Circulating monocyte counts coupled with a 4-gene signature at leukapheresis predict survival of lymphoma patients treated with CAR T

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 still relapse. Biological mechanisms explaining lack of disease-response are largely unknown. To identify mechanisms of response and survival before CAR T manufacturing in 95 R/R LBCL receiving tisagenlecleucel or axicabtagene ciloleucel, we performed phenotypic, transcriptomic and functional evaluations of leukapheresis products (LK). Transcriptomic profiling of T cells in LK, revealed a signature composed of 4 myeloid genes able to identify patients with very short progression-free survival, highlighting the role of monocytes in CAR T therapy response. Accordingly, response and survival were negatively influenced by high circulating absolute monocyte counts at the time of leukapheresis, and the combined evaluation of peripheral blood monocytes and the four-gene signature in LK, identifies LBCL patients at very high risk of progression after CAR T. The transcriptomic analysis was performed on a cohort of 77 relapsed/refractory large B-cell lymphoma patients. CD3+ T cells selected from 77 patient leukapheresis and 8 leftover lymphocytes from donor lymphocyte infusions (healthy controls) were profiled using the nCounter 780 gene CAR-T characterization panel.