Monocytes in leukapheresis products affect the outcome of CD19-targeted CAR T-cell therapy in lymphoma patients.

CD19-directed chimeric antigen receptor (CAR) T cells can induce durable remissions in relapsed/refractory large B-cell lymphomas (R/R LBCL), but 60% of patients do not respond or relapse. Biological mechanisms explaining lack of response are emerging but they are largely unsuccessful in predicting disease response at the patient level. Additionally to maximize the cost-effectiveness of CAR T-cell therapy, biomarkers able to predict response and survival prior to CAR T manufacturing would be desirable. We performed transcriptomic and functional evaluations of leukapheresis products in 95 R/R LBCL enrolled in a prospective observational study, to identify correlates of response and survival to tisagenlecleucel and axicabtagene ciloleucel. A signature composed of 4 myeloid genes expressed by T cells isolated from leukapheresis products, is able to identify patients with a very short progression-free survival, highlighting the impact of monocytes in CAR T therapy response. Accordingly, response and progression free survival were also negatively influenced by high circulating absolute monocyte counts at the time of leukapheresis. The combined evaluation of peripheral blood monocytes at the time of leukapheresis and the four-gene signature, represents a novel tool to identify R/R LBCL patients at very high risk of progression after CAR T, and could be used to plan trials evaluating CAR T cells versus other novel treatments or allogeneic CAR T cells, but also highlights the need to incorporate monocyte depletion strategies for better CAR T production.