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A roundtable discussion filmed in Tampa, FL, during the iwCAR-T 2022 meeting with experts Noelle Frey, Bijal Shah and Shannon Maude, who share their insights into the future of CAR-T therapy for acute lymphoblastic leukemia (ALL).

Welcome to The ALL Sessions brought to you by the Video Journal of Hematological Oncology (VJHemOnc)! In this exclusive roundtable session, Noelle Frey, Bijal Shah and Shannon Maude, share their insights into the future of CAR-T therapy for acute lymphoblastic leukemia (ALL). They talk on the impact of the approval of tisagenlecleucel (tisa-cel) in adult patients, stressing the importance of finding strategies to improve the persistence and durability of responses to CAR-T therapy. They also comment on the advent of allogeneic CAR-Ts and highlight the advantages of humanized products, as well as the different strategies to manufacture dual targeting CAR-Ts.

The future of CAR-T therapy in ALL

 

Full Transcript

Noelle Frey:

Hi, my name’s Noelle Frey, and I’m here with Dr. Bijal Shah and Shannon Maude. We are at the Fourth International Working Group for CAR-T Therapy down here in Tampa Bay, Florida. We just finished what I thought was a very enlightening and exciting session about CAR T-cell therapy for adults and pediatrics with B-cell ALL. I don’t know about you guys, but I thought the session was so exciting. I think what’s clear is we’re all so aware of these initial successes that we’ve had with CART-19 products in ALL and how this has really launched this field of CAR-T therapy to go after other diseases and other antigens. But what we really saw today, I think, is the next phase of CAR-T therapy for ALL. Dr. Maude talked about using a humanized CAR-T product instead of a mirroring or mouse-based CAR-T product, hoping to improve persistence of the CAR-T, which would translate into less CD19-positive relapses. I talked, and others did too, about going after more than one antigen on the leukemia cell. Again, the goal there is we have these great remission rates. How can we take it to that next step and improve relapse-free survival? Bijal, we finally now have an FDA-approved product to treat adults with ALL. It was exciting to hear that data. We also heard about an off-the-shelf CAR, which could overcome a lot of the barriers that we face when we use an autologous product. So what’s inspired you guys and what are you most excited about?

Bijal Shah:

Well, I’ll start. I mean I’m excited that I can treat grownups. How’s that? I mean I never really understood the cutoff of 26 for tisagenlecleucel. It was always something that I found mystifying. I understand we have to take the trials and figure out how to bring them forward, but you had published data showing that this could be delivered safely to adults. I can tell you we did try to deliver it to adults off-label, and we’re not successful getting that off the ground. And so, it was really, really exciting to finally have a therapy we could bring to adults. I think it emphasized that there’s still room to make it better. I think this issue of intention to treat, although I hate the term, it does emphasize that folks can get sick while you’re in that phase, trying to get them to CAR-T immunotherapy. At least for me, it emphasizes the need to intervene earlier and ideally with lower tumor burden, where, nicely enough, we still see activity and perhaps even better safety. And so, that was really the crux of what I wanted to bring forward. In terms of the allogeneic CAR-T products, I have had the pleasure of being able to work with Nathan on this protocol for relapsed/refractory lymphomas and ALL, and it’s been really cool. We’re at a point now where we’re seeing expansion that’s commensurate with what we would see with an autologous CAR-T product. Now we get to do the watchful waiting, the hard part. Is that really going to translate into these durable remissions that we want to see in ALL and in non-Hodgkin lymphoma? And so, we’re in that process now. But it’s been very, very exciting to see that develop and to now have an option that we’re actually specifically taking for those post-autologous CAR-T relapses.

Shannon Maude:

I think as well that now that we’ve seen these exciting results and now that we have this available across the age spectrum, I think we’re all thinking now what? How can we improve upon this? Because it’s been remarkable, but it also brings to light… when we see these remarkable results in a substantial fraction of patients, you want it for everybody. And so, it brings to light the failures of these therapies and how can we improve upon that? I think that’s what I’m excited about too. I think, as you mentioned, getting to the patients who haven’t been able to get to this therapy in the past, but then also thinking about the patients who have an initial response, but then have the CAR-Ts fail them by one mechanism or another. I think we’re learning a lot about how can we improve upon these therapies and make them last longer, make them overcome and be able to recognize the ways that the leukemia can hide and get around it. And so, I’m excited about that. I think I’m also excited about the prospect of bringing this into earlier lines, as you talked about and as we have been trying to do in pediatrics as well. I think we’re going to see improvements of those outcomes as we bring this into our earlier lines as well.

Noelle Frey:

Yeah. It’s very exciting. Shannon, you have such a large experience, perhaps, in the world of these large cohorts of pediatric patients treated initially with what’s now tisagenlecleucel and now with the humanized version of it. You shared your data today, but what’s your instinct about the difference between a mirroring versus a humanized product? Do you think it’s something we should keep exploring, worth that effort?

Shannon Maude:

I do think it is. I think that we have seen that a humanized product can overcome some of the problems that we see in patients who have had poor persistence. But even more importantly, I think if you’re starting with a humanized or fully human product, you may run into less of those issues down the road, that I think we’re starting to see the hints of improved persistence of those products. Perhaps we can see improved safety as well.

Shannon Maude:

I think it’s a little bit early to know that, and the patient population treated on the trials was different. However, in my view, I think the humanized or fully human products are probably where we need to head to improve upon these therapies. I think doing them on their own or also in combination is where I hope we’re going to be going.

Noelle Frey:

That’s great.

Bijal Shah:

No, I wanted to ask you, because I thought your presentation was fascinating, that we can come in now with a 19 and a 22 CAR, not only see it prove effective and perhaps improve on that persistence benchmark but the kinetics of expansion and the fact that you can see one CAR in a sense pull up the other. Again, I’m just fascinated about that. I’m curious, what are your thoughts as it relates to that and does that also give us some insight into how we should be targeting multiple antigens as opposed to trying to build them all into one cell?

Noelle Frey:

Yeah. So I think it’s just a really exciting area in the field right now. I think next year, we’re going to have so much more to talk about. Even within this conference, I think we’re going to hear a couple other talks in the lymphoma session just about other approaches to this dual targeting. So the approach that we’ve used in our trials at Penn is to actually manufacture two separate CAR-T products, one targeted to 19, one to 22, and infuse them into the patient at the same time. Of course, there’s other approaches, manufacturing a product with a single vector with bispecificity or a bicistronic vector, or using two vectors, encoding separate CARs in the same product. I think each of these approaches have strengths and weaknesses, speaking to our own experience using what I think, as I mentioned, is the simplest method. You make two products and give them to the patient. I think the challenges with that approach, there’s logistical and cost challenges. You’re manufacturing two products. What we learned is that you need to think about the two products and their cellular kinetics, how it is when you give them as a single agent and how is that changed when you give the two products together. For example, if the CART-19 product we’re using tends to have an earlier expansion. How is that cytokine storm that’s generated there going to influence that more delayed expansion of the CART-22, both in terms of efficacy, potentially, making that CART-22 potentially more efficacious, but also in terms of toxicity? The other challenge that I think we could have predicted, which, fortunately, we didn’t see is if there’s these two products in the body each going after the same cell, different antigens, is one of those going to be more successful and, as a byproduct of that, the other product dies off? So you lose that potential for dual functionality if one of the CAR-Ts just doesn’t persist. I think we’ll hear some other talks, but an elegant method of a single vector encoding a CAR with bispecificity. We’ve learned there’s lots of structural issues related to how that CAR is on the surface of the cell that might actually impact the ability of that cell to maintain functionality of both of those antigens. So I think all of the approaches that are under investigation have this potential for great success. I think less of comparing different approaches and more in terms of optimizing each approach. I think in solid tumors, this might be really important, too.

Shannon Maude:

Noelle, what I found so fascinating, as you have alluded to, is that we’ve seen all these different approaches being developed simultaneously. In some ways you may think, are we putting in a lot of effort with all these different approaches? But it’s really we’ve seen that the outcomes that you see are much different and the behavior of the products are really much different the way that you do it. I think what we need to think about going forward, it was mentioned in the solid tumor day yesterday as well, is how can we design clinical trials that we can get a signal from all of these different approaches and pick the winner or figure out what needs to be optimized and developed? I think that’s going to be our challenge.

Bijal Shah:

Oh, absolutely.

Noelle Frey:

Well, I certainly look forward to next year. So I want to thank you guys and thank the audience for being with us today.

 

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