在接受 CD19 靶向嵌合抗原受体 (CAR) 修饰 T (CAR-T) 细胞免疫疗法治疗大 B 细胞淋巴瘤 (LBCL) 的患者中，超过一半的患者未达到持久缓解，部分原因可能是 PD- 1/PD-L1相关的CAR-T细胞功能障碍。我们报告了一项 1 期临床试验的数据，其中患有 LBCL 的成人患者在 CAR 治疗之前或之后开始接受自体 CD19 CAR-T 细胞 (JCAR014) 联合递增剂量的抗 PD-L1 单克隆抗体 durvalumab 治疗。 T细胞输注。在 JCAR014 中添加 durvalumab 是安全的，并且与自身免疫或免疫效应细胞相关毒性的增加无关。在输注 JCAR014 之前开始使用 durvalumab 的患者细胞因子释放综合征发病较晚、持续时间较短，且疗效较差，这与 CAR-T 细胞积累较慢和血液中炎症细胞因子浓度较低有关。在输注 JCAR014 之前开始使用 durvalumab 会导致可溶性 PD-L1 (sPD-L1) 水平早期增加，这与血液中 CAR-T 细胞最大积累的时间一致。在体外，sPD-L1 诱导 CAR-T 细胞效应功能的剂量依赖性抑制，这可能导致在 JCAR014 之前接受 durvalumab 的患者中观察到的疗效较差。尽管缺乏疗效改善和类似的 CAR-T 细胞动力学，但 JCAR014 后持续进行的 durvalumab 治疗与血液中 CAR-T 细胞的重新扩增、CD19 和 CD19- 肿瘤的晚期消退以及反应持续时间延长有关。我们的结果表明，开始 PD-L1 阻断的时间是影响成人 LBCL 患者 CD19 CAR-T 细胞免疫治疗后结果的关键变量。版权所有 © 2023 美国血液学会。

Over half of the patients treated with CD19-targeted chimeric antigen receptor (CAR)-modified T (CAR-T) cell immunotherapy for large B-cell lymphoma (LBCL) do not achieve durable remission, which may be due in part to PD-1/PD-L1-associated CAR-T cell dysfunction. We report data from a phase 1 clinical trial, in which adults with LBCL were treated with autologous CD19 CAR-T cells (JCAR014) combined with escalating doses of the anti-PD-L1 monoclonal antibody, durvalumab, starting either before or after CAR-T cell infusion. The addition of durvalumab to JCAR014 was safe and not associated with increased autoimmune or immune effector cell-associated toxicities. Patients who started durvalumab before JCAR014 infusion had later onset and shorter duration of cytokine release syndrome, and inferior efficacy, which was associated with slower accumulation of CAR-T cells and lower concentrations of inflammatory cytokines in blood. Initiation of durvalumab before JCAR014 infusion resulted in an early increase in soluble PD-L1 (sPD-L1) levels that coincided with the timing of maximal CAR-T cell accumulation in blood. In vitro, sPD-L1 induced dose-dependent suppression of CAR-T cell effector function, which could contribute to inferior efficacy observed in patients who received durvalumab before JCAR014. Despite the lack of efficacy improvement and similar CAR-T cell kinetics, ongoing durvalumab therapy after JCAR014 was associated with re-expansion of CAR-T cells in blood, late regression of CD19+ and CD19- tumors, and enhanced duration of response. Our results indicate that the timing of initiation of PD-L1 blockade is a key variable that affects outcomes after CD19 CAR-T cell immunotherapy for adults with LBCL.Copyright © 2023 American Society of Hematology.