Andre Goy, MD, MS: When we meet a patient who typically got the product axi-cel [axicabtagene ciloleucel] from the ZUMA-1 data…when we tried to do it commercially, because Medicare’s reimbursement has some issues. But typically, they have fevers within 24 hours to 48 hours, so that makes it difficult to have a...in our patient. The Kymriah [tisagenlecleucel] product is a little bit delayed, so it sometimes is a bit easier, and then a lower fraction of patients gets mediated.
But what is impressive is that although the toxicity is somewhat dramatic, it is manageable, and the toxicity is reversible, patients recover. I remember a patient when I was on call a few months ago, a patient on a Friday night was on day 4 or day 5 of the axicabtagene ciloleucel. They had extensive disease, came from Carolina, and had fever. That was expected, right? The next day she was intubated and then obviously in the ICU [intensive care unit]. It lasted 24 hours. She had some…because of toxicity. She recovered, and she has been at least 6 months out now. We see some amazing responses. What we are missing in the CAR [chimeric antigen receptor] T-cell therapy is—obviously the next third-generation and fourth-generation of CAR T and other therapies we’ll talk about in a minute—is also having good biomarkers that identify who’s going to have a clinical benefit.
This is because we know, and I think we should touch upon this, that it is so exciting and generates a lot of interest among physicians, providers, and patients, and their families. But when patients fail CAR T-cell, the situation is very difficult, right? Before we go into the next generation of CAR T and how to overcome that, how do we manage a patient who failed CAR T-cell, Peter?
Peter Martin, MD: The question was partially addressed at ASH [the American Society of Hematology 2018 annual meeting] when we saw a presentation looking at outcomes post CAR T-cells, suggesting, as you’d expect, that if somebody does not respond to a very good therapy, that they typically have a lymphoma that is not likely to do very well with standard chemotherapy or simple CAR T-cells. There have been reports of people having responses to additional doses of CAR T-cells in some clinical trials. There have been reports of people having responses to some chemotherapy, granted short duration. I think we’ll talk a little bit later about bispecific antibodies, which I think have potential promise. In general, at our institution, that’s been our bias, to look for bispecific antibody clinical trials, and we’ve had them available or elsewhere.
Andre Goy, MD, MS: So far this has been the only therapy that has improved some patients with some durability.
Peter Martin, MD: There was originally some thought that the immune checkpoint inhibitors might have the ability to pull some people back. In my anecdotal experience, I have not been particularly impressed with that strategy.
Andre Goy, MD, MS: We have a handful of patients who relapsed, did well, and relapsed 3 months later and had rapidly growing mass. So 2 or 3 patients, we gave them low-dose radiation for the abscopal effect with a checkpoint inhibitor. Two or 3 of them have been in sustained radiation. I think this is really interesting that the checkpoint inhibitor seems very logical because we know that the PD-1 [programmed cell death protein 1], PD-L1 [programmed death-ligand 1] matters obviously in that setting. But we don’t have a lot of great data. There are trials that are ongoing. There was the ZUMA-6 that was looking at combination with anti—PD-L1, atezolizumab, and then showing that you have probably higher amplification of durability of the CAR T. But I agree with you, there is an opportunity, and I think the data that are most impressive in prediction, at the 2019 ASH meeting already presented before, was the day 28 MRD [minimal residual disease]-negative. It’s very impressive. Even patients who do not have a great response clinically do very well, so I think there’s opportunity to do something there.
Let’s talk about what’s the next step in CAR T, and how we can improve it. I heard there are 7500 trials on cell therapy in the United States alone. I don’t know how many globally, worldwide, but that’s definitely a field that has momentum. There’s a third generation and fourth generation…. What do you think is promising, Grzeg, in that field?
Grzegorz S. Nowakowski, MD: I think if you look at this, one is to add something to the existing products, and this would be PD-1 antibodies. People are also studying IMiDs [immunomodulatory imide drugs] and other targeted therapies in this setting. There’s a good rationale to combine it, and we’ll see what’s going to happen to those. The other compound that you could add to CAR T-cell therapy is bispecific antibodies, up front is where they are being used. You have to be careful about toxicity there, but if you think about this...is very appealing, particularly the bispecific antibody that targets CD3 and CD20, which is not a target of approved CAR T-cells….
Andre Goy, MD, MS: That would make it a...CAR T.
Grzegorz S. Nowakowski, MD: Exactly. It brings the CAR T-cells and links it even more to the tumor cells, so those strategies look extremely attractive, and I think we’ll be watching those very closely. As you mentioned, modifying the product itself while having 2 targets is definitely very appealing as well. This is because we know that some of the patients who relapse particularly late after CAR T-cells may actually be CD19 negative, and that’s one of the mechanisms of escape. For some of the patients with early relapses though, CD19 appears to be still present on the cells. So those are the candidates which might be working an existing CAR T-cell clone, which has this therapy, rather than looking for additional targets.
Andre Goy, MD, MS: When you look at the durability of response and when you talk to patients, they ask how we predict, and obviously we don’t have a good way. They ask the question, “Do we need a CAR T that persists over time?” I know there’s a lot of discussion about this. It is controversial and debated. But I am not a believer that we need to necessarily have the CAR T detectable for long response. We have about 30% of patients in ZUMA-1 who have had long response and didn’t have any detectable CAR-T. I really believe that what matters is the early amplification, and that’s what really does the trick.
Grzegorz S. Nowakowski, MD: I probably agree with you, but I’ll tell you for sure in 5 years.
Andre Goy, MD, MS: Nathan, what do you think?
Nathan H. Fowler, MD: It’s interesting. We’ve also seen some studies that I think were presented in 2018 that looked at the rate of expansion. It looks like patients who had a rapid expansion, although they achieved remission, some of those patients were more likely to relapse early. That was also correlated with bulk. Whether this is a correlation or causal is unknown. But patients with bulky disease expanded rapidly, but then the thought is that they develop T-cell exhaustion. Those are the patients who progress. I looked at that early steroid data, and it looked like some of the responses—again, this is extrapolating—it looked better than what we had seen. Actually, the response rate was extremely high. I want to say the durable CR [complete response] rate was in the 50% range and wondered maybe what they’re doing is slowing expansion down a little bit and maybe helping some of these CAR T-cells perhaps persist long term.
Andre Goy, MD, MS: Take a deep breath.
Grzegorz S. Nowakowski, MD: Yes, take a deep breath and maybe not get quite as exhausted. I totally agree with you that unlike maybe some of the acute leukemia trials, the first 3 months is essential. We’ve seen that again and again that the patients who are achieving early CRs and CRs that are especially still there at 6 months are the ones who do well. You don’t see anybody who eventually gets into remission at 12 months. It’s either going to happen early, or it’s not going to happen at all in most of these patients.
Transcript Edited for Clarity