ASCO 2024 | A novel armored CAR-T that shows promise in R/R lymphomas following anti-CD19 CAR-T failure

We all know that there is a great unmet need for patients who are progressing after the currently available second generation anti-CD19 CARs, and so we designed our trial to use a novel, completely new type of CAR that we refer to as huCART19-IL18. It’s what in the field of CAR-T we refer to as an armored CAR-T or fourth generation CAR. It was developed internally at the University of Pennsylvania by Doctor Carl June, and we selected specifically patients who are progressing after anti-CD19 CARs. So their prognosis in, you know, retrospective studies, if they progress after the commercially available products is poor. I mean, the overall response rates are low, the overall survival is actually short. And so specifically for this population when we used in our first in-human trial, the armored CAR-T, we’ve seen encouraging responses. The overall response rate was 81% with 52% of complete response rates. And these responses were durable.

So we feel that, you know, this is still very early, but combining the fact that the responses were encouraging and that we haven’t seen any new toxicities other than what would be expected from CAR therapies such as CRS and ICANS, but they were all manageable and sort of in line with what we would see with the commercial products. So again, we feel that this is a product that needs to be expanded and further studied in this population of patients who, you know, tend to have poor prognosis.

I mean, the other I think exciting part about this project is that, you know, this is, to our knowledge, the first in-human study to use this type of a product where the CAR has the capacity to secrete a transgenic protein. And so we do a lot of correlative studies in pre and post infusion biopsies. And looking at the effect of the IL18 and how it may enhance the CARs. And so there is a lot of hope that some of these armored CAR-Ts and this technology may actually make some breakthroughs in solid tumors where CARs haven’t been as effective or there have been challenges in terms of the tumor microenvironment. And so perhaps having this pro-inflammatory cytokine, like IL18, in the environment may allow things like recruiting the proper cells to that site, such as macrophages and, you know, the other parts of the immune system that may be very important for the efficacy of these products. And so, so hopefully some of the findings will be applicable to other settings.

It is basically very similar to traditional CARs because it’s an autologous CAR-T product. It has the 4-1BB co-stimulatory domain, and it has a chimeric antigen receptor that targets CD19. But the extra component is that, when we use a lentivirus for making these CARs and the construct has not only basically the coding for the receptor, but also for IL18. And so again, our feeling is that once this CAR gets to the site of the tumor, it has the specificity to sort of go after the CD19 positive B-cells, but also at that time secretes IL18 into that environment.