CAR+ and CAR- T cells share a differentiation trajectory into an NK-like subset after CD19 CAR-T cell infusion in patients with B cell malignancies
Chimeric antigen receptor (CAR) T cell therapy is effective in treating B-cell malignancies, but factors influencing the persistence of functional CAR+ T cells, such as product composition, patients' lymphodepletion, and immune reconstitution, are not well understood.To shed light on this issue, we conduct a single-cell multi-omics analysis of transcriptional, clonal, and phenotypic profiles from pre- to 1-month post-infusion of CAR+ and CAR- T cells from patients from a CARTELL study (ACTRN12617001579381) who received a donor-derived 4-1BB CAR product targeting CD19. Following infusion, CAR+ T cells and CAR- T cells shows similar differentiation profiles with clonally expanded populations across heterogeneous phenotypes, demonstrating clonal lineages and phenotypic plasticity. We validate these findings in 31 patients with longitudinal mass-cytometry data, identifying an association between NK-like subsets and clinical outcomes at 6 months with both CAR+ and CAR- T cells. These results suggest that non-CAR-derived signals can provide information about patients' immune recovery and be used as correlate of clinically relevant parameters.