iwNHL 2023 | Expanding the CAR platform in NHL

David Maloney: Greetings. I’m Dr David Maloney from the Fred Hutch Cancer Center in Seattle. And I’m here with my two colleagues here at the iwNHL meeting, 20th year of this meeting, Dr Jason Westin from MD Anderson and Dr David Miklos from Stanford. Jason, why don’t you kick it off here. We hear great summaries from the three different products and from second line. Give us your take.

Jason Westin: Thank you. We had a great session this morning and covered a lot of ground. We heard about the three FDA-approved products, starting with tisagenlecleucel. We heard from Dr Schuster about the early studies that showed how that product, targeting CD19, autologous product using 4-1BB showed some very good promise. However, as that trial moved from third line into second line, there were some challenges and that product is not approved in second line because of some perhaps design challenges in the BELINDA trial. Dr Schuster also shared some of his data about different lymphodepletion regimens, including bendamustine, and we’ll look forward to seeing more data about that at the ASH meeting. Then we heard from Dr Sattva Neelapu talking about axicabtagene, both in the ZUMA-1 trial as well as in now up to ZUMA-25, lots and lots and lots of trials looking at axicabtagene, a CD19 autologous product using CD28. That has shown, in the ZUMA-7 trial, to now have a superior overall survival compared to platinum-based chemo followed in responding patients by autologous stem cell transplant, which we know is the standard of care for almost 30 years. We made the case that there’s a new paradigm where now CAR-T cells should be considered a second line approach as opposed to chemo and transplant. And lastly, you presented some great data on lisocabtagene maraleucel, the other FDA-approved product, using CD19 as the target. And again, 4-1BB showing a very high response rate and a slightly favorable toxicity profile compared to axicabtagene, again in second line showing a superiority to standard of care for event-free survival and a trend towards overall survival improvement. So effectively we’ve got a new standard, which is always a great thing for treating patients with cancer, where second line now, CAR-T cells, specifically axi-cel and liso-cel are the preferred approach.

David Maloney: Yeah, I think it was a great discussion. A lot of lively discussion about how you choose products for different populations at your own center. All right, David, it doesn’t work in everybody. If we still fail and the product fails the patient, I guess in 60% of patients, what do we do next?

David Miklos: Well, we had an opening discussion of how the product may fail and what are some of the mechanisms of failure: antigen loss, exhaustion, large tumor burden, poor tumor microenvironment, inhibitory cells. So in that realm, we considered some options amongst a number of speakers. I kicked it off with a discussion of: is it possible to make an autologous product that it’s going to target another antigen? And in our situation it was CAR22. This is a study that Dr Matt Frank led at our program and has treated patients. This Phase I safety efficacy was all manufactured in-house, and the efficacy on the 27 patients treated with the recommended dose, level one, has gone forward now into a company-sponsored study and it’s open in a number of multi-sites. So that seems like it’s possible, you can still harvest from patients who’ve been through CAR and make another autologous. And the idea of choosing a new antigen might be a good idea just to avoid the idea of antigen loss.

We heard a lot by Dr Siddiqi in regards to a number of competing programs in the allogeneic or off-the-shelf space. The idea there is that time is important and getting the patients’ therapy quickly would be helpful. And if the product is in the freezer, liquid nitrogen, then moving from consent to treatment on a clinical trial space could be relatively quick. There again, we talk about what are the targets, what are the mechanisms to avoid graft-versus-host disease of therapies that are going to be immunologically different. The histocompatibility is going to lead to some immunological rejection of these products. How do you avoid this? Whether it’s TCR depletion, beta-2 microglobulin, using checkpoint blockades. What we, I think, heard though was that we need to think about the durable response evidence in order to move therapies that are not shown in large patient cohorts with thousands of real-world outcomes to a second line or to compete with the autologous CAR-T cells that have proven benefit, especially in these randomized second line. Think I’ll stop there.

David Maloney: Yeah, I think it was… I was struck by the fact that some of these alloCAR-T programs use very high dose lymphodepletion, like 60 per kilo of Cy times two plus five days of fludarabine. It’s more like a TIL type regimen. How do you disassociate the response just to that chemotherapy from your actual product? Because if you’re looking at initial responses at day 28, I guess I wouldn’t be too surprised that you’re responding to a transplant regimen, at least transient…

David Miklos: Therefore, the emphasis on durable response is being demonstrated for six month minimum and possibly even longer. And what about-

David Maloney: But I think you need biologic correlates, right? I’d like to see T-cell proliferation. I’d like to see T-cell expansion, some correlation of T-cell expansion with outcome, like we’ve seen in some of the other trials.

David Miklos: Yeah, you would think that the PK of these allogeneic products is driving the decisions to escalate dose, to change the lymphodepletion. What if you have good expansion on these really large lymphodepletion regimens now, could we pull back and have less lymphodepletion and have a more tolerable experience for long-term immune reconstitution and hopefully avoid some late infections?

David Maloney: Yeah. Well, I think that’s the next topic that we should mention, which is really… We’re treating these patients. We’re curing them, as I think of the data you showed in minority of patients.

David Miklos: Dr Westin really did make the case, and I’m going to highlight again what you highlighted. Read the paper because the discussion actually used the word cure in the-

David Miklos: … comparison of second line with overall survival benefit with axi-cel.

David Maloney: But what about long-term issues? It’s not just CRS and neurotoxicity. We have other issues.

Jason Westin: Yeah. I mean, infections clearly are a problem. And I think that that’s something that David made the case, that we need to look at outcomes, not just for the first 28 days or the first couple months, but looking at long-term outcomes including risk of infections. And I think the studies that are ongoing now, it’s incumbent on them to report these data, especially when we’re using very high doses of lymphodepleting chemotherapy, which we know increases the risk of bad infections. So I think that looking at on-target effects of hypogammaglobulinemia, that’s durable. That’s, of course, a luxury to have versus being dead of your cancer. But in the long-term sense where you’re curing more and more people, you got to look at what is the long-term outcome for the quality of life of patient. And if they’re chronically having a congested sinus and needing IVIG, that’s not a trivial outcome. I think that late toxicities need to be looked at now that we’ve moved out of the early days of CAR-T cells.

David Miklos: Yeah. And I think my message, I hope, was that collecting this data is going to be a long-term, not just for the safety or REMS consideration of what the FDA negotiated, but for the community to be able to learn how to compare the established therapies, auto and allo, with these new CAR-T cells, and I assume the T-cell engagers. It would be a shame if we took T-cell engagers forward and didn’t capture their long-term follow-ups and infectious complications in this established ecosystem of what CIBMTR helps us with already with registry data collection.

David Maloney: I think that’s a key point because James Kochenderfer also presented data from the original trials that actually led to axi-cel back in, what, 2008. And it was great to see the long-term follow-up, but I was also struck by the fact that if you have complete B-cell reconstitution, but you don’t have Ig reconstitution, IgG reconstitution, or you still need transfusion, how much of this is really a carryover from their being bathed in rituximab for years before they even get to treatment? So I think we really need comparative groups, and I really think that the Phase III trials in the second line will provide us some opportunity to look at what happened in the control group. The control group would’ve either gotten salvage chemotherapy alone, if they didn’t respond enough to get to a transplant, or they got transplanted. Well, I know that many of my patients have IgG deficiency before we even start, more than 50%. And if you’re looking at levels like 400. So it is really expensive. There was a lot of discussion about the cost of ongoing IVIG. Well, let’s make sure it’s actually due to the CAR-T cells, because if the CAR-T cells are gone, the B-cells are back, then I don’t know that there’s a good rationale for ongoing B-cell depletion related to the CAR. So interesting.

David Miklos: It’s a good place to leave it. It’s very exciting. It’s exciting to use the word cure at a large seminar, symposium. And the iwNHL did a great job of having wonderful conversations, discussions. Really wonderful to be here. I’m so glad to participate.

David Maloney: Well, I’d like to thank my colleagues. And greetings from iwNHL number 20.