肿瘤细胞治疗研究
英文原题：In vivo generation of anti-BCMA CAR-T cells in relapsed or refractory multiple myeloma: a phase 1 study.
5例经多线治疗的男性患者（中位既往治疗线数为3线）被连续入组，并接受中位6.0个月的随访。
体内嵌合抗原受体（CAR）-T细胞生成可绕过体外制造和淋巴细胞清除，可能简化并加速细胞治疗的获取；初步临床经验支持其可行性并提示初步疗效。这项1期、单臂、开放标签试验评估了ESO-T01在复发或难治性多发性骨髓瘤成人患者中的安全性和耐受性；ESO-T01是一种纳米抗体导向的、免疫屏蔽的慢病毒载体，编码人源化抗B细胞成熟抗原（BCMA）CAR。ESO-T01以单次静脉输注0.2 10 9 转导单位给药，未进行白细胞单采、体外制造或淋巴细胞清除性化疗。连续入组5例接受过大量既往治疗的男性患者（中位既往治疗线数为3线），中位随访6.0个月。该试验于2025年提前停止，未再进行更多入组。主要终点为安全性和耐受性，次要终点包括疗效、ESO-T01的药代动力学和药效动力学。未发生剂量限制性毒性。所有患者均发生3级或以上不良事件。4例患者发生细胞因子释放综合征（3例为3级，1例为2级），并通过皮质类固醇、tocilizumab或支持治疗进行处理。最常见的毒性为短暂性血细胞减少和可逆性肝酶升高，3例患者发生2级感染。1例患者发生1级免疫效应细胞相关神经毒性，并死于髓外病变相关脊髓压迫。观察到初步抗骨髓瘤活性：5 例患者中有 4 例达到客观缓解，包括 3 例严格完全缓解，截至第 60 天，所有可评估缓解者（4/4）均达到微小残留病阴性（10 -5）。这些发现为使用免疫屏蔽载载体体内生成 CAR-T 的可行性和安全性提供了初步证据。ClinicalTrials.gov 注册号：NCT06791681。
In vivo chimeric antigen receptor (CAR)-T cell generation can bypass ex vivo manufacturing and lymphodepletion, potentially simplifying and accelerating access to cellular therapy; preliminary clinical experience supports feasibility and suggests preliminary efficacy. This phase 1, single-arm, open-label trial evaluated the safety and tolerability of ESO-T01, a nanobody-directed, immune-shielded lentiviral vector encoding a humanized anti-B cell maturation antigen (BCMA) CAR, in adults with relapsed or refractory multiple myeloma. ESO-T01 was administered as a single intravenous infusion of 0.2 10 9 transduction units without leukapheresis, ex vivo manufacturing or lymphodepleting chemotherapy. Five heavily pretreated male patients (median three prior lines) were consecutively enrolled and followed for a median of 6.0 months. The trial was stopped early in 2025, and no further enrollment was performed. The primary endpoint was safety and tolerability, and secondary endpoints included efficacy, pharmacokinetics and pharmacodynamics of ESO-T01. No dose-limiting toxicities occurred. All patients developed grade 3 or higher adverse events. Cytokine release syndrome occurred in four patients (three grade 3 and one grade 2) and was managed with corticosteroids, tocilizumab, or supportive care. The most frequent toxicities were transient cytopenias and reversible hepatic enzyme elevations, and three patients experienced grade 2 infections. One patient developed grade 1 immune effector cell-associated neurotoxicity and died from extramedullary lesion-related spinal cord compression. Preliminary antimyeloma activity was observed: four of five patients achieved objective responses, including three stringent complete remissions, with minimal residual disease negativity (10 -5 ) in all evaluable responders (4/4) by day 60. These findings provide preliminary evidence on the feasibility and safety of in vivo CAR-T generation using an immune-shielded vector. ClinicalTrials.gov registration: NCT06791681 .
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