肿瘤细胞治疗研究
英文原题：Phase I Trial of GD2.CART Cells Augmented With Constitutive Interleukin-7 Receptor for Treatment of High-Grade Pediatric CNS Tumors.
静脉注射GD2.CARTs联合或不联合C7R均耐受良好。接受C7R-GD2.CARTs治疗的患者表现出神经功能缺损的短暂改善以及循环细胞因子/趋化因子的增加。C7R-GD2.CARTs治疗代表了一种新方法，值得对这些无法治愈的CNS癌症患儿进行进一步研究。
修饰嵌合抗原受体（CAR）的T细胞（CARTs）已证实对血液系统恶性肿瘤有效；然而，对CNS肿瘤患者的获益有限。为增强T细胞对GD2+ CNS恶性肿瘤的活性，我们用组成性激活的白细胞介素（IL）-7受体（C7R-GD2.CARTs）修饰了靶向GD2的CART细胞（GD2.CARTs）。
年龄1-21岁、患有H3K27改变的弥漫性中线胶质瘤（DMG）或其他复发性GD2表达中枢神经系统肿瘤的患者符合这项I期试验（ClinicalTrials.gov标识符：NCT04099797）的入组条件。所有受试者在入组研究前均接受了标准治疗的辅助放疗或化疗。第一个治疗队列单独接受GD2.CARTs（1 × 10 7 cells/m 2），后续队列接受C7R-GD2.CARTs，设有两个剂量水平（1 × 10 7 cells/m 2；3 × 10 7 cells/m 2）。所有剂量水平均包含使用环磷酰胺和氟达拉滨的标准淋巴细胞清除。
11例患者（年龄4-18岁）接受了治疗，未出现剂量限制性毒性。GD2.CART队列未出现毒性，但在残余神经功能缺损短暂改善（≤3周）后出现疾病进展。C7R-GD2.CART队列中，8例中有7例（88%）出现1级肿瘤炎症相关神经毒性，可用anakinra控制。8例中有6例（75%，除1例外均为1级）观察到细胞因子释放综合征，并与循环IL-6和IP-10升高相关（P < .05）。接受C7R-GD2.CARTs的患者神经功能缺损较基线出现暂时改善（范围2至>12个月），8例中有7例（88%）仍符合接受额外治疗周期的条件（范围2-4个周期）。在接受C7R-GD2.CARTs治疗的7例DMG患者中，2例（29%）根据iRANO标准观察到部分缓解。
PURPOSE: T cells modified with chimeric antigen receptors (CARTs) have demonstrated efficacy for hematologic malignancies; however, benefit for patients with CNS tumors has been limited. To enhance T cell activity against GD2+ CNS malignancies, we modified GD2-directed CART cells (GD2.CARTs) with a constitutively active interleukin (IL)-7 receptor (C7R-GD2.CARTs). METHODS: Patients age 1-21 years with H3K27-altered diffuse midline glioma (DMG) or other recurrent GD2-expressing CNS tumors were eligible for this phase I trial (ClinicalTrials.gov identifier: NCT04099797). All subjects received standard-of-care adjuvant radiation therapy or chemotherapy before study enrollment. The first treatment cohort received GD2.CARTs alone (1 × 10 7 cells/m 2 ), and subsequent cohorts received C7R-GD2.CARTs at two dose levels (1 × 10 7 cells/m 2 ; 3 × 10 7 cells/m 2 ). Standard lymphodepletion with cyclophosphamide and fludarabine was included at all dose levels. RESULTS: Eleven patients (age 4-18 years) received therapy without dose-limiting toxicity. The GD2.CART cohort did not experience toxicity, but had disease progression after brief improvement of residual neurologic deficits (≤3 weeks). The C7R-GD2.CART cohort developed grade 1 tumor inflammation-associated neurotoxicity in seven of eight (88%) cases, controllable with anakinra. Cytokine release syndrome was observed in six of eight (75%, grade 1 in all but one patient) and associated with increased circulating IL-6 and IP-10 ( P < .05). Patients receiving C7R-GD2.CARTs experienced temporary improvement from baseline neurologic deficits (range, 2 to >12 months), and seven of eight (88%) remained eligible for additional treatment cycles (range 2-4 cycles). Partial responses by iRANO criteria were observed in two of seven (29%) patients with DMG treated by C7R-GD2.CARTs. CONCLUSION: Intravenous GD2.CARTs with and without C7R were well tolerated. Patients treated with C7R-GD2.CARTs exhibited transient improvement of neurologic deficits and increased circulating cytokines/chemokines. Treatment with C7R-GD2.CARTs represents a novel approach warranting further investigation for children with these incurable CNS cancers.
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