Overcoming resistance to prior CAR-T therapy: Efficacy and safety of a sequential, multi-antigen targeted CAR T-cell strategy in B-cell NHL.

7021 Background: Relapse following CAR T-cell therapy is a significant unmet need for patients with B-cell non-Hodgkin lymphoma (B-NHL). Strategies to effectively salvage these patients are urgently required. We report the results of a prospective study evaluating a novel approach of sequential CAR T-cell administration, often with alternative antigen targeting, in this heavily pre-treated population. Methods: In this single-center, Phase I/II investigator-initiated trial, we enrolled patients with R/R B-NHL who had progressed after at least one prior CAR T-cell infusion. Patients received a second autologous CAR T-cell product targeting a different (e.g., CD20, CD22, CD79b) or re-challenging the same antigen with a different construct. The primary endpoints were safety and overall response rate (ORR). The cohort included high-risk subtypes such as primary central nervous system lymphoma (PCNSL). Results: As of the data cut-off, 26 patients with R/R B-NHL (DLBCL, n=18; PCNSL, n=6; Burkitt, n=2) were infused. The median number of prior therapies was 5 (range 3-8). All patients had failed a prior CAR-T therapy. With a median follow-up of 10.2 months, the ORR was 88.5% (23/26), with an outstanding CR rate of 73.1% (19/26). Efficacy was profound even in the most challenging histologies; in the cohort of 6 patients with R/R PCNSL, the CR rate was an unprecedented 83.3% (5/6). The safety profile was highly encouraging. Cytokine release syndrome (CRS) occurred in 92.3% (24/26) of patients, with the majority being Grade 1 (61.5%) or Grade 2 (30.8%). No Grade ≥3 CRS was observed. Immune effector cell-associated neurotoxicity syndrome (ICANS) was rare and mild, with only Grade 1 events reported in 19.2% (5/26) of patients; no Grade ≥2 ICANS occurred. Hematologic toxicities were manageable and reversible. Conclusions: Sequential CAR T-cell therapy is a highly effective and safe strategy that can induce high rates of durable complete responses in B-NHL patients who have relapsed after initial CAR-T treatment. The exceptional activity observed in PCNSL suggests this approach can overcome the blood-brain barrier and address a critical unmet need. These results support the integration of sequential CAR T-cell therapy as a new standard of care for this patient population. Clinical trial information: ChiCTR1900025419.