COMy 2025 | The potential of using PD-1 inhibition to resensitize CAR-T refractory myeloma

We’ve done a lot of work looking at exhaustion and what are the mechanisms of sort of resistance or why does myeloma come back after you use CAR T-cells. One of the mechanisms obviously is T cell exhaustion. We’ve seen that markers of T-cell exhaustion such as PD-1, PD-L1, other markers such as TIGIT, LAG-3, et cetera, are overexpressed on patients in the T-cell population. What we did was gave repeated CARs and then gave these patients nivolumab, a small subset of patients. But what we were able to do was re-harness the response of this, not so much because of the CAR T-cell itself, but what we found was in the surrounding microenvironmental cells, the non-CAR T-cell population, there was an increased expression of these exhaustion markers and by giving them a checkpoint inhibitor, such as nivolumab, in this case, we were able to reinstate response, albeit for a short period of time. 

So, I think the future still is where we need to study these again in the context of myeloma, whether or not, you know, we talked a little bit earlier about novel T-cell constructs. Well, there are novel T-cell constructs where you can target some of these exhaust checkpoint markers, whether it’s PD-1, whether it’s TIGIT, whether it’s LAG-3, and if you can include them in the CAR construct, you can actually overcome this resistance mechanism. So, a lot more work to do, but at least as a proof of principle, you can use drugs like nivolumab to help with some of the resistance mechanisms with CAR T-cells.

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