Single cell multi-omic dissection of response and resistance to chimeric antigen receptor T cells against BCMA in relapsed multiple myeloma

Abstract

Markers predicting response and resistance to chimeric antigen receptor (CAR) T cells in relapsed/refractory multiple myeloma are currently missing. We subjected cells isolated from peripheral blood and bone marrow before and after the application of CAR T cells directed against B cell maturation antigen to single cell multi-omic analyses to identify markers associated with resistance and early relapse. Differences between responders and non-responders were already identified at time of leukapheresis. Non-responders showed an immunosuppressive microenvironment characterized by increased numbers of monocytes expressing the immune checkpoint molecule CD39 and suppressing CD8+ and NK cell function. The analyses of CAR T cells showed cytotoxic and exhausted phenotypes in hyperexpanded compared to low/intermediate expanded clones. We identified potential immunotherapeutic targets on CAR T cells, like PD1 and KLRB1, to improve their functionality and durability. Our work provides first evidence that an immunosuppressive microenvironment is associated with resistance to CAR T cell therapies.