Effects of an Initial Anti-CD19 CAR T-cell Therapy on Subsequent Anti-CD22 CAR T-cell Manufacturing and Clinical Outcomes in Patients with Relapsed/Refractory LBCL

Abstract Patients with large B-cell lymphoma that progresses after anti–CD19 chimeric antigen receptor (CAR) T-cell (CAR19) therapy have poor outcomes. Subsequent CAR T-cell therapy shows promise, but the impact of residual CAR19 and early relapse remains unclear. We evaluated 37 patients with CAR19-refractory large B-cell lymphoma who received anti–CD22 CAR T-cell (CAR22) in a phase Ib trial (NCT04088890). Residual CAR19 was unquantifiable in 17 of 33 evaluable patients post-CAR22 infusion. Single-cell RNA sequencing revealed minimal CAR19/CAR22 co-transduction. Peak CAR19 transgene levels did not affect CAR22 efficacy or toxicities. CAR22 products from patients undergoing leukapheresis ≥6 months after CAR19 had higher CD4+ naïve T and CD4+/CD8+ T central memory (TCM) cells, with lower CD4+ T effector memory (TEM) cells. High and low percentages of CAR22 TCM and TEM, respectively, were correlated with CAR22 transduction efficiency and complete response. Residual CAR19 and leukapheresis timing did not significantly affect outcomes, whereas CAR22 product composition was significantly correlated with treatment response. Significance: Late leukapheresis (>6 months after CAR19) resulted in less residual CAR19, higher CAR22 CD4+ naïve T and TCM cells, less TEM cells, and higher CD8+ TCM cells, but similar clinical outcomes to those with early leukapheresis. CAR22 responses were associated with higher transduction efficiency and CD8+ TCM and less CD8+ TEM cells.