iwNHL 2024 | CAR T-cell therapy in NHL: selecting between agents, managing toxicities, & the potential of allogeneic products

Catherine Bollard:

Hi, I am Cath Bollard from Children’s National and George Washington University in Washington, DC and I’m here at the iwNHL meeting in Nice, France. And I have the privilege to be here with my colleagues, Dr Steve Schuster from University of Pennsylvania, and Dr Jason Westin from MD Anderson Cancer Center in Houston, Texas. And we have just finished a very exciting, highly dynamic session focused on CAR T-cells. Predominantly for lymphoma, but we also had broad ranging discussions including CLL, and even touched on at the end Hodgkin lymphoma.

But Dr Schuster talked about a very interesting study where they are using off the shelf allogeneic CAR T-cells that are gene engineered to be safe in terms of mitigating the risk of GvHD. And Dr Westin talked about whether autologous transplant is dead, and should we all just give everybody a CAR-T. But both Dr Schuster and Dr Westin are really pioneers in the use of the now commercialized CD19 CAR T-cell products for lymphoma. So I’m actually going to pose initially quite a general question to them both about when they see a patient in second-line, how do they figure out what patient should get what treatment given we are now in this really exciting area of so many CARs. So maybe you can start and I will then land to Steve.

Jason Westin:

Thank you, Dr Bollard. So I think we’re in a fascinating era now where we’ve got lots of choices, and now have approvals in the US and in many countries for second-line autologous CAR T-cells, specifically axi-cel and liso-cel. And those products have shown improvements in both event-free survival, but also overall survival. Axi-cel being statistically significant. And so if those products are available for our patients, we do prefer to use those as a second-line therapy, not trying chemotherapy first and saving CAR T-cell only if it doesn’t work.

However, sometimes patients have an urgent need to start chemotherapy. They might have rapidly progressive disease or pain or other reasons that they need to have a treatment. And if a patient achieved a complete response to chemotherapy in that setting, that might be reasonable if you’d not yet started apheresis to consider taking that patient to transplant. The reason transplant survived as the standard of care for a quarter century is it does cure those patients who can be chemotherapy sensitive in a second-line setting. However, we know that that’s a minority of patients that actually derive benefit from chemo. So in my practice we’ve shifted largely over to going for CAR T-cell as our immediate second-line therapy and using chemo more as a bridge after we’ve already done apheresis.

Stephen Schuster:

Exactly. I agree with Jason. Although, and certainly from a population standpoint, we can treat more patients in the relapsed/refractory setting. I mean we’ve treated at Penn patients up to age 90 with CAR T-cells. We don’t do auto-transplants in people that are age 90, okay? So the number of patients that we can now have effective second and third-line therapy for has increased.

Anecdotally, I can tell you though, I’ve had a few patients in my practice who failed CAR T-cell therapy who then went on to auto transplant, have been in remission for more than two years. So we can’t have too many tools basically. And not every patient is identical. And we don’t have a crystal ball to know for sure. But in general, I am with Jason, I go with the CAR-T approach.

Catherine Bollard:

So you are from the center that developed the tisa-cel, and is it correct you are not using tisa-cel anymore in your second-line?

Stephen Schuster:

It’s not approved for second-line.

Catherine Bollard:

I know, but-

Stephen Schuster:

Yeah, yeah. It was a flawed study. I don’t think we need to go into that, but it’s a long story.

Catherine Bollard:

Okay. So let’s-

Stephen Schuster:

I don’t think it’s biologically different than any other 4-1BB CAR really. I think that it was all about the study design. To get a label as a second-line, you had to basically get some salvage chemotherapy, second-line chemotherapy, still have an inadequate response. Then you could go on if you were responding or you would randomize either way. But what they did with the tisa-cel study is you actually had to fail two platinum based regimens, which is not what we do in the United States. That’s one of the major reasons that the study failed. The other was it was during COVID, and it took almost, what, almost two months to get a product, Jason?

Jason Westin:

About 50 days.

Stephen Schuster:

And very few patients in the United States had bridging therapy to stabilize their disease. Jason showed a nice slide from a study that we were both involved in indicating that if your disease is not controlled, your outcome’s much worse. So there was a number of reasons why that failed. But clearly for second-line, I’m following the FDA, I do what’s approved.

Jason Westin:

In many countries, it is available in third-line and it may be available and preferred over other third-lines in the toxicity profile. So there might be a role for it in context where you’re not in second-line and you’re in a country where you may not have access to liso-cel and you’re worried about toxicities of axi-cel. So clearly for large cell it’s lost some of its luster, but it’s approved for follicular, for allele. There are indications. And then I think of course the new version, rapcabtagene autoleucel or YTB 323, very attractive in that it’s a rapid manufacturing. So it’s almost an allogeneic-like timeline for an autologous CD19 product. Similar to tisagenlecleucel, it’s a 4-1BB product. But the manufacturing preserves a lot of the naive T cell phenotype. And in early days, the CRS rates look lower and the ICANS rates look lower. And so we are very intrigued with the potential for that product, including maybe even on a frontline high-risk population.

Catherine Bollard:

So thank you for bringing that up because you did give a very elegant talk on that as well. Okay, I will go to a less controversial topic. So I know you didn’t talk about this today, but it was at the session about the ICANS risk and other toxicity risks. And I’m curious about what you are using as your standard of practice. We heard a lot about the different approaches and so-

Stephen Schuster:

I can tell you quite frankly, where I live and work in Philadelphia at the University of Pennsylvania, I am not using the CD28 based products because those patients need to be admitted to the hospital. And we are very tight in terms of hospital beds. So I do most of the CAR T cells and outpatient. So I’m using generally liso-cel or tisa-cel because it’s 4-1BB, there’s much less… It’s the neurotoxicity. I think grade three is like 25% almost with a CD28. Now, certain designated comprehensive cancer centers in the United States, they can admit patients and not lose money. It’s a different situation. So you have centers that can do it in centers that can’t, for reasons that are not always biological. How’s that?

Catherine Bollard:

So how did we get controversial again? So I guess-

Stephen Schuster:

You got the wrong audience.

Catherine Bollard:

So Dr Westin, okay, so at your institution you do use a lot of axi-cel. So what sort of prophylactic strategies are you employing?

Jason Westin:

Yeah, I think this is a key question for the field because if we believe that axi-cel and other CAR T-cells that have a risk of neurotoxic specifically with CRS are viable curative options, we really need to get better at mitigating these toxicities, which are a real barrier. Even though we’re discussing that second-line therapy is preferred to be autologous CAR T cell, globally, the vast majority of patients in second-line are still not receiving CAR T-cell, many times due to barriers related to toxicity. So these have to be administered at specialized centers at UPenn or MD Anderson type centers. They can manage the toxicities. They’re not administered in the community because of this fear of CRS and of neurologic toxicity. So if we’re able to prophylax or to modify the products or do something to mitigate that risk, it would allow CAR T cells to scale, to be delivered to a lot more patients. So just to speak to our strategy for mitigating, we don’t really have a good answer either. So we-

Stephen Schuster:

It’s because we don’t know what causes it.

Jason Westin:

That’s right. That’s the main problem.

Stephen Schuster:

It helps to understand something if you’re designing a treatment.

Jason Westin:

If you don’t have a what to go after, it’s a challenge to know how to manage that. But we have tried limited use of corticosteroids. So in our series from MD Anderson, Paolo Strati published this, that we thought that early and high dose corticosteroids might actually be detrimental. There’ve been a number of other series showing that early corticosteroids, not high dose but preventative, might mitigate that risk. And of course, cytokine, targeting therapies like anakinra have been explored, but so far have been relatively modest in their benefits. So that is clearly an unmet need of how to better mitigate these toxicities, both so that our centers are able to deliver these, but also so that it can scale outside of academic centers.

Stephen Schuster:

But the good news is it almost always gets better regardless of what we do. And very seldom do we lose a patient to neurotoxicity. It’s very upsetting to the family to have a disoriented family member, and the doctors don’t like it either, nor do the nurses. But fortunately, it resolves in most cases.

Catherine Bollard:

So I think we can end on that high note. But I also just want to end on a future note. I think both you and I spoke about the potential for off-the-shelf all0geneic CAR T-cell products. I think that is an exciting area to watch. I mean, if we could make our therapy truly off the shelf and avoid all the..

Stephen Schuster:

One donor can make a product for 100 patients, the number one. And you asked a great question about you’re not knocking out HLA-I or II possibilities with the class II transactivator knockout or beta-2 microglobulin, but we don’t do that with platelet transfusions either. And very few patients get alloimmunized, okay? And so far it looks good. I actually was a skeptic. I was totally a skeptic until we started trying and treating some patients. And actually I think there’s a future. Not all patients have healthy fit lymphocytes or decent counts and we need to be able to treat those people.

Catherine Bollard:

Right. And I think even though this is an NHL meeting, we did talk about CLL and I especially worry about that patient population, that allo CAR T may be really a game-changer there. So on that happy note, I want to thank you both very much for talking with us today. And that’s signing out from iwNHL 2024.