COMy 2025 | Which next-generation CAR constructs hold promise for treating myeloma?

So I think we are at a very early stage in CAR T-cell development. What we have is two CAR products already. We have ide-cel and cilta-cel. And if you think about them, both of these are second-generation CAR T-cells. They bind to a tumor-associated antigen called BCMA. They use 4-1BB as a co-stimulatory domain with CD3-Zeta. So that is basically your second-generation CAR. We already have third, fourth, and armored CARs in the context of myeloma right now. 

In the case of multiple myeloma, I think we’re focusing mostly on fourth-generation cars where we’re doing dual CAR constructs. There’s one in clinical trials already, which is going to be targeting both GPRC5D as well as BCMA. We also have CAR T-cells which are targeting other cytokines. For example, we have our own homegrown academic CAR T-cell which is being developed at the MGH Cancer Center and this is targeting BCMA as well as TACI through a ligand called APRIL and by doing so you are going to overcome the heterogeneity of BCMA expression or BCMA loss. So this is an ongoing trial. What we are doing there is using trimeric or triPRIL, which is a trimeric antigen against APRIL, giving it more of a possibility of that antigen binding in this case. We’ve done the Phase I dose escalation part of the study. We are in the process of dose expanding and hopefully you’ll see clinical data from this. 

There are other CAR constructs also which I’m quite excited about. For example, there’s one from Gracell now which is being developed by AstraZeneca and that is a CAR which targets not just BCMA but also CD19 and there are people who believe that CD19 can in fact be present on precursor cells in the case of multiple myeloma. The data so far, which has been presented at ASH and ASCO as well as EHA in relapsed/refractory as well as newly diagnosed patients shows very high responses and durability of responses. 

I’ll mention one last one which is furthest in its development, it’s still a second-generation CAR but I do think the binding of that CAR and this is ddBCMA or anito-cel, the Phase III trials have just about started, iMMagine-3 has just about started and this is a synthetically derived CAR construct and the binding domain is such that it binds very tightly to BCMA and because of the small structure of this binding domain there doesn’t seem to be that much of tonic signaling so less T-cell exhaustion. So lots of different things happening in the CAR T-cell space. I think we’re just about scratching the surface of this whole technology and it’s really exciting to see what we will be coming up in the near future.

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