Phase 1 Study of Cellular Immunotherapy Using Optimized IL13Ra2 Specific CAR T cells for the Treatment of Malignant Glioma

描述：（申请人提供） 即使使用目前的积极治疗，包括手术，放疗和放射治疗， 化疗，大多数恶性胶质瘤（MG）患者生存不到两年， 证明了对新的替代疗法的需求。连续免疫疗法使用经遗传修饰以表达MG特异性嵌合抗原受体（CAR）的T细胞，所述嵌合抗原受体识别由神经胶质瘤细胞表达的细胞表面蛋白。这些T细胞可以通过大脑迁移，并能够识别，靶向和杀死恶性细胞。 根据本申请人，临床前和临床研究都已经证明，特异性识别MG相关抗原IL 13 Ra 2的CAR+ T细胞可以从MG患者产生，并成功地用于靶向表达该受体的胶质瘤细胞。然而，在1期临床试验中，MG肿瘤确实复发，并且遗传修饰的T细胞在肿瘤微环境中不存在。因此，已经开发了一种新的制造平台以产生更好的优化的IL 13 Ra 2特异性CAR+ T细胞，其具有改善的持久性，并在小鼠模型中介导上级抗肿瘤功效。 本建议的目的是评估这些药物的可行性和安全性。 将优化的IL 13 Ra 2特异性CAR+ T细胞瘤内植入患有复发性MG的人类患者中。将从每个患者分离混合的⑶ 4+和⑶ 8 + T细胞，并对其进行遗传修饰以表达IL 13 Ra 2特异性CAR。然后将这些细胞直接回输至每例患者的肿瘤或肿瘤切除腔中（视情况而定）。 该研究的具体目的是：目的1：评估可行性和安全性，并确定复发性MG患者肿瘤内/腔内施用优化的IL 13 Ra 2特异性CAR+ T细胞的推荐2期剂量计划;目的2：评估转移后优化的IL 13 Ra 2特异性CAR+ T细胞的体内效应功能的替代指标。

DESCRIPTION: (provided by the applicant) Even with current aggressive therapies, that include surgery, radiotherapy and chemotherapy, most patients with malignant glioma (MG) survive less than two years, demonstrating the need for novel, alternative therapies. Adoptive immunotherapy uses T-cells that have been genetically modified to express an MG-specific, chimeric antigen receptor (CAR) that recognizes a cell-surface protein expressed by the glioma cells. These T-cells can migrate through the brain, and are able to recognize, target and kill the malignant cells. According to th applicant, both preclinical and clinical studies have demonstrated that CAR+ T-cells that specifically recognize the MG-associated antigen, IL13Ra2, can be generated from MG patients, and successfully used to target their glioma cells which express this receptor. However, in Phase 1 clinical trials, MG tumors did recur and the genetically modified T-cells did not persist in the tumor microenvironment. Therefore, a new manufacturing platform has been developed to generate better optimized IL13Ra2-specific CAR+ T-cells that have improved persistence, and mediate superior antitumor efficacy in mouse models. The objective of this proposal is to assess the feasibility and safety of administering these optimized IL13Ra2-specific CAR+ T-cells intratumorally into human patients who have recurrent MG. Mixed CD4+ and CD8+ T-cells will be isolated from each patient and genetically modified to express the IL13Ra2-specific CAR. These cells will then be administered directly back into the tumor or tumor resection cavity of each patient, whichever is applicable. The specific aims of the study are: Aim 1: To assess the feasibility and safety, and to determine the recommended Phase 2 dose plan for the intratumoral/intracavitary administration of optimized IL13Ra2-specific CAR+ T-cells in patients with recurrent MG; and Aim 2: To evaluate surrogate indicators of in vivo effector function of the optimized IL13R�specific CAR+ T cells after transfer.