Single-cell multi-omics provide insights into molecular drivers of CAR T Cell Persistence and Function in Multiple Myeloma

Here, we applied single-cell multiomics, coupled with gene regulatory network analyses, to evaluate CAR-T cell transcriptional heterogeneity, dynamics and clonal evolution, in longitudinal bone marrow (BM) and peripheral blood (PB) paired samples, collected from MM patients treated with BCMA CAR T cells.

We identify several regulons with increased activity, within CAR T cell infiltrating the BM, as key drivers of the more activated and exhausted phenotype observed in those cells compared to their PB counterparts. Interestingly, regulatory dysfunctions in the effector-to-memory axis promoted higher presence of terminally differentiated cells, leading to a lack of CAR T cell persistence. Moreover, we identified a hyperexpanded CAR T clone in the BM of a patient with partial response.