iwNHL 2025 | Expanding the CAR platform for NHL

Catherine Bollard:

It’s my pleasure here today to do a recap of our last and most exciting session on real-world CAR T-cell therapies, or CAR T-cell therapies in the real world. My name’s Catherine Bollard, and I’m from Children’s National and George Washington University in Washington, DC, and it’s my privilege to share the session today with three of the six speakers that were speaking in our panel. So I will ask each of them to introduce each other individually. So over to you. 

Mazyar Shadman:

Hi, my name is Mazyar Shadman. I’m from Fred Hutch Cancer Center and University of Washington in Seattle. 

Tanya Siddiqi:

Hi, I’m Tanya Siddiqi. I’m from City of Hope in Southern California. 

1. Connor Johnson:

And hi, I’m Connor Johnson. I’m from Mass General Hospital right here in Boston, Massachusetts. 

Catherine Bollard:

So this was a terrific session and really sort of ended, in my mind, the whole meeting on a high note. Of course, I am a little bit obviously prejudiced there. But so the good news is that the session started really doing an overview of how the three commercially available products are really performing in the real world. So Dr Shadman, do you want to perhaps give us a summary? You presented on axi-cel, but I’m sure you have real-world experience delivering all three products. So are you able to try and untangle all that for us? 

Mazyar Shadman:

Of course. We have learned a long time ago that the data we get from clinical trials, the clinical trial setting, is important and is relevant, and most of the time, we start using that data in educating our patients and counseling them about treatment options. It’s also important to see what happens in real practice once we get those, in this case, products available for our patients. So the focus today was on, number one, making sure the data we see from clinical trials is consistent with what we see in practice. We call it real-world experience. It’s a very general term which used to be retrospective analysis, and now we have high-quality data using some of the registries, including CIBMTR, and we learned about the French Descartes registry. So once we had each speaker talking about the three approved products for large-cell lymphoma, axi-cel, liso-cel, and tisa-cel. And overall, it seems that the efficacy and at least short-term safety data are consistent with what we saw with the respective trials for each product, both in the second-line setting for axi-cel and liso-cel and for tisa-cel in later lines of therapy. Speakers also looked at some special situations which we encounter in practice on a daily basis, for example, the secondary CNS lymphoma, that’s not an area where we have a lot of data from trials. There was a focus on the elderly population and whether or not these products are safe and which ones could be more or better tolerated by our patients. And then covering some of the rare lymphomas where, unfortunately, we have not made much progress despite all the advancements, namely Richter’s transformation and Burkitt lymphoma. I think in summary, for efficacy and short-term safety, we learned that the experience in the real world is consistent with the trials. We learned that for small, rare diseases, we need to do more work, and in Richter’s and Burkitt, for example, regardless of the product, we have not made much progress. We learned that long-term toxicities and infections are important to note. We presented the five-year follow-up, for example, in case of axi-cel that showed high mortality, relative to the type of data we saw from the trial, related to infections. And we reviewed a number of small studies kind of trying to compare these products – that’s a very complicated and difficult task to do in the retrospective way. There are reasons why investigators, or I should say clinicians, pick one product versus the other, and to control for those confounding factors in the retrospective manner, you would need a lot of both clinical and statistical sophistication. So I think we agreed that for liso-cel and axi-cel, at least, we consider them as equally as effective as we saw in the trials. And for safety profile, liso-cel does come with a better safety profile, which we did confirm with this real-world data. 

Catherine Bollard:

But I did hear that if you have a patient who’s rapidly progressing, the preference is axi-cel because the vein-to-vein time is shorter. Was I hearing that correctly? 

Mazyar Shadman:

Yes. And related to the data that’s published and presented, I would say that’s more relevant. At the current time, we still see some difference in terms of the manufacturing time, but that gap has narrowed significantly. So still, I would say in the range of maybe four or five days, whether or not that’s clinically significant enough for us to pick a product over the other one, you know, that’s a case by case decision. But fortunately, that manufacturing time has improved significantly with even liso-cel. But there seems to be less than a big difference in that manufacturing time. 

Catherine Bollard:

So thank you. So I’m actually going to hand over to our next speakers now because actually they were talking about decreasing the vein-to-vein time from five days to basically zero days. So Dr Johnson, could you talk to us a bit about the sister of tisa-cel? 

1. Connor Johnson:

Yeah, absolutely. We talked today about rapcabtagene autoleucel, which is structurally identical to tisagenlecleucel, which compared to axi-cel and liso-cel doesn’t appear to have as favorable long-term outcomes. But rapcabtagene, as opposed to its sister, tisa-cel, has a novel manufacturing platform where it’s really focused on shortening the amount of time in vivo culture and trying to generate a product with more memory T-cell phenotypes and more stemness. And what’s interesting about that is A, that actually shortens the manufacturing time. And B, at least in the clinical trial data that we have so far, we’re seeing, I would say, encouraging response rates that look more similar to some of the other products. And I think most importantly, it’s a proof of principle that continuing to improve upon our manufacturing strategies has the potential to continue to augment the types of outcomes we can get from products. 

Catherine Bollard:

And do you want to briefly summarize some of the outcomes that have been seen so far? 

1. Connor Johnson:

Absolutely. So what we’ve seen with rapcabtagene autoleucel is some recent data from ASH presented by Peter Riedell. And this was a 16-month follow-up of a clinical trial that treated patients in the third line and later setting. So a little bit different than maybe where we use products most commonly, at least in my practice, I’m often using CAR in the second-line setting. And in this setting, patients who were treated had a complete response rate of 65%. And the 12-month progression-free survival rate was close to 50% in these patients, again, in the multiply relapsed setting. And the patients, particularly, who achieved a complete response, the vast majority of these patients, those were the CR at month three, for example. 80% of those patients remained in a durable CR. And so despite that, in terms of toxicity, actually less than half of patients had cytokine release syndrome and less than 10% of patients had neurologic toxicity. I find those particular toxicity rates encouraging. So we’re seeing a more stem type of phenotype that’s translating to, I would say, better raw response rates than what we might have expected with tisa-cel and also encouraging toxicity. 

Catherine Bollard:

So, you know, Dr Shadman was talking about that population of patients who we might not have a home run yet with the commercial CARs, certainly Burkitt’s. But, you know, Richter’s, some of the data all three of you discussed maybe suggests that some of these newer products might have potency in Richter’s. Do either of you want to talk about that? 

Tanya Siddiqi:

So yes, I talked a little bit about multi-targeting CAR T-cells as well as in vivo CAR T-cells. And these are sort of a little bit different than the standard CD19-targeting CAR T-cells. So the multi-targeting CAR T-cells that I spoke about was CD19/20 targeting or 19 and 22 targeting. And we still have… it’s pretty early phase data that we have at this point, various products from different companies or different labs. But one of the products being tested, the CD19/20 product that Dr Nirav Shah published on and presented, did have Richter’s as one cohort on their B-cell lymphoma trial. And it seemed to be encouraging in the sense that, you know, the response rates were high. But I think just following long-term durability of responses is always key because in my experience, most Richter’s patients after monotherapy with CAR T-cells seem to relapse in less than a year or at most a year. And so we don’t think single agent CAR-T would be good. But in this case, because it’s a double-headed CAR, will it actually more precisely and more deeply suppress the tumor, remains to be seen. There were some toxicities that were concerning on that particular trial, more HLH type toxicity that makes us all take a little pause. 60% of patients had that on that particular trial. So I think we need to just be careful of that, but the response rates seem to be pretty notable. 

Catherine Bollard:

So I think, you know, and we ended the session with discussion around the potential for in vivo CARs. And I know we now have what you said, some clinical trial, you know, information very early, but patients are today receiving in vivo CARs. So I will be very fascinated in a year or two years where that field is and how this discussion that we’re having today will change. And, you know, one speaker who is not here today, Jason Westin, was talking about expanding access for patients and that certainly having an in vivo CAR where you just literally inject the, you know, the vector essentially or the mRNA and then it integrates into your own T-cells could be a real game changer for our patients. So I would like to thank you all really for just being so gracious, and it was just such a fantastic panel today and great speaking and great talks. So thank you all very much. 

All:

Thank you.

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