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iwNHL 2022 Session 4: Advances in T-cell therapies for NHL – CD19, CD20, CD30 & CD5-directed CAR-T therapy and third party EBV T-cells


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Hi, I’m Catherine Bollard, and I’m here at the iwNHL meeting here in Barcelona in 2022. And we have just finished a very exciting T cell therapy session. And we have three of the speakers from that session here, and we’re going to go straight to Jeremy Abramson, who gave a great overview of the real world experience of CD19 CAR T cells. And so, Jeremy, can you give our audience the highlights of what you think the takeaway from your very comprehensive talk?

Sure, I’d love to. Thanks, Cath. You know, the longer we’ve had these products available in the clinic, the more experience were getting at treating patients. Both who would have been eligible for the pivotal trials that garnered the approvals and those who would not be. And it’s remarkable when you look across these real world studies that half or more of patients being treated with a CD19-directed CAR T cell for large B cell lymphoma wouldn’t have even been eligible for the ZUMA-1 or JULIET trials. Um, currently, the real world data we have are really just for those two products for the axicabtagene ciloleucel and tisagenlecleucel. Liso-cel is too recently FDA approved. We don’t have those real world data yet. So one of the big message is, is that we can treat a broader population of patients. Then we’re allowed to the strict eligibility criteria. We can treat patients who are older. We can treat patients with moderate medical comorbidities, including moderate renal insufficiency. As long as the fludarabine is dose reduced. Moderate cardiac and hepatic comorbidities ECOG performance status of 2 may be associated with inferior outcome. But those patients can still have durable responses, other things that keep people out of clinical trials like other second malignancies, even if they’re in remission. A recent blood clot, et cetera. All of these patients have been studied in real world settings and can do very well. The other thing we’re seeing, particularly with axi-cel, which induces a high rate of CRS and Neurotoxicity, is there is a suggestion that the longer these products are out, the lower the risk of severe cytokine release syndrome, and I think that reflects that in the pivotal trials with our hands were tied as far as when we could use tocilizumab and corticosteroids. And we have more data now that earlier use of these rescue medications can reduce the risk of severe cytokine release syndrome less so, perhaps with severe neurotoxicity. But I think that’s true with with severe cytokine release syndrome. Uh, and so I think that says that were actually learning from our experience and probably doing better because the studies do show higher rates of use of rescue medications than in the pivotal trials. I think the other thing that more recent real world analyses are starting to look at is comparative safety and efficacy between tisa-cel and axi-cel. These, of course, are different products in large B cell lymphoma. They both part target CD 19. They have different co stimulation domains. They have different transmembrane domains. They have different doses, and they have different lymphodepleting chemotherapy. So they’re really quite different treatments. And across the real world data, we see an interesting theme emerge. One is that axi-cel with the CD28 costim domain certainly is a more toxic product. The vast majority of patients develop cytokine release syndrome. Most patients develop neurologic toxicity. Severe CRS now appears to be less than 10% severe neurotoxicity can be in the range of a third of patients, which is a high number, and about a third of patients end up being transferred to the ICU. So axi-cel is a toxic product, though clearly manageable in most cases. Tisa-cel, on the other hand, as reflected in the pivotal JULIET trial, has much lower rates of any grade CRS much lower rates of any grade neurotoxicity and very low rates of both severe neurotoxicity and severe CRS. So it’s clearly a safer product than axi-cel. And we’re also seeing that reflected in prescribing patterns. Tisa-cel appears to be given more elderly and frail patients, whereas axi-cel seems to be preferred in younger patients and patients with high risk features in large cell lymphoma. Perhaps getting to how providers view the efficacy of these drugs. And though these drugs have never been compared head to head. We do have some recent comparative data from both Spain and in the United States that have looked at patients who have received commercial axi-cel and commercial tisa-cel, and multiple retrospective studies now have looked at them in a matched compared multivariable analysis and found that actually sell is associated with an improved progression-free survival, uh, relative to thyself, uh, and, uh, maybe improved overall survival, uh, in some of the real world analysis. So I think in aggregate, I’d say that tisa-cel appears to be less toxic, but unfortunately, it may be less effective and then has to inform how we pick a product for patients.

So just to play a bit of devil’s advocate there, you know, I think you showed very compellingly that tisa-cel is safer. Um, but you also convinced me that we’re prescribing based on that information. And so is it that those patients that you’re prescribing tisa-cel are your worst prognosis players anyway. And so I am assuming we can’t drill into that level with the real-world data. So I think that would be and I have no financial conflicts of interest with either any of the companies. I should just say.

Yeah, we certainly cannot be definitive. Cath, you’re absolutely right. The risk factors, I think go both ways actually sell teams to be preferred in patients with high ldh as well as primary refractory disease. Those are adverse outcomes, not favorable outcomes. Um, you know, and so one might expect that makes axi-cel patients look like they do a bit worse. Tisa-cel has given more older patients, but interestingly, Axi-cel has, on a recent analysis, had more patients with high medical comorbidities. Ultimately on the real world studies, they’ve done multi-variable analyses where they adjust for the low-hanging fruit age refractoriness, Co morbidities. But they can’t adjust for everything, since patients are famously multi variable on multiple levels. And so nothing short of a head to head prospective trial or answer it would answer these questions. I doubt we’re going to see that between these products, I doubt we’re going to see that as well.

And next year when you come back, you might have some liso-cel data. Who knows, Thank you.

All right, so after we had the state of the nation with the real-world, CD19 CAR-T data, we then heard from David Maloney, who talked about where they’re going with the CD19 T cell products next generation, including humanization of the CAR and and off the shelf approaches, and we also heard, um, from a speaker from also from Seattle, who was talking about, uh, quite promising data with the CD20 CAR, which is now going to advanced Phase trials. So, on that theme of moving beyond CD19, we then heard from Barbara Savoldo, who is here with us and talked about her CD30 CAR T cell program can you provide us with your talking points, take home points for us.

Thank you, Cath, obviously. So we’re very excited that we’re moving beyond Hodgkin’s lymphoma. You know, the CAR CD30. We tested them in Hodgkin’s lymphoma with very promising results. And so we’re ready to move to different diseases. And, you know, the next, uh, you know, patient population that we want to target is obviously CD30-positive T cell lymphoma. They’re not all of them positive. But, you know, CD30 is expressing a subset. And those, uh, you know, have been starting to be receiving CD30 CAR T cells. The results are not as effective as you know, great as Hodgkin lymphoma, but I think they were teasing out the issues, and some are related to, you know, the aggressiveness of the disease. That obviously has to be tailored that with. So we need to tailor the production to the aggressiveness of the disease. But certainly, um, you know, we’re seeing a durable response in those that achieve complete response, and so those are durable, and that is particularly encouraging. And so what we’re looking now is you know how we can predict the patient, who are the patients that will respond right away. And so this is ongoing. Um, one of the aspect of that we’ve also started looking at is actually trafficking, so we know that it’s important for T cells to look for their tumor before they can kill it. And so one of the a good excuse for CD30 is to co-express the chemokine receptor that will help them drive in the right place. Obviously, we have done this for Hodgkin lymphoma, and now we’re, uh, you know, transferring this similar approach to cutaneous T cell lymphoma because they have in common. This attack production in TARK has a cognitive receptor, which is CCR4, and that’s what we have expressed with the CAR T cell. And this is really remarkable not only in the Hodgkin, but we started. Now that we’re reaching the highest dose we’re seeing some response is also in cutaneous T cell lymphoma. So there are nice pictures for, you know, these responding patients that are impressive. And so there is still time to go, and still we need to reach the highest dose level, but I think looks pretty promising. So

Yeah, I agree it looks really promising. And I think, you know, we had a T cell lymphoma session this morning where we heard of a different CAR T cell approach for T cell lymphoma. And they’re having challenges with persistence in vivo of the T cells. And and certainly, I think, you know, the your response rates looks really encouraging knowing that your T cells are also persisting. Correct?

Yeah. I mean, obviously it’s less so. The talk that we heard this morning was more broadly applicable because it would be, uh, for every single T cell lymphoma. CD30 is just a subset, but I think that providing a therapy that is safe and effective even if it’s a small court in a small court, I still, you know, something that we should pursue for. I agree. I agree.

And on that note will then end with Doctor Maksim Mamonkin. And he talked about his CD5 T cell program also for T cell malignancies. So, Max, over to you.

Yes. Thanks, Cath. So, you know, developing CAR T cells for T cell malignancies is famously difficult because of all these limitations and T cell targeting and fratricide and preservation of normal T cell compartment. And so particularly when you’re targeting antigens like CD5, which are broadly expressed on T cells, malignant T cells across various subtypes of T cell lymphoma and ALL there’s always this concern that the CAR T cells would kill each other, and they will also induce T cell aplasia. But what was interesting is that we developed a CAR that allowed these T cells to escape fratricide, or self-killing , by very efficiently degrading CD5 very quickly on themselves, and that is a process that is driven by CAR engagement. And so, as a result, they sort of lost the target antigen, and they expanded very nicely automatically, without having to do any CRIPSRing or any other manipulations with it. This is pretty much unique to see, we don’t really see the same thing with other targets. We have to do some active interventions there. But CD5 has this property where it’s intrinsically resistant to, uh, fratricide. So that allowed us to move it to the Phase I clinical trial. And we saw also going back to the previous point, we saw nice expansion, persistence of the cells and These cells work fairly well in T cell lymphoma and induced about 44% overall response, including some CRs um, including long term responses as well. So those those were durable, particularly with products that were manufactured with a shortened method where we sort of limit the duration of expansion of these CAR T cells. But the problem is, this approach didn’t really work well for patients with lymphoblastic disease, the T-ALL, and T-cell lymphoblastic lymphoma, and, um and so we we started thinking, What is wrong there? Why it works in T cell lymphoma but not in T-ALL. And we realized that this very process of you know, evasion of fratricide essentially triggers, uh, continues CAR signaling that engages CD5 on these T cells and that CAR signaling leads to progressive differentiation to a short lived, uh, population of effector cells, which are fantastic at killing but not so good at persisting. And so we thought, What if we, you know, just mute the CAR signaling with pharmacologic inhibitors, the tyrosine kinase inhibitors? And we found a particular combination of ibrutinib and dasatinib did the job essentially just completely, you know, blocked car signaling and preserve these beneficial T cell populations. And we treated, um, patients with this, uh, new products and we saw remarkable, uh, you know, improvement in in persistence. And we also implemented manufacturing of CAR T cells from healthy donors for patients who relapsed post-allotransplant from their previous stem cell donor. And we also amended our protocol. That and we saw out of six patients now, four achieved complete remissions, which is, you know, great compared to one transient CR out of eight patients with the previous protocol. So again, the patient number is very limited. But you know, the clinical team and the trials led by LaQuisa Hill and Ryan rouse in Houston Methodist and TCH. I should have mentioned it in the beginning, but they are quite encouraged by these responses. And so we hope to expand to large patient population, and hopefully it pans out.

Yeah, I mean, I think that’s really encouraging, you know? I mean, I think the car t cell field has struggled a bit because people think it can’t go beyond CD19 to that sort of response rate. And so I think the work that both of you are doing, uh, in that, you know, outside of the CD 19 car T cell space is so important. And so I know you didn’t really talk about it, Max, But do you want to just briefly talk about where you’re going also with T cell ALL with the CD7 CAR program?

Yes. Thanks Cath, so it’s It’s always great to target more than one antigen, as we’ve learned in B cell malignancies. And so see, CD5 is very well expressed in T cell lymphoma and in ALL But see, CD7 is really screaming at you in ALL, it’s so bright. And it’s a fantastic target T-cell ALL. So we’ve developed a new approach that should be published, uh, with where we can generate CD7 CAR-Ts without having to produce any manipulations by using the same tyrosine kinase inhibitors to inhibit fratricide which otherwise would completely destroy them. And then we’ve moved that to Phase I trial that is currently ongoing, and we’ve treated several patients with very, very encouraging responses, including one patient with T cell lymphoma who went into CR. We are at the early stages of that, but it looks promising. So, you know, I don’t want to, you know, eat my words later, but I’m really, you know, encouraged by the progress that collectively we made in the field, you know, in the US and abroad. And I think I’m optimistic that T cell malignancies will actually be tackled very soon with various approaches that, uh, collectively we as a field are developing so. You know

I think it’s really exciting. And, you know, I ended the session talking about off the shelf EBV t cells and actually tantalizingly sort of said at the end, you know, they are potential to combine with a CAR strategy and use them as an off the shelf CAR approach. And I think you know, the field is moving so fast. And I think if the four of us get together next year, we’ll have completely different data to show. And, um, that’s why this field is so, you know, amazing. So on that note, I would like to thank you all for coming here to Spain and giving your talks. It really was a fantastic session. I felt very energized, and I think the audience did too, so thank you very much.