me, this is really kind of one of the great things about this meeting, be able to speak with other clinicians, investigators: How can we improve outcomes for patients? So there is, I think, a very lively interaction between the speakers and the audience. And I certainly feel like I’ve learned a lot, probably one of the important take-homes for me was how CAR-T cells are probably contributing within the micro-environment to the third major toxicity of CAR-T cells cytopenias. So, you know, we have some stuff to go back and work on, on the lab.

Rapid CAR manufacture

Hi, I’m Caron Jacobson and I’m here at iwCAR-T 2023 in Scottsdale, Arizona. And we just had a really fascinating panel discussion and presentations centered around point of care, manufacturing and rapid manufacturing of CAR-T cells to really ease the burden of the logistics of CAR-T cell delivery. And also to hopefully actually improve the effectiveness of CAR-T cell by selecting better T cells. And so I’m joined here by Doctor Frigault and Doctor Ortiz-Maldonado, and we’re gonna jump right in and talk about what was so fascinating about the discussion. So, Doctor Ortiz-Maldonado first I’ll start with you. You presented really, I think really fascinating data about what a single institution can do. And then really the forward thinking of the Spanish Health Ministry or authority to take that progress and actually allow you to manufacture cells for a larger community. Can you just tell us about what your, how that happened and what it meant for your institution to work with the Spanish authorities? We’d love to replicate that in the US.

Well, thank you for the question. That happened because in 2013, we did not have any option for CAR-T cell therapy in Spain. So at that moment, we had a group of colleagues that were very, very, very, had the initiative to start the development right from the start. Also the lack of having several monoclonals targeting different CDs and we jumped to it. So we started with a first CAR 19 product which would help treat most of the patients that we had in need. So one of the key elements to the current success of this project is that we, we have on board right from the start before we started anything we have on board, the Spanish Medicines Agency. So we have contacted them and they, it’s very important for them to see this project also as their own. So it’s like a project of public health. So that’s the way to make it happen.

Yeah. So Matt, do you think that something like that could ever happen in the US?

I think it would be really hard to do in the US. I think the regulatory environment is very different and I think you somehow were able to do something rather amazing to get all the parties to come together like that and provide the care. So I’m optimistic that we can hopefully be creative like that. But you know, the number of patients you’ve treated, the outcomes you’re having and how you’ve worked, that’s pretty remarkable.

And the cost savings, right? So, you’ve demonstrated in your 100 yards system where the cells go from one point to another, never frozen right into the patient at a fraction of the cost of what these commercially manufactured CARs cost. So I think that’s just really remarkable, a faster turnaround time than we’re seeing. Yeah, but speaking of that, so if we are unable to do this in our own homes, you presented some really interesting strategies for the commercial companies to improve efficiencies, speed up manufacturing and hopefully still improve access for our patients. Why don’t you tell us about some of those strategies? Yeah.

So um we, we basically talked about the fact that, you know, I think we were very focused on quantity dose um in our manufacturing processes and sometimes the quality may be better than having an absolute quantity. And so the rapid manufacturing is more so using the patient as the reactor, if you will to allow the cells to expand. And what we’re seeing is that younger, more naive cells, even at a much, much lower dose can be as effective if not more effective in treating both lymphoma, myeloma and you know, some of the other diseases we’ve talked about. So, you know, in doing that, we could take something that could be a 24 day turnaround time and bring it down to say 9 or 10 days, which I think potentially decreases resources, increases throughput, opens up manufacturing suites and means that when we see a patient, we know within, you know, 14 days or so, whether we can start treating them or not, which gives us a little bit more comfort because I think that 4 to 8 week window sometimes that’s somewhat vague right now. It’s all scary because the patients are progressing. We’re trying to get them to their next therapy and not all of them make it.

And so you presented some data from one of the Novartis products that is being tested in large cell lymphoma. And you reported sort of the stemness of the T cells as being superior to their parent product, Kymriah or Tisagenlecleucel.

Do you understand what that stemness is?

So I you know, looking at the, a lot of the information I believe is derived from the collaboration with Penn and whatnot. So mainly looking at central memory phenotypes from a flow standpoint that was more RNA expert profiling. I believe they were looking at a subset of known genes that they’re associated or what they had tracked, at least with their initial pilot runs for correlating with those types of factors. But that is one thing I was not able to get more detail on is how are they defining stemness with that expression profile and it just reminds me, did you look in your manufactured cells, sort of what the product was that came out and compared it to what we know about some of the commercial products.

Well, we, we, what we know is is that R1 cells in the way that we manufacture it right now, it’s composed around 60% for central memory and effector memory cells. We don’t really know if that would change if we cut down the time of production. In fact, we may stop several manufacturing at eight days, but we could do it before if you just wanted one dose. So usually we manufacture more than one dose for one patient, two or three doses at max. So it’s really, it’s really important these outcomes that come from for the charge platform that maybe with the same bioreactor, by avoiding this expansion ex vivo you might end up with a better quality product. That would be amazing.

And then I’m going to ask a provocative question. I think we’ve talked about sort of this, decreasing the vein to vein time. We’ve talked about even allogeneic off-the-shelf CARs. But I think there are several companies now that are starting to get much closer to clinical trials and first-in-human experiences with in vivo production of CAR-T cells. So using a variety of sort of ways to allow the, you know, allow the DNA to enter the T cell in the patient’s body. Any thoughts? We’ll just end with this. So any thoughts that you have on sort of the potential for success? I mean, that certainly would get rid of a ton of these logistical considerations.

I think that this for frankly very attractive option. And of course, we don’t know if this would work for CAR-T cells, but we in medicine, we are already doing that for ophelia, for example. And so we also are taking out now, stem cells modify and giving it back. So I think it is possible it will arrive a day for that. And I I think we will hopefully get to that day where it’s possible. I just know things are always more complicated, turn out to be more complicated than we think when we start down that path. But you know, if you look back where we started with CAR-T in the early 2000, no one thought that we would be at iwCAR-T talking about the thousands of patients we’ve treated. So, you know, I hope because it would expand access, get CAR-T, hopefully make it safer, make it cheaper. And ultimately, you know, we could be talking about frontline therapies. Yeah.

Yeah, awesome. I think that’s a great place to end. This was a fascinating discussion. You guys have done great work. Uh And so we’ll see you next year.

Updates in AML

Hello, my name’s David Sallman from Moffitt Cancer Center in Tampa, Florida. It’s really my pleasure to be here with two colleagues, Marion Subklewe from Munich in Germany and Roman Shapiro from the Dana Farber Cancer Institute. And we are at iwCAR-T in Scottsdale, Arizona in April of 2023. And we really just wrapped up an acute myeloid leukemia session. And I, I think where CAR-T has really been that paradigm shift in hematological malignancies. It hasn’t quite gotten us there yet, as maybe sort of one common message. So maybe Marion I’ll start with you, like, what do we need to do to kind of overcome the challenges that we had? How do you see CAR-T and then bispecifics as maybe our past forward for patients that are lacking options.

Yes. Sort of frustrating that the results so far and bispecifics and CAR-T cells have been rather underwhelming if you compare to the B-cell malignancies, considering that allogeneic stem cell transplantation has been the most successful antileukemic treatment in AML. So I cannot accept that this will not work, but we have to sort of modulate further. So I think one of the challenges is identifying suitable target antigens. I mean, we know that there’s a huge antigen heterogeneity intra-individually. So that is one of the challenges. And I think why we are trying to find a more specific target antigen, we probably should possibly accept hematotoxicity. I mean, these are all mild add lineage antigens. They are also express

it was in the healthy hematopoietic system. And I think maybe if we go a step back instead of replacing allogeneic stem cell transplantation, one of the strategies might be to integrate CAR-T cells into an allogeneic stem cell approach, part of the conditioning regimen and show efficacy, reduced relapse rate after allogeneic stem cell transplantation might be one of the strategies.

Yeah. No, no, I agree. I think you know that hope for that single antigen CAR is probably not realistic. And I think you nicely showed in some of your data, how heterogeneous it is not only do you have the mark or not, but what sort of the intensity of expression? And so can we choose some combination? And I think what is that combination? How many targets that we need so that we can really try to cover over 100% blasts? Actually, I think those are key translational data that to me are not, not that clear and may be very different in molecular subset. So a patient with an IDH or p53, maybe they have a phenotypic expression that is best to target with product A, product B, you know, I think we’d love to have one product that covers everybody, but maybe that’s not necessarily realistic.

Roman, what do you think are some other challenges we have in sort of the cellular therapy, you know, challenges that we’ve had again in AML patients.

Yeah. And you know, there are many and I think we are systematically overcoming them, but it’s going to take time. But you know, one of the challenges that comes to mind even from our session earlier today are the leukemia stem cells. And I know there’s been debate in the field about whether these things really exist. But, you know, I’m in the camp that believes that leukemia stem cells exist and these are potentially more difficult to target. They don’t cycle as readily, there are fewer of them. They might not express antigens like for instance, what was discussed with NKG2D. And so the ability to target those cells that ultimately prevent even later relapses, you know, let’s say you took 100% blasts and went down to 0% blasts, but you did not really eradicate the leukemia stem cell that can perhaps later, six months or eight months or two years later result in relapse. That will be a key thing I think in AML. And it’s interesting that for NKG2D is an example, I mean, there have been studies and groups that have shown that you can up regulate ligands for NKG2D with certain drugs like PARP inhibitors. As an example, there’s a paper that’s published in Nature a few years ago, there are strategies that one can potentially implement to combine these modalities with cellular therapy to perhaps target the leukemia stem cells.

And I think another challenge that we heard is sort of, what is the T cell fitness? Of course, with autologous products, that could be an issue. So, you know, Marion, I know you’re doing a lot of work. Do you think this is the disease setting, the prior therapies, molecular subsets, I mean, what is the biggest challenge with the T cell fitness? You talked a lot, you know, if we’re just sort of constantly engaging with continuous bispecifics that, you know, we get this exhausted, you know, phenotype in the end. So what do we need to be thinking about, both maybe in CAR-T and bispecifics, thinking about the actual T cell itself. So first of all, I think we need to learn as much as possible from the B-cell field. So, I mean, it has been shown for BLIN that it works best in the MRD setting, low disease burden. So I think this is one of the things we need to improve. We are currently applying bispecifics and CAR-T cells often in patients where there was high disease burden, that had received a lot of prior treatment lines. So I think that is one of the things we can probably translate from the B-cell malignancies. But then I think there are probably differences and we know that T cells from AML patients, even at initial diagnosis are already compromised in function that’s been shown in transcriptional, but also on functional data.

And we know that the T cell fitness is further decreasing with each prior treatment line, we know the T cell fitness is decreasing at time of relapse. And at least from our group, we could show that if you’re targeting an antigen that is ubiquitously expressed and you are sort of giving the bispecific, and I think the same applies to the CAR-T cells is sort of continuously engaging a ubiquitously myeloid lineage target antigen, you’re further inducing T cell exhaustion just like in chronic viral infections. So I think in that context, the target antigen is also contributing to T cell fitness. And in the bispecifics, clearly, I would argue that you have to apply the bispecific and have that treatment free intervals. And that the way you dose your bispecific actually also makes an impact on T cell fitness.

Yeah. And I think we have so many moving parts, right? We have target, we have T cell, we have other immune micro environment issues. And I think we need to be very cognizant of that when we’re developing our trials. So are we at least in multiple different cohorts trying to answer these questions and getting the key sequential bone marrow specimens to maybe help answer those translationally? But you know, maybe, maybe CAR-T cells are not the answer. And I think, you know, maybe Roman, are NK cells the future? We’ve chosen the wrong cell with T cell, NK is the answer? Maybe if you want to comment on anything else. So gamma delta T cells or, or maybe you know, alternative approaches other than T cells.

Yeah. So, you know, I think we’re all collaborators and we have a collaborative spirit and we like to work together. And in fact, that’s my bias in this space. I think that the answer for leukemia will not be one kind of cell. I think that, you know, I’m biased towards NK cells. I work a lot with NK cells. I think about NK cells all day. And so I believe that NK cells can definitely form part of the puzzle to attain a deep remission, sustaining that remission is a challenge. And I think that ultimately, you know, we alluded to this earlier, the success of just bone marrow transplant right. The fact that we can cure 60% of leukemias, at least, you know, that’s at the, at the very beginning, if you think about it, you know, that’s a success of cellular therapy. Can we replicate that in the relapse setting? And with bone marrow transplant, if you look at the graphs, there are all kinds of cells in there, not just NK cells, not just T cells, there are monocytes, there are neutrophils, there are many other cells in the graph that might be contributing to the success of bone marrow transplant. I think that in the relapse setting, you know, if we’re going to use a CAR product, it’s going to have to go into various cell types that will have to work together. In the NK cell, in the early phase NK cell trial that we talked about in the session, you know, I that BPDCN case example was just, you know, we were so interested in this. I was trying to understand this better. Is it how is it possible that we infused a bunch of NK cells and a bunch of T cells ended up in the tumor site where there were no T cells there before? You know, clearly there is interaction between the different immune effector cells. How to take advantage of that, how to make them work together to accomplish a sustained prolonged remission, I think is going to be ultimately the way forward.

Yeah, I think we’ve heard it’s, it’s unfortunately going to be, be, be quite complicated, maybe like just taking us home, you know, Marion. Like, what is, what is your sort of message of optimism, you know, are we going to have our, you know, immune therapy breakthrough and how are we going to get there?

Yeah. So I really caution that we conclude from the data. We have to be too pessimistic, right? So I think we really have to remember the success of allogeneic stem cell transplantation. We have all the data also from the B-cell malignancies that platforms do work. So I think we are need to apply our CAR-T cells and bispecific in a different clinical scenario. And we have to move earlier into a clinical trial. And then I think we have to think of combinatorial strategies. I mean you are conducting this trial with also membrane IL-15 bound. We have to think of combinatorial small molecules with maybe CAR-T cells bispecifics, apply this in a low disease tumor burden early in treatment line before we kill a platform, just because we don’t see efficacy if we apply this now in fifth line of therapy. So and I also think AML is a heterogeneous disease, so probably one approach is not applicable to all kinds of AML. So we also have to adjust to the different genotype and phenotype of AML, making a little more complicated I must admit, but I think there’s so many aspects that are obvious for improvement that I think it would be a mistake to give up at this

 point. 

Yeah, I agree. I think this, it’s just highly endorsed that obviously we need clinical trials and actually to get these clinical trials going as soon as possible and maybe even, you know, reaching out to our regulatory authorities, preventing some of these, they’re kind of very harsh rules on getting these trials, getting enough patients treated quickly enough so that we can really try to see if the therapy is efficacious or not. But I think with that, you know, just thank you for listening, kind of for this AML wrap up at iwCAR-T.