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

Abstract

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, here 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 large B cell lymphoma treated with CD19 CAR T therapy. For these patients, we identify using longitudinal mass-cytometry data 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.

Phenotype of cells in the infusion product as well at specific post-infusion time points has been associated with clinical response to CD19 CAR T cells. Here the authors present a single-cell multi-omics analysis of pre- and post-infusion CAR+ and CAR- T cells from patients with relapsed or refractory B-ALL or LBCL who received CD19 CAR T therapy.