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

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 (T_CM) cells, with lower CD4⁺ T effector memory (T_EM) cells. High and low percentages of CAR22 T_CM and T_EM, 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 T_CM cells, less T_EM cells, and higher CD8⁺ T_CM cells, but similar clinical outcomes to those with early leukapheresis. CAR22 responses were associated with higher transduction efficiency and CD8⁺ T_CM and less CD8⁺ T_EM cells.