Axicabtagene ciloleucel (axi-cel) 是一种自体抗 CD19 嵌合抗原受体 (CAR) T 细胞疗法，已批准用于复发/难治性 (R/R) 大 B 细胞淋巴瘤 (LBCL) 患者。大多数接受 axi-cel 治疗的患者都会经历细胞因子释放综合征 (CRS) 和/或不良神经系统事件 (NE)。为了探索使用 axi-cel 降低 CAR T 细胞相关毒性的潜在方法，在关键的 ZUMA-1 试验中添加了几个安全性扩展队列。ZUMA-1 队列 3 是一个探索性安全队列，研究了 IL-1 的使用6 受体阻断抗体托珠单抗和抗惊厥左乙拉西坦作为 axi-cel 治疗患者 CRS 和 NE 的预防。R/R LBCL 患者入组第 3 组，在第 -5 天至 -3 天接受预处理化疗，然后单次输注第0天的axi-cel（2×106细胞/kg）。axi-cel输注后48小时给予预防性托珠单抗（8 mg/kg）。主要终点是 CRS 和 NE 的发生率和严重程度。关键的次要终点包括不良事件的发生率、客观缓解率 (ORR)、缓解持续时间、无进展生存期、总生存期 (OS) 和生物标志物分析（例如循环 CAR T 细胞、细胞因子、趋化因子）。 40-第 3 组中纳入了两名患者，其中 38 名患者接受了 axi-cel 治疗。在24个月的分析中，92%和87%的患者发生任何级别的CRS和NE，分别有3%和42%的患者发生≥3级CRS和NE。发生 1 例 5 级 NE（脑水肿）。最短随访时间为 24 个月，ORR 为 63%，39.5% 的患者有持续缓解。经过 48 个月的随访，中位 OS 为 34.8 个月（95% CI，5.4 - 不可估计）。 ZUMA-1 队列 3 中的 CAR T 细胞扩增与关键队列 1 和 2 相当。与托珠单抗介导的 IL-6R 抑制一致，血清 IL-6 水平相对于队列 1 和 2 有所增加。≥3 级 NE 为与脑脊液中 IL-6 水平、促炎细胞因子和骨髓细胞升高相关。基于这些发现，不建议预防性使用托珠单抗来预防 CAR T 细胞相关的不良事件，并且预防性左乙拉西坦对患者的有益效果仍不确定与 R/R LBCL。版权所有 © 2024。由 Elsevier Inc. 出版。

Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved in patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Most patients treated with axi-cel experience cytokine release syndrome (CRS) and/or adverse neurologic events (NEs). To explore potential approaches for reducing CAR T-cell-related toxicities with axi-cel, several safety expansion cohorts were added to the pivotal ZUMA-1 trial.ZUMA-1 Cohort 3 was an exploratory safety cohort that investigated the use of the IL-6 receptor blocking antibody tocilizumab and anticonvulsant levetiracetam as prophylaxis against CRS and NEs in patients treated with axi-cel.Patients with R/R LBCL were enrolled in Cohort 3 and received conditioning chemotherapy on Days -5 through -3 followed by a single infusion of axi-cel (2 × 106 cells/kg) on Day 0. Prophylactic tocilizumab (8 mg/kg) was administered 48 hours after axi-cel infusion. Primary endpoints were incidence and severity of CRS and NEs. Key secondary endpoints included the incidence of adverse events, objective response rate (ORR), duration of response, progression-free survival, overall survival (OS), and biomarker analyses (eg, circulating CAR T cells, cytokines, chemokines).Forty-two patients were enrolled in Cohort 3, 38 of whom received axi-cel. In the 24-month analysis, any-grade CRS and NEs occurred in 92% and 87% of patients, and Grade ≥3 CRS and NEs occurred in 3% and 42% of patients, respectively. One Grade 5 NE (cerebral edema) occurred. With 24-month minimum follow-up, the ORR was 63%, and 39.5% of patients had ongoing response. With 48-month follow-up, median OS was 34.8 months (95% CI, 5.4-not estimable). CAR T-cell expansion in ZUMA-1 Cohort 3 was comparable with pivotal Cohorts 1 and 2. Consistent with tocilizumab-mediated inhibition of IL-6R, serum IL-6 levels were increased relative to Cohorts 1 and 2. Grade ≥3 NEs were associated with elevated IL-6 levels, proinflammatory cytokines, and myeloid cells in the cerebrospinal fluid.Based on these findings, prophylactic tocilizumab is not recommended to prevent CAR T-cell-related adverse events, and beneficial effects of prophylactic levetiracetam remain uncertain in patients with R/R LBCL.Copyright © 2024. Published by Elsevier Inc.