Defining Antigen-Dependent and Antigen-Independent Mechanisms for EGFRviii-Expressing Tumor Escape From Therapy

项目摘要/摘要 胶质瘤是一种癌症，发生在大脑和中枢神经系统的神经胶质细胞中。神经胶质瘤有很大的 由于缺乏或无效的治疗方法，儿童和成人的预后很差。常用的可用 胶质瘤和其他脑癌的治疗方法包括手术、放射治疗和化疗。然而， 这些疗法只会延长生存期，很少能完全消除肿瘤。胶质瘤的一种潜在治疗方法 已经在临床试验中测试的是针对表皮生长因子变体3(EGFRvIII)的CAR T细胞治疗。 类似的CAR T细胞疗法已被证明有效，并被批准用于血癌，包括弥漫性大B细胞- 细胞性淋巴瘤(DLBCL)、急性淋巴细胞白血病(ALL)和多发性骨髓瘤。然而，CAR T细胞 已被证明对胶质瘤和其他实体瘤以及某些肿瘤细胞从CAR T细胞逃逸的效果较差 治疗，并对CAR T细胞产生抵抗力。可能导致逃逸的潜在肿瘤细胞内在因素 包括缺乏同质抗原表达、EGFRvIII靶抗原本身突变以及突变 在其他导致抵抗杀戮的基因中。在这项资助中，我提议研究基因组学和转录学。 肿瘤逃脱CAR T细胞治疗的机制，并假设肿瘤逃脱 CAR T疗法通过激活APOBEC胞苷获得不同的靶向突变负荷 脱氨酶。我建议产生肿瘤，这些肿瘤逃脱并对次优T细胞产生抵抗力 体内和体外的细胞治疗，并表征突变负载和转录变化 在逃避汽车治疗时发生。根据发生的基因组和转录组变化，我将 建议并测试针对突变途径的化疗组合，如APOBEC，或 针对小鼠新表位的免疫治疗联合疗法。如果成功，这一举措的总体影响 研究将识别CAR T细胞导致的基因突变和表达变化 逃逸变种的治疗，以及针对CAR逃逸变种的潜在联合疗法。

PROJECT SUMMARY/ABSTRACT Glioma is a form of cancer that occurs in glial cells in the brain and central nervous system. Glioma has very poor prognoses in children and adults due to lack of, or ineffective, available therapies. Commonly used available therapies for gliomas and other brain cancers include surgery, radiation therapy, and chemotherapy. However, these therapies only prolong survival and rarely completely eliminate the tumor. One potential therapy for glioma that has been tested in clinical trials is CAR T cell therapy targeting epidermal growth factor variant 3 (EGFRviii). Similar CAR T cell therapies have proven effective and are approved in blood cancers, including diffuse large B- cell lymphoma (DLBCL), acute lymphoblastic leukemia (ALL), and multiple myeloma. However, CAR T cells have proven less effective in glioma and other solid tumors and certain tumor cells ‘escape’ from CAR T cell therapy, and develop resistance to CAR T cells. Potential tumor cell intrinsic factors that may lead to escape include lack of homogeneous antigen expression, mutations in the EGFRviii target antigen itself, and mutations in other genes leading to resistance to killing. In this grant, I propose to study genomic and transcriptomic mechanisms for tumors that escape from CAR T cell therapy, and hypothesize that tumors that escape from CAR T therapy acquire distinct targetable mutational loads through the activation of APOBEC cytidine deaminase enzymes. I propose to generate tumors that escape from and develop resistance to sub-optimal T cell therapies both in vivo and in vitro, and characterize the mutational load and transcriptional changes that occur upon escape from CAR therapy. Depending on genomic and transcriptomic changes that occur, I will propose and test either a chemotherapeutic combination targeting mutational pathways such as APOBEC, or an immunotherapeutic combination therapy targeting neoepitopes in mice. If successful, the overall impact of this research will be the identification of mutations and changes in gene expression that are the result of CAR T cell therapy in escaped variants, and a potential combination therapy to target CAR escaped variants.