IMS 2025 | Endogenous immune profiles linked to PFS in patients with RRMM treated with CAR T-cells

I would start by saying that even though antigen escape is by far the most predominant and probably the most relevant mechanism of resistance to these immunotherapies, it is also true that these are not universal and there are many patients that relapse without antigen escape. The same applies for depth of response. Once again, depth of response is important, but there are patients that achieve MRD negativity and relapse, and also some patients that do not attain the best possible response and nonetheless enjoy a long progression-free survival. So the idea is that eventually the patient’s immune status before, throughout, and after CAR-T infusion may also provide information and determinants of response and resistance. Because of that, we looked at endogenous T-cell phenotypes prior to apheresis and we found that there were some specific phenotypes associated with ongoing responses that may help identify patients that will achieve better outcomes with ide-cel therapy. We also found that the percentage of CAR T-cells at month one after infusion, as well as the CD4-CD8 ratio and specific CAR-T phenotypes, were also associated with PFS. And again, we don’t want to oversell this as an outstanding biomarker, but rather what we are claiming is that those bone marrow aspirates that are being taken, let’s say at month one after infusion or month three for MRD assessment, can be used simultaneously to detect CAR-T’s, quantify and characterize from the phenotypic point of view. And then we know that CAR-T’s will disappear over time, eventually after 6-12 months in many, most patients. And after that, we also hypothesize that time until progression could be associated with the extent of immune surveillance or immune escape coming from endogenous T-cells that could be activated with all the tumor lysis coming from CAR-T expansion early on. And again, we identified some hallmarks of immune suppression associated with T-reg expansion, also the expression of inhibitory checkpoints that were associated with inferior PFS long after CAR-T clearance.

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