肿瘤细胞治疗研究
英文原题：Multi-antigen-targeting T cells in pediatric central nervous system tumors: a phase 1 trial.
中枢神经系统（CNS）肿瘤是儿童中最致命的癌症，凸显了对新疗法的需求。
中枢神经系统（CNS）肿瘤是儿童中最致命的癌症，凸显了对新疗法的需求。肿瘤相关抗原（TAA）WT1、PRAME 和 survivin 在这些肿瘤中广泛表达，并且已开发出一种制造技术，利用自体、非基因工程 T 细胞靶向这些细胞内 TAA。因此，我们在此开展了 ReMIND，这是一项开放标签、1 期适应性剂量探索研究，旨在确定靶向 WT1、PRAME 和 survivin 的自体、系统性给药三价 T 细胞在 CNS 肿瘤患儿中的安全性/可行性。符合条件的患者包括新诊断的弥漫性内生型脑桥胶质瘤且未进行淋巴细胞清除者（A 组，n = 16 入组，n = 11 输注），以及复发/难治性非脑干 CNS 恶性肿瘤且未进行（B 组，n = 28 入组，n = 18 输注）或进行（C 组，n = 7 入组，n = 4 输注）淋巴细胞清除者。主要终点为安全性、可行性和最大耐受剂量确定；次要终点包括初步疗效和免疫生物学相关性，包括体内 TAA-T 持续存在和全身免疫激活。剂量水平 3（8 × 10 7 个细胞每 m 2 每剂）被确定为最大耐受剂量。治疗耐受性良好，疲劳和头痛是最常见的不良事件，尽管发生了 2 例可能相关的肿瘤肿胀严重不良事件。1 例弥漫性内生型脑桥胶质瘤伴脑积水、肿瘤水肿和呼吸衰竭患者的 5 级事件被归类为剂量限制性毒性。A 组的中位总生存期为自诊断起 13.7 个月（范围，6.2-32.0），B/C 组的中位无进展生存期为自输注起 5.0 个月（范围，0.5-51.6）。B/C组中有3例患者分别在31.8、41.2和51.6个月时无病生存，且未接受进一步治疗，其中包括1例完全缓解。该试验达到了安全性/可行性的主要终点，并显示出一些初步的疗效信号。ClinicalTrials.gov注册号：NCT03652545。
Central nervous system (CNS) tumors are the deadliest cancers in children, highlighting the need for new therapies. The tumor-associated antigens (TAAs) WT1, PRAME and survivin are widely expressed by these tumors, and a manufacturing technique has been developed to target these intracellular TAAs using autologous, nongenetically engineered T cells. Here we therefore conducted ReMIND, an open-label, phase 1 adaptive dose-finding study to determine the safety/feasibility of autologous, systemically administered trivalent T cells targeting WT1, PRAME and survivin in children with CNS tumors. Eligible patients had newly diagnosed diffuse intrinsic pontine glioma without lymphodepletion (arm A, n = 16 enrolled, n = 11 infused) and relapsed/recurrent nonbrainstem CNS malignancies without (arm B, n = 28 enrolled, n = 18 infused) or with (arm C, n = 7 enrolled, n = 4 infused) lymphodepletion. Primary end points were safety, feasibility and maximum tolerated dose determination; secondary end points included preliminary efficacy and immunobiological correlates, including in vivo TAA-T persistence and systemic immune activation. Dose level 3 (8 × 10 7 cells per m 2 per dose) was determined as the maximum tolerated dose. Treatment was well tolerated with fatigue and headache being the most common adverse events, although two possibly related serious adverse events of tumor swelling occurred. One grade 5 event in a patient with diffuse intrinsic pontine glioma with hydrocephalus, tumor edema and respiratory failure was categorized as a dose-limiting toxicity. Median overall survival for arm A was 13.7 months from diagnosis (range, 6.2-32.0) and median progression-free survival for arms B/C was 5.0 months from infusion (range, 0.5-51.6). Three patients in arms B/C are alive without disease at 31.8, 41.2 and 51.6 months without further treatment, including one complete response. This trial met safety/feasibility primary end points with some preliminary signals of efficacy. ClinicalTrials.gov registration: NCT03652545 .
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