CELL INTELLIGENCE · 肿瘤细胞治疗研究

Multiantigen targeting chimeric antigen receptor (CAR) T cells have emerged as a strategy to mitigate antigen escape observed after single antigen targeting therapy. Our initial experience with a bivalent CD19.22.BB CAR T-cell construct in children, adolescents and young adults (CAYA) with B-cell acute lymphoblastic leukemia (B-ALL) demonstrated limitations in CD22 recognition, but a tolerable safety profile and efficacy prompted further evaluation. This trial enrolled patients between the ages of 3-39 with relapsed/refractory B-ALL. Following dose-escalation, patients who enrolled at the recommended phase 2 dose (RP2D) of 3 10 6 transduced CAR T cells/kg constitute this report. 30 CAYA were treated at the RP2D; 28 with B-ALL and 2 with Burkitt lymphoma. Across patients with B-ALL, 20 (71.4%) patients developed cytokine release syndrome (CRS); only 2 (10%) were grade > 3. Grade 3 immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 3 (10.7%) patients; there were no cases of immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome. Following a protocol amendment to evaluate the efficacy of siltuximab as a first-line treatment of CRS, one patient received siltuximab with full resolution of CRS after two doses without needing additional anti-cytokine-directed therapies. A measurable residual disease-negative complete remission (CR) was attained in 25 (89.3%) patients, including 6 who had neither CRS nor ICANS. 23 patients (82.1%) proceeded directly to hematopoietic stem cell transplant (HSCT) following CAR T-cell infusion within a median of 51 days (range, 45-68 days), supporting the utility of this construct as a bridge to HSCT. All three non-responders had persistent non-central nervous system (CNS) extramedullary disease (EMD), although four of seven patients with non-CNS EMD achieved a CR. Median relapse-free survival among the 25 patients achieving CR was not reached, and the median overall survival for all 28 patients was 34 months (95% CI 17 to not estimable) from infusion. This extended experience demonstrates that CD19.22.BB CAR T-cell therapy is safe and clinically active, particularly as a bridge to HSCT. Non-response was confined to patients with non-CNS EMD, highlighting the persistent challenge of effectively targeting EMD and informing the design of future CAR constructs. Trial registration number NCT03448393.