Allogeneic CAR-T PBCAR0191 with intensified lymphodepletion is highly active in pts with relapsed/refractory B-cell malignancies

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Published: 11 Dec 2021
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Dr Bijal Shah - H. Lee Moffitt Cancer Center & Research Institute, Tampa, USA

Dr Bijal Shah speaks to ecancer about the impact of molecular features of diffuse large B-cell lymphoma on treatment outcomes with anti-CD19 chimeric antigen receptor (CAR) T-cell therapy.

Initially, he explains the background of the study. He says that this study presents the results of eLD conditioning in subjects with CD19+ NHL or ALL. Dr Shah then talks about the methodology and key results of this study.

He explains that eLD mitigated PBCAR0191 rejection to improve peak CAR T cell expansion and persistence with predictable and manageable toxicity. A single infusion of PBCAR0191 following eLD provided clinical benefit in most patients.

He concludes by discussing the impact of these results in the future treatment of B-cell lymphoma.

The study that we’re presenting is a trial of allogeneic CAR T-cell therapy for patients with relapsed and refractory aggressive B-cell malignancies. That is going to include acute lymphoblastic leukaemia in one cohort and then aggressive B-cell histologies in the other.

The principal challenge with allogeneic CAR T-cell therapy is host versus graft, meaning as the immune system recovers from lymphodepletion you really get this rapid drop-off in the allogeneic CAR T-cell product, as you might expect – the cells are foreign to this particular individual. The key question we wanted to answer is whether we can circumvent that by intensifying the lymphodepletion. We would anticipate if this works seeing a higher peak, meaning we are going to get more expansion of this allogeneic CAR T-cell product but also more persistence. So now instead of seeing a rapid drop-off in the CAR T-cells as the immune system recovers, we would anticipate now seeing the CAR T-cells persist to a greater degree.

With that background, when we started the study the first thing that we observed with this allogeneic CAR T-cell product is, number one, as we increase the dose of the CAR T-cells that were infused with a standard lymphodepletion that, yes, we could see some modest increases in the cell expansion but by the time we got to around day 10 that rapid drop-off that I mentioned has been a problem for all allogeneic CAR T-cell products. What we did next in terms of the lymphodepletion was to add an additional day of fludarabine. So, more specifically, we went from fludarabine at 30mg/m2 for three days to now giving it for four days and we doubled the dose of cyclophosphamide. So we were giving 500mg/m2 for three days, now we’re doing 1,000mg/m2 for three days. So that was the intensified lymphodepletion that was explored here.

We, as expected for an allogeneic CAR T-cell trial, enrolled very, very refractory patients. I think the median was five lines for both the ALL cohort and the aggressive NHL cohort. But we saw in both cohorts that there were patients who had as many as 12-15 prior lines. So just emblematic of what we’re seeing, particularly in B-cell lymphomas, where we’re starting to see some new therapies make their way through clinical trials into the clinical space but with those newer therapies we’re not seeing cures, we’re seeing some activity but then, unfortunately, relapses that follow. So this was the cohort that we enrolled.

The intensified lymphodepletion and the CAR T-cell therapy proved to be safe, by which I mean to say we did not observe any severe CRS. We had one grade 3 case of ICANS but all the other patients across both cohorts no severe neurologic toxicity. We observed no graft versus host, which I think is really important. We did see grade 3 infections, grade 3 and above infections, in both cohorts, a reflection of the patients that we enrolled but also that intensified lymphodepletion that I mentioned.

I think the really, really cool piece to this is what we observed then in terms of the pharmacokinetics. We achieved a peak expansion, measured by CAR T transgene, into the 105 range. So we’re at that range now that is similar to what we achieve with autologous CAR T-cell products. This was a marked increase over what we had achieved with standard lymphodepletion. So, again, using the same cell dose, just enhancing lymphodepletion – dramatic increase in the peak. But what was also really amazing is we also saw that translate into persistence. So now we’re still measuring these allogeneic CAR T-cells at day 28; that’s a really major step forward for allogeneic CAR T-cell therapies. We’re not building in CD52 knockouts and [??] as the allogene group has done. We’re not tweaking the system in any other way except, again, to enhance lymphodepletion as I described. So this is, as I said a minute ago, really, really important for the field.

This translated into improved response rates, as you might expect. The overall response rate in the NHL cohort was 69% of which 56% were CRs. In the ALL cohort it was 80% overall and complete remission rates.

There was something really peculiar that was falling out of the data. What do I mean by that? I mentioned that these patients were heavily pre-treated – up to 12-15 prior lines. It turns out that a subset of the patients had also received prior autologous CAR T-cell therapy. So we saw in total five patients, including one ALL patient and four of the NHL patients, had received a prior autologous CD19 directed CAR T-cell therapy. So we wanted to take a little bit of a deeper look at that cohort. In these five patients we observed an overall response rate of 100% and a CR rate of 80%. So that was a little bit unexpected for us. So we took a deeper dive and we wanted to understand then not just the response rate but how did the durability of these responses with the allogeneic product compare to the durability they had with the original autologous product. In three out of the five patients we actually saw a longer duration of response with the allogeneic CAR T product, again built on this principle of enhanced lymphodepletion.

When we talk about durability I think that some of these patients are still in ongoing follow-up but we have two ongoing remissions beyond six months, two additional with response at around 140 days, one of which went onto a subsequent allogeneic transplant. In the ALL cohort we have one of our patients who actually failed two prior allogeneic transplants still in ongoing remission now, over nine months later. We also have another patient who was successfully bridged to an allogeneic transplant right around 90 days. This was my patient and I can tell you he had failed blinatumomab and inotuzumab and chemotherapy and all the things that we had tried giving him. So this was a pretty amazing result – he had gotten an MRD negative remission after the allogeneic CAR and again sufficient to get him to the transplant.

So we’re seeing some really deep remissions, we’re seeing some of these really prove to be durable and we’re seeing in some of these cases, more specifically in three out of the five cases where they had prior autologous CAR T that the remission that we’re getting with the allogeneic product is longer. All of these are reasons for excitement. It tells us that we’re able to successfully deliver an allogeneic product with enhanced lymphodepletion, get meaningful remissions and take advantage of those remissions for these patients with allogeneic transplant for our ALL patients. I think it also sets the stage for what we want to do next which is really try to get a deeper sense of what is this going to do for other patients who have progressed after autologous CAR T where, right now, I would argue that’s a major, major unmet medical need. So that, in five minutes, is a quick summary of our data.