The Evolution of Chimeric Antigen Receptor T Cell Therapy - Episode 3
David Maloney, MD, PhD: I’d like to transition to one of the 2 key abstracts, and that was these real-world data. Because I found this tremendously exciting. What did you guys think of those data?
Matthew Lunning, DO: I thought it was one of the best presentations at ASH [American Society of Hematology] 2018. I may be a little bit biased, as we contributed some cases to it, but I think it showed that people want to get together and really learn across institutions and continue to put out the data that get these CAR T cells growing from that standpoint. But the data were very interesting because if you looked at them, I think 40% of the patients would not have been eligible for ZUMA-1, and the results look fairly comparable, almost uncannily comparable, to the ZUMA-1 population.
David Maloney, MD, PhD: I think they put together 300 patients in 1 abstract and about 100 in the other abstract, so almost 400 patients with real-world experience. And a large number of those were not eligible for the clinical trial eligibility criteria, which I think is the key factor because that’s the art of medicine translating from an FDA approval, which just says twice-relapsed large cell lymphoma, to who you actually do treat. What else struck you guys on this?
Nilanjan Ghosh, MD, PhD: So I think some of the reasons why they were not eligible helps with our real-world experience. They did take some patients who had slightly poor performance status. They had patients whose end organ function didn’t meet the exact criteria. So from a renal standpoint or from a cardiac standpoint, those things stood out. I think overall, it really appeared to mirror what was seen. Now, they did see a trend toward slightly worse outcomes for people who didn’t meet the strict eligibility criteria. But it still was really early.
But the other thing that stuck out was how there were a significant number of patients on a separate presentation above the age of 65 who also seemed to have just as good responses as the below-65 population, which, hopefully, increases the access to patients who are above 65. And the toxicity did not seem to be much worse. So we’ve all treated patients who are in their high 70s or even up to 80, and although we are worried so much about CRS [cytokine release syndrome] and neurotoxicity, as you pointed out well before, the majority of this is reversible. And even in the real-world experience, we are not seeing too many deaths. It was actually very similar to what was presented in ZUMA-1 in terms of deaths. Even in the real world outside clinical trial, the majority of these toxicities are reversible if you are allowed to use aggressive measures to treat them.
Michael Pulsipher, MD: So I think the key points are that CAR T cells cause problems with fluid that leads patients to be intubated, so you don’t want to start them hypoxic; CAR T cells cause renal problems; and CAR T cells cause neurologic problems and potentially heart problems, so those patients have all been screened out of any CAR T-cell protocols. What we don’t know is what comorbidities are really no-go for CAR T cells and what comorbidities are OK. And just like what we’ve had to do with transplant, we have to figure out the level of comorbidity that patients have to be at in order to safely give these.
Leo I. Gordon, MD, FACP: And we do have a sense of that with transplant, but we’re not yet clear on what to do.
Michael Pulsipher, MD: Yes, those studies need to be done.
David Maloney, MD, PhD: Even transplant is a bit of an art.
Michael Pulsipher, MD: It is.
David Maloney, MD, PhD: Because those transplant centers are more aggressive than ours.
Nilanjan Ghosh, MD, PhD: But there are clinical trials trying to look for that border between a person who may not be eligible for transplant but is now potentially eligible for CAR T. Juno has a study that is looking at that.
Matthew Lunning, DO: But I think what these retrospective experiences have at least put out to the oncologic community is that in the relapsed/refractory lymphoma population, age shouldn’t define whether or not you could get a CAR T cell. If you don’t have CAR T cell at your institution, trying to get that person to an institution that has CAR T cell available—whether it’s commercial or clinical trial, and at least having the discussion about CAR T-cell therapy—is appropriate in 2018, especially coming after ASH 2018 data.
David Maloney, MD, PhD: It seems clear to me that we need to get this therapy to more patients. The other point that came out of these talks was that if you actually had less disease, you then would have a better outcome and you seem to have less toxicity. And this was from analysis of the ZUMA-1 trial, and it seemed to be echoed across some of the real-world data as well. If we could get these patients to treatment before they have massive disease that’s refractory to everything, we can even improve on these outcomes that we’re seeing in the clinical trials. The second point that I think was key was that the ZUMA-1 trial did not allow bridging therapy of significance. In the real-world data, that was the major reason why people would have not been eligible for the ZUMA-1 trial. We had to do something to keep them alive while the cells were being manufactured. And to me, I think that shows that those people did as well, and I think that’s going to be key going forward.
Matthew Lunning, DO: I think there is still a true art in that bridging chemotherapy, too, because on one hand, those patients are progressing very quickly. But you might give them something that is potentially going to set them back hematologically or present high infection risk without much benefit in the disease because these people are coming in triple refractory to R-CHOP [rituximab/cyclophosphamide/doxorubicin hydrochloride/vincristine sulfate/prednisone], R-ICE [rituximab/ifosfamide/carboplatin/etoposide, GEM/OX [gemcitabine hydrochloride/oxaliplatin], and bendamustine. So you have to be, in some ways, still choosy, but a lot of us are trying to find less intensive regimens and convincing the patients and their caregivers that this is the first time with stable disease and acceptable performance status where you’re not getting that ECOG migration, where you’re having the 1 becoming a 2, or 2 becoming a 3, because of the chemotherapy that you’ve chosen to get to lymphodepletion. But what those data also showed me is that we’re actually getting good at choosing what that lymphodepletion chemotherapy may be. It may not be the full dose of bendamustine. It may be a little bit lower of a dose and so on and so forth, to tease out in the right timing after apheresis prior to lymphodepletion.
Michael Pulsipher, MD: One thing that we really need to look at, as we look at patients earlier in therapy, is the quality of the T cells going into the procedure and the exposure that those T cells have had to various types of chemotherapies. There are a number of studies that have shown that very significant chemotherapy can affect T cells and you get a type of T-cell population where the CARs just don’t work very well. And we’re not very good at identifying the right mix of T cells, and I think as studies move forward and we use it a little bit earlier on, we may find better responses just because there are better T cells.
Leo I. Gordon, MD, FACP: Right. One of the things actually in thinking about the difference between the studies is the ZUMA study required a certain number of T cells to be present, a certain ALC [absolute lymphocyte count]. Whereas the TRANSCEND study from Juno really didn’t have that requirement. So again, we can’t compare across studies, but I think that’s something we need to look at as we go forward with this kind of treatment.
Transcript Edited for Clarity