Gene-engineered adoptive T cell immunotherapy of GBM

描述（由申请人提供） 摘要：恶性原发性脑肿瘤比肾癌或黑色素瘤造成更多的死亡，现在是儿童和年轻人癌症死亡的最常见原因。胶质母细胞瘤（GBM）是这些肿瘤中最常见和最恶性的肿瘤，目前的治疗包括手术切除，然后是放疗和化疗，这受到全身组织和周围功能脑的毒性的限制。尽管有积极的治疗，这些肿瘤仍然普遍致命，因此，重要的是开发这种致命疾病的替代疗法。由癌症引起的对正常“自身”蛋白质的微妙修饰可以以表面蛋白质的形式检测到，或者内部加工并呈现在细胞表面MHC分子上。由于这些变化改变了正常组织的结构，因此它们提供了特定的靶点。免疫疗法，最近在转移性黑色素瘤和前列腺癌患者的几个III期临床试验中显示出有效性，为根除肿瘤提供了一种特定的靶向方法。肿瘤反应性T细胞的连续性细胞转移（ACT）免疫疗法利用细胞免疫系统靶向离散的肿瘤抗原并破坏携带它们的病变细胞。这些T细胞应答可以通过使用γ-逆转录病毒或慢病毒载体系统在新受体分子中进行基因工程来指导。编码高度亲合力的T细胞受体（TCR）或嵌合抗原受体（CAR）（其将高度亲合力的抗体可变区与T细胞信号传导分子组合）的基因在遇到靶抗原时诱导T细胞活化。遗传TCR重定向的T细胞在针对肿瘤的免疫治疗中非常有效，并且已经显示出消除患有转移性黑素瘤的患者中的大体积肿瘤，并且最近使用靶向CD 19的CAR载体治疗患有播散性淋巴瘤的患者的临床试验是安全的，并且在晚期疾病中产生了显著的临床应答。将CAR T细胞技术与GBM的免疫疗法相结合，提供了一个可能消除患者中这种癌症的平台，而没有在全身治疗中看到的非特异性毒性。GBM具有几种理想的汽车抗原靶标，包括致瘤性EGFRvIII肿瘤特异性突变和CMV抗原，发现其在肿瘤中特异性表达，但不在周围正常组织中表达。虽然我们建议治疗GBM患者，但该平台可以很容易地扩展到杜克脑肿瘤中心内的其他CNS癌症（如髓母细胞瘤）的靶抗原。这笔赠款将允许建立一个专门的基于T细胞的基因治疗设施，在临床前模型中构建和测试不同的CAR构建体，并将其快速转化为癌症患者的临床试验。 公共卫生相关性：GBM是最常见和最恶性的脑肿瘤，目前的治疗方法包括手术，其次是放疗和化疗，这会对患者造成毒性和对周围组织的损伤。利用基因工程，我们计划将GBM患者自身的T细胞重定向到靶向并摧毁他们的癌症，作为一种主动免疫疗法。

DESCRIPTION (Provided by the applicant) Abstract: Malignant primary brain tumors account for more deaths than cancer of the kidney or melanoma and now represent the most common cause of cancer death in children and young adults. Current therapy for glioblastoma (GBM), the most common and most malignant of these tumors consists of surgical resection followed by radiation and chemotherapy, which is limited by toxicity to systemic tissues and surrounding eloquent brain. Despite aggressive therapy, these tumors remain universally fatal; therefore, it is important to develop alternate therapies fo this deadly disease. Subtle modifications to normal 'self' proteins caused by cancer are detectable in the form of surface protein, or internally processed and presented on cell surface MHC molecules. Since these changes alter the structure of otherwise normal tissues, they provide a specific target. Immunotherapy, recently shown to be effective in several Phase III clinical trials for patients with metastatic melanoma and prostate cancer, offers a specific targeted approach for the eradication of tumors. Adoptive cell transfer (ACT) immunotherapy of tumor-reactive T cells utilizes the cellular immune system to target discrete tumor antigens and destroy the diseased cells bearing them. These T cell responses can be directed by genetically engineering in new receptor molecules using gamma-retroviral or lentiviral vector systems. Genes encoding highly avid T cell receptors (TCR) or chimeric antigen receptors (CAR), which combine highly avid antibody variable regions with T cell signaling molecules, induce T cell activation upon encounter of the target antigen. Genetically TCR re-directed T cells have been extremely potent in immunotherapy against tumors and have been shown to eliminate bulky tumor in patients with metastatic melanoma, and recent clinical trials using CAR vectors targeting CD19 to treat patients with disseminated lymphoma have been safe and produced dramatic clinical responses in advanced disease. Combining CAR T cell technology to immunotherapy of GBM provides a platform to potentially eliminate this cancer in patients, without the non-specific toxicity seen in generalized therapy. GBM has several ideal antigenic targets for CARs, including the tumorigenic EGFRvIII tumor-specific mutation, and CMV antigens, found to be expressed specifically in tumor, but not surrounding normal tissues. While we propose to treat patients with GBM, this platform can readily be expanded to target antigens from other CNS cancers, such as medulloblastoma, within the Brain Tumor Center at Duke. This grant would allow for the establishment of a dedicated T cell based gene therapy facility to construct and test different CAR constructs in preclinical models and rapidly translate them into clinical trials for patients with cancer. Public Health Relevance: Current therapy for GBM, the most common and most malignant brain tumors consists of surgery, followed by radiation and chemotherapy, which causes toxicity to the patient and damage to surrounding tissues. Using genetic engineering we plan to redirect GBM patients' own T cells to target and destroy their cancer as an active immune therapy.