Metabolic Control of Immune Suppression in Gliomas

 描述(申请人提供)：多形性胶质母细胞瘤(GBM)是最常见和最具侵袭性的原发脑癌。即使在手术切除、放疗和化疗后，GBM患者的中位生存期仍只有14.6个月，其中26%的患者在2年后仍能存活。GBM诱导的强大免疫抑制是寻找有效免疫治疗的主要障碍之一。这种免疫抑制与调节性T细胞(CD4+CD25+FoxP3+，Tregs)在肿瘤微环境中的大量聚集有关，被认为是抑制CD8+细胞毒性T细胞的肿瘤排斥功能的主要障碍之一。因此，重要的是，未来的免疫治疗，同时手臂效应CD8+细胞毒性T细胞，同时抑制免疫抑制机制。基于我们在脑肿瘤免疫学方面的专业知识，我们现在建议阐明GBM免疫抑制的机制，并在I/II期人类临床试验的背景下研究一种新的免疫调节剂的功能。总而言之，我们的研究将全面描述胶质瘤的免疫抑制微环境，并测试一种能够逆转GBM介导的免疫耐受的新药的临床疗效。

 DESCRIPTION (provided by applicant): Glioblastoma multiforme (GBM) is the most common and aggressive form of primary brain cancer. Even after surgical resection, irradiation and chemotherapy, the median survival for patients with GBM remains at only 14.6 months, with 26% of patients alive after 2 years. The potent immunosuppression induced by GBM is one of the primary obstacles to finding effective immunotherapies. This immunosuppression is associated with a significant accumulation of regulatory T cells (CD4+CD25+FoxP3+, Tregs) within the tumor microenvironment and is considered to be one of the primary obstacles inhibiting the tumor rejection functions of CD8+ cytotoxic T cells. It is therefore important that future immunotherapies simultaneously arm effector CD8+ cytotoxic T cells, while at the same time inhibiting immunosuppressive mechanisms. Building on our expertise in brain tumor immunology, we now propose to elucidate the mechanisms involved in GBM immunosuppression and to investigate the function of a novel immunomodulatory agent in the context of a phase I/II human clinical trial. Cumulatively, our studies will comprehensively characterize the immunosuppressive microenvironment of gliomas and test the clinical efficacy of a new drug capable of reversing GBM mediated immune tolerance.