嵌合抗原受体（CAR）T细胞疗法已经显示出对复发/难治性（R/R）大B细胞淋巴瘤（LBCL）患者具有临床益处，但约60%的患者无反应或最终复发。我们研究了CD19定向的CAR T细胞疗法axicabtagene ciloleucel（axi-cel）与4-1BB激动剂抗体utomilumab联合应用的安全性和可行性，作为提高CAR T细胞疗法疗效的一种方法。在单臂ZUMA-11试验的1期中，R/R LBCL患者按剂量递增设计接受单次axi-cel输注（目标剂量：2×106细胞/kg），并每4周静脉注射utomilumab 10-200 mg，最多连续6个月。主要终点是与utomilumab相关的剂量限制性毒性（DLTs）的发生率。关键次要终点包括安全性、抗肿瘤活性、药物动力学和药物动力学。在接受axi-cel和utomilumab治疗的患者中（n=12），未观察到DLTs。10名患者（83%）出现≥3级不良事件；没有出现≥3级细胞因子释放综合征或神经事件。客观缓解率为75%，7名患者（58%）完全缓解。最高CAR T细胞水平呈utomilumab剂量依赖性增加，最高可达100毫克。接受utomilumab 100毫克的患者与其他剂量水平相比，在57-168天间持续增加CAR T细胞。utomilumab与IL-2、IFNγ和IL-10的剂量相关性增加有关。utomilumab介导的4-1BB激动与axi-cel疗法具有可控的安全性。双重4-1BB和CD28共刺激是一种可行的治疗方法，可能增强LBCL患者的CAR T细胞扩张。

Chimeric antigen receptor (CAR) T-cell therapies have shown clinical benefit for patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL), yet approximately 60% of patients do not respond or eventually relapse. We investigated the safety and feasibility of the CD19-directed CAR T-cell therapy axicabtagene ciloleucel (axi-cel) in combination with the 4-1BB agonist antibody utomilumab as an approach to improve efficacy of CAR T-cell therapy.In Phase 1 of the single-arm ZUMA-11 trial, patients with R/R LBCL received a single axi-cel infusion (target dose: 2×106 cells/kg) plus utomilumab 10-200 mg intravenously every 4 weeks for up to 6 months in a dose-escalation design. The primary endpoint was incidence of dose-limiting toxicities (DLTs) with utomilumab. Key secondary endpoints were safety, antitumor activity, pharmacokinetics, and pharmacodynamics.No DLTs were observed among patients treated with axi-cel and utomilumab (n=12). Grade ≥3 adverse events occurred in 10 patients (83%); none were Grade ≥3 cytokine release syndrome or neurologic events. The objective response rate was 75% and 7 patients (58%) had a complete response. Peak CAR T-cell levels increased in a utomilumab dose-dependent manner up to 100 mg. Patients who received utomilumab 100 mg had persistently increased CAR T cells on Days 57-168 compared with other dose levels. Utomilumab was associated with dose-dependent increases in IL-2, IFNγ, and IL-10.Utomilumab-mediated 4-1BB agonism combined with axi-cel therapy had a manageable safety profile. Dual 4-1BB and CD28 costimulation is a feasible therapeutic approach that may enhance CAR T-cell expansion in patients with LBCL.