肿瘤细胞治疗研究
英文原题：Treatment of non-Hodgkin lymphoma with point-of-care manufactured CAR T cells: a dual institution, phase 1 trial.
床旁 CAR-T 细胞生产在各中心均可行且可复制。
背景：嵌合抗原受体（CAR）T 细胞的即时制备可显著缩短单采至输注的时间。本研究开展一项双机构 I 期试验，评估这一制备模式的安全性和可行性。方法：CASE 2417 为一项 I 期临床试验。既往接受过 2 线全身治疗的复发或难治性 CD19 阳性非霍奇金淋巴瘤（R/R NHL）成人患者符合入组条件。MB-CART-19 是一种抗 CD19 CAR-T 产品，使用 CliniMACS Prodigy 设备制备，包含 4-1BB 和 CD3 共刺激结构域。淋巴清除方案为氟达拉滨 25 mg/m²、连续 3 天，以及环磷酰胺 60 mg/kg、1 天；允许预防性使用托珠单抗。按照 3 + 3 剂量递增设计，测试 3 个剂量水平：0.5、1.0 和 2.0 × 10⁶ 个细胞/kg。主要终点是确定 MB-CART-19 治疗 R/R NHL 的安全性，安全性按剂量限制性毒性定义；共同主要终点是确定 MB-CART-19 的 II 期剂量。次要终点包括界定毒性特征并评估 MB-CART-19 治疗 R/R NHL 的初步疗效。试验注册号：ClinicalTrials.gov NCT03434769。结果：2018 年 7 月至 2021 年 1 月共入组 31 例患者。24 例（原文报告 77%）为侵袭性淋巴瘤，7 例（24%）为惰性淋巴瘤（滤泡性淋巴瘤和边缘区淋巴瘤）。既往治疗次数中位数为 5 次（范围 2–13，四分位距［IQR］3–5）。所有入组患者均接受 MB-CART-19。单采至输注时间中位数为 13 天（范围 9–20，IQR 9–13）。剂量递增阶段观察到 1 例剂量限制性毒性（致死性 CRS）；剂量扩展阶段另有 1 例患者死于噬血细胞综合征。两例死亡均被认为与治疗有关。20 例（65%）发生 CRS，其中 3 例为 3 级；10 例（32%）发生免疫效应细胞相关神经毒性综合征（ICANS），其中 4 例为 3 级。最常见的 3 级不良事件为中性粒细胞减少（n = 28，90%）、血小板减少（n = 15，48%）和贫血（n = 13，42%）。29 例可评估应答的患者中，25 例（86%，95% 置信区间［CI］68%–96%）出现疾病应答，22 例（76%，95% CI 56%–90%）达到完全缓解；可评估的侵袭性淋巴瘤患者（n = 22）总体缓解率为 82%（n = 18，95% CI 60%–95%），完全缓解率为 73%（n = 16，95% CI 50%–89%）。中位随访 24.5 个月（IQR 17–32），PFS 中位数为 26 个月（95% CI 19 个月至未达到［NR］），OS 中位数未达到（95% CI 25 个月至 NR）。2 年 PFS 和总生存期（OS）估计值分别为 63%（95% CI 47%–83%）和 68%（95% CI 52%–88%）。侵袭性淋巴瘤患者的 PFS 中位数为 26 个月（95% CI 7 个月至 NR），2 年 PFS 估计值为 53%（95% CI 36%–78%）；OS 中位数未达到（95% CI 19 个月至 NR），2 年 OS 估计值为 60%（95% CI 43%–85%）。研究者解读：CAR-T 即时制备在不同研究地点均可行且可复制。MB-CART-19 的安全性特征与其他 CAR-T 产品相当，缓解率较高。推荐 II 期剂量为 2 × 10⁶ 个 MB-CART-19 细胞/kg。较短的 CAR-T 制备时间可使快速进展淋巴瘤患者及时接受治疗；这类疾病风险较高的患者通常难以获得自体免疫效应细胞疗法。经费来源：本临床试验由 University Hospitals Seidman 癌症中心和华盛顿大学医学院机构经费资助。相关性分析部分由欧盟 Next Generation EU-NRRP M6C2-投资 2.1（增强和强化 NHS 生物医学研究，项目编号 PNRR-MAD-2022-12376059）及意大利卫生部 2019 年最终研究项目资助；原文在此处截断。
BACKGROUND: Point-of-care manufacture of chimeric antigen receptor (CAR)-T cells can significantly reduce the time from apheresis to infusion. We conducted a dual-institution phase I trial aimed evaluating the safety and feasibility of this manufacturing model. METHODS: CASE 2417 was a phase I clinical trial. Adults with relapsed or refractory CD19 positive non-Hodgkin lymphoma (R/R NHL) treated with 2 prior systemic therapies were eligible. MB-CART-19 is an anti-CD19 CAR T-cell product manufactured using the CliniMACS Prodigy device with 4-1BB and CD3 costimulatory domains. Lymphodepletion included fludarabine 25 mg/m 2 for 3 days and cyclophosphamide 60 mg/kg for 1 day. Prophylactic tocilizumab was allowed. Three dose levels (0.5, 1.0 and 2.0 10 6 cells/kg) were tested using a 3 + 3 dose-escalation schema. The primary outcome of this study was to determine the safety as defined by the dose limiting toxicities of MB-CART-19 in patients with relapsed and refractory NHL, co-primary outcome was determining the phase 2 dose of MB-CART-19. Secondary outcomes include defining the toxicity profile and to evaluate the initial efficacy of MB-CART-19 against relapsed or refractory NHL. This study was registered in ClinicalTrials.govNCT03434769. FINDINGS: Thirty-one patients were enrolled between July 2018 and January 2021. Twenty-four (77%) had aggressive lymphoma, 7 (24%) had indolent lymphoma (follicular lymphoma and marginal zone lymphoma). The median number of previous therapies was 5 (range 2-13, interquartile range [IQR] 3-5). All enrolled patients received MB-CART-19. Median apheresis to infusion time was 13 days (range 9-20, IQR 9-13). One dose limiting toxicity (DLT) was observed in dose escalation (fatal cytokine release syndrome [CRS]), whereas one patient died in dose expansion secondary to hemophagocytic syndrome. Both deaths were considered treatment-related. Twenty (65%) patients had CRS, three (10%) grade 3. Ten patients (32%) experienced immune effector cell neurotoxicity syndrome (ICANS), four (13%) grade 3. Neutropenia (n = 28, 90%), thrombocytopenia (n = 15, 48%) and anaemia (n = 13, 42%) were the most frequent grade 3 adverse events. Twenty-five out of 29 (86%, 95% confidence interval [CI]: 68-96%) response-evaluable patients had disease response and 22 (76%, 95% CI: 56-90%) had complete response; the overall and complete response rates for response-evaluable aggressive lymphoma patients (n = 22) were 82% (n = 18, 95% CI: 60-95%) and 73% (n = 16, 95% CI: 50-89%). Median follow up was 24.5 (IQR 17-32) months, median progression free survival (PFS) was 26 months (95% CI: 19-not reached [NR]) and median PFS was not reached (95% CI: 25 months-NR). Two-year estimates of PFS and overall survival (OS) were 63% (95% CI: 47-83%) and 68% (95% CI: 52-88%), respectively. Median PFS was 26 months (95% CI: 7-NR) for aggressive lymphoma patients with 2-year PFS estimate of 53% (95% CI: 36-78%), while median OS had not been reached for aggressive lymphoma patients (95% CI: 19 months-NR), and 2-year OS estimate was 60% (95% CI: 43-85%). INTERPRETATION: Point-of-care CAR T-cell manufacture was feasible and replicable across sites. MB-CART-19 has a safety profile comparable to other CAR T-cell products and high response rates. The recommended phase 2 dose is 2 10 6 MB-CART-19 cells/kg. Short CAR T-cell manufacturing time permits treatment of patients with rapidly progressive lymphoma, a group of patients with high risk disease for whom access to autologous immune effector cellular therapies is usually limited. FUNDING: This clinical trial was funded through University Hospitals Seidman Cancer Center and Washington University School of Medicine Institutional Funds. Correlative analyses were funded in part by the European Union-Next Generation EU-NRRP M6C2-Investment 2.1 Enhancement and strengthening of biomedical research in the NHS (project #PNRR-MAD-2022-12376059), and the Italian Ministry of Health Ricerca Finalizzata 2019 (project
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