CELL INTELLIGENCE · 肿瘤细胞治疗研究

PURPOSE: Chimeric antigen receptor (CAR) T-cell therapies have improved outcomes in patients with relapsed/refractory large B-cell lymphoma (LBCL). However, up to two thirds of these patients do not maintain long-term responses. The phase 1/2 ZUMA-6 study investigated the feasibility of combining the CD19-directed CAR T-cell therapy axicabtagene ciloleucel (axi-cel) with the PD-L1 inhibitor atezolizumab as a potential approach to increase treatment efficacy while maintaining acceptable safety. PATIENTS AND METHODS: Patients with refractory diffuse LBCL received a single axi-cel infusion (2 106 cells/kg), followed by atezolizumab 1,200 mg i.v. every 21 days for four cycles. Primary endpoints were dose-limiting toxicities (phase 1) and complete response rate (phase 2). Other efficacy and safety outcomes and pharmacokinetics/pharmacodynamics were assessed. RESULTS: Overall, 34 patients received axi-cel plus atezolizumab in ZUMA-6. The median follow-up for the final analysis was 56.9 months. In phase 1, one patient experienced dose-limiting toxicities (grade 4 neutropenia and thrombocytopenia). Thirty patients (88%) experienced grade 3 treatment-emergent adverse events. Three (9%) and 11 (32%) patients experienced grade 3 cytokine release syndrome and neurologic events, respectively. In the final analysis, 15 patients (54%) had a complete response. The median progression-free survival and overall survival were 9 and 32.2 months, respectively. Peak CAR T-cell and cytokine profiles were comparable with those previously reported for axi-cel monotherapy (ZUMA-1). CONCLUSIONS: Axi-cel plus atezolizumab had a manageable safety profile, with no new safety signals. Safety and efficacy of this combination were consistent with axi-cel monotherapy. Correlative analyses could inform with regard to which patients with LBCL may benefit from axi-cel and immune checkpoint inhibitor combinations.