Antigen-switch and BCR-axis–enriched multi-target CAR T re-infusion after prior CAR T failure in R/R B-cell NHL.

e19017 Background: Relapse after CAR T-cell therapy remains a critical unmet need in relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL), frequently associated with antigen escape and limited effective salvage options. We evaluated a non–single-antigen approach emphasizing antigen/construct switching beyond conventional CD19-only retreatment, incorporating targets across the B-cell antigen landscape, including the B-cell receptor (BCR) axis component CD79b, and enabling rapid sequential CAR-T administration in clinically aggressive disease. Methods: Patients with R/R B-NHL who had failed at least one prior CAR-T therapy received subsequent CAR-T infusion(s) targeting CD20, CD22, CD79b, CD19-BAFFR, CD19-NKG2D, or CD19/22 constructs. The primary objectives were safety and efficacy (overall response rate, ORR). Responses were assessed per standard lymphoma response criteria (best overall response). Safety was graded using ASTCT criteria for CRS/ICANS and CTCAE for hematologic toxicity. Results: Thirteen post–CAR-T-exposed patients were analyzed (DLBCL spectrum predominating; including primary CNS lymphoma). The strategy achieved an ORR of 84.6% (11/13) with a complete response (CR) rate of 69.2% (9/13); progressive disease occurred in 23.1% (3/13). Responses were observed across multiple non-CD19 targets, including CD20-, CD22-, and CD79b-directed products, supporting clinical activity of antigen-switch strategies after CAR-T failure. In several patients, CAR-T products were administered in close temporal sequence (approximately within 48 hours in the recorded treatment course), demonstrating feasibility of rapid multi-target deployment. No unexpected safety signals were observed; inflammatory toxicities were manageable, with no high-grade CRS/ICANS reported in this cohort (per available dataset), supporting the tolerability of multi-target and rapid sequential approaches. Conclusions: In this real-world/IIIT cohort of R/R B-NHL patients previously failing CAR-T therapy, multi-target CAR-T re-infusion enriched for non-CD19 and BCR-axis targets produced a high ORR and CR rate with feasible rapid sequential administration and manageable toxicity. These findings support prospective, protocolized evaluation of antigen-switch and BCR-axis–informed multi-target CAR-T strategies to address post–CAR-T relapse. These data align with the current ASCO focus on overcoming post–CAR-T antigen escape by rational antigen switching and multi-target sequencing, including BCR-axis targeting, to improve depth of response in ultra-refractory B-NHL. Clinical trial information: ChiCTR1900025419.