Neoantigen-specific Adoptive T Cell Therapy for Glioblastoma, IND-BB-13135, protocol submitted 04/25/2020

TVAX Biomedical开发了一种新的免疫疗法，新抗原特异性过继免疫疗法。 T细胞疗法（NACT），有可能显着改善新的结果， 确诊的胶质母细胞瘤患者有一个显著未满足的医疗需求， 胶质母细胞瘤的治疗手术联合替莫唑胺放化疗提供了适度的 生存益处，而不是治愈。此外，O 6-甲基鸟嘌呤甲基转移酶阴性（MGMT 未甲基化）亚组，其由大约60%的胶质母细胞瘤患者组成，相对较低。 对放化疗中的替莫唑胺耐药。NACT结合1）新抗原特异性癌症 细胞/免疫佐剂疫苗接种，2）过继转移离体活化的癌症新抗原特异性 效应T细胞和3）白细胞介素2，以产生一种治疗方法， 可切除的胶质母细胞瘤作为自体免疫疗法，NACT仅产生短暂（24-72小时）等级 1和2毒性。患者自身的癌细胞与强免疫佐剂结合成疫苗 （粒细胞巨噬细胞集落刺激因子）产生多克隆癌症新抗原特异性免疫 这种应答显著增加了肿瘤细胞中癌症新抗原特异性效应T细胞前体的数量。 病人的身体。这些癌症新抗原特异性T细胞可以从血液中收获并离体刺激 T细胞活化剂。其结果是产生大量的癌症新抗原特异性效应子 T细胞能够在返回患者体内后协调有效的癌细胞杀伤。 NACT是最有效的，当病人有一个健康的免疫系统和最小的疾病。这项随机 50-受试者研究旨在比较NACT和标准治疗的联合治疗与标准治疗 单独作为新诊断的MGMT未甲基化胶质母细胞瘤患者的治疗。免疫疗法将 当用于治疗免疫系统相对健康的患者和已经被 通过标准化放疗减少。标准治疗的减少或逆转也可能带来益处 免疫抑制。预期成功，因为临床前胶质瘤研究和先前的1/2a期临床试验 对手术、放疗和化疗失败的复发性高级别星形细胞瘤患者的研究 提供证据表明NACT是安全有效的，可以治愈。该2b期临床试验将 与内科肿瘤科的神经肿瘤学和神经外科团队合作进行 - 新泽西罗格斯癌症研究所医学系神经肿瘤学。在临床上的成功 试验将导致进行更大规模的2/3期临床试验，旨在生成可能导致 FDA批准上市，随后将NACT作为MGMT的治疗方法商业化 非甲基化胶质母细胞瘤这将是第一次对这种疗法进行安全性测试， 新诊断的MGMT未甲基化胶质母细胞瘤患者的疗效和免疫学效应。

TVAX Biomedical has developed a novel form of immunotherapy, neoantigen-specific adoptive T cell therapy (NACT), that has the potential to significantly improve outcomes for newly diagnosed glioblastoma patients. There is a significant unmet medical need for safer, more effective treatments for glioblastoma. Surgery combined with temozolomide chemoradiotherapy provides modest survival benefit and is not curative. Moreover, the O6-methylguanine methyltransferase negative (MGMT unmethylated) subgroup, which is comprised by approximately 60% of glioblastoma patients, is relatively resistant to the temozolomide component of chemoradiotherapy. NACT combines 1) neoantigen-specific cancer cell/immunological adjuvant vaccination, 2) adoptive transfer of ex vivo-activated cancer neoantigen-specific effector T cells and 3) interleukin 2 to produce a treatment that has the potential to be effective against surgically resectable glioblastomas. As an autologous immunotherapy, NACT generates only transient (24-72 hours) grade 1 and 2 toxicity. The patients’ own cancer cells are combined into a vaccine with a strong immunological adjuvant (granulocyte macrophage colony-stimulating factor) to produce a polyclonal cancer neoantigen-specific immune response that significantly increases the number of cancer neoantigen-specific effector T cell precursors in the patient’s body. These cancer neoantigen-specific T cells can be harvested from the blood and stimulated ex vivo with T cell activating agents. The result is the generation of high numbers of cancer neoantigen-specific effector T cells that have the ability to orchestrate effective cancer cell killing following their return to the patient’s body. NACT is most effective when the patient has a healthy immune system and minimal disease. This randomized 50-subject study is designed to compare the combination of NACT and standard therapy to standard therapy alone as a treatment for newly diagnosed MGMT unmethylated glioblastoma patients. Immunotherapy would be maximal when used to treat patients with relatively healthy immune systems and disease that has been reduced by standard chemoradiotherapy. Benefit may also accrue from standard therapy’s reduction or reversal of immunosuppression. Success is anticipated because preclinical glioma studies and previous phase 1/2a clinical studies with recurrent high-grade astrocytoma patients who had failed surgery, radiotherapy and chemotherapy provided evidence that NACT is safe and effective and could be curative. This phase 2b clinical trial will be performed in collaboration with the neuro-oncology and neurosurgical team in the Division of Medical Oncology - Neuro-Oncology, Department of Medicine at the Rutgers Cancer Institute of New Jersey. Success in this clinical trial will lead to performance of a larger phase 2/3 clinical trial designed to generate data that could lead to marketing approval by the FDA and subsequent commercialization of NACT as a treatment for MGMT unmethylated glioblastoma. This will be the first time that this treatment will have been tested for safety, efficacy, and immunological effects in patients with newly diagnosed MGMT unmethylated glioblastoma.