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
Raymond H. Y. Louie, Curtis Cai, Jerome Samir, Mandeep Singh, Ira W. Deveson, James M. Ferguson, Timothy G. Amos, Helen M. McGuire, Kavitha Gowrishankar, Thiruni Adikari, Robert Balderas, Martina Bonomi, Marco Ruella, David Bishop, David Gottlieb, Emily Blyth, Kenneth Micklethwaite, Fabio Luciani
Abstract
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.