OVERCOMING LOCAL AND PERIPHERAL IMMUNE SUPPRESSION IN GLIOMA TO FACILITATE EFFEC

该项目的长期翻译目标是克服 免疫抵抗降低了脑胶质瘤患者的免疫治疗效果，尤其是 胶质母细胞瘤(GBM)。在前一个周期中，我们完成了I期临床试验和II期临床试验 实验性疫苗免疫治疗术后复发GBM患者的临床试验 切除手术。这些试验表明，自体胶质瘤来源的热休克蛋白多肽 Complex-96(HSPPC-96)疫苗是安全的，可激发CD4+和CD8+肿瘤特异性T细胞反应 与既往对照相比，可提高复发的GBM患者的存活率。在 在之前的孢子周期中，我们也发现了与胶质瘤免疫耐药有关的蛋白质， 包括表达在胶质瘤细胞表面的B7-同源1(B7-H1)，诱导CD8+T- 我们的观察解释了PI(3)K/B7-H1是如何 途径可以直接抑制T细胞对肿瘤的杀伤作用。在这个项目的下一个周期中，我们计划测试 假设PI(3)K/B7-H1通路激活对肿瘤的免疫抑制作用也可以 间接介导，通过扩大调节性T细胞(Treg)池(目标1)和通过 低级别肿瘤患者肿瘤浸润性巨噬细胞B7-H1蛋白表达的研究 星形细胞瘤(LGA)、间变性星形细胞瘤(/^A)和基底细胞瘤。以确定其临床影响。 PI(3)K/B7-H1通路激活对脑胶质瘤免疫治疗反应的影响 比较护理标准(静脉注射贝伐单抗)和HSPPG-96的随机试验 联合贝伐单抗治疗复发性基底膜患者(目标3)。

The long-term translational goal of this project is to overcome mechanisms of immunoresistance that diminish efficacy of immunotherapy for glioma patients, particularly glloblastoma (GBM). In the previous cycle we completed a Phase I clinical trial and a Phase II clinical trial for recurrent GBM patients immunized with an experimental vaccine, after surgical resection. These trials demonstrated that autologous glioma-derived heat shock protein peptide complex-96 (HSPPC-96) vaccine Is safe, evokes a CD4+ and CD8+ tumor specific T-cell response and Increases survival of recurrent GBM patients as compared to historical controls. In the previous SPORE cycle we also identified proteins that contribute to glioma immunoresistance, including B7-Homologue 1 (B7-H1) that is expressed on the glioma ceil surface, induces CD8+ T- cell apoptosis and Is positively regulated by PI(3)K. Our observations explain how the PI(3)K/B7-H1 pathway can directly inhibit T-cell killing of tumor. In the next cycle of this project we plan to test the hypothesis that Immunosuppressive tumor effects of PI(3)K/B7-H1 pathway activation can also be mediated indirectly, through expansion of the regulatory T cell (Treg) pool (Aim 1) and through expression of B7-H1 protein on tumor infiltrating macrophages (Aim 2) in patients with low grade astrocytoma (LGA), anaplastic astrocytoma (/^A), and GBM. To determine the clinical impact of PI(3)K/B7-H1 pathway activation on response to glioma immunotherapy we will initiate a randomized trial comparing the standard of care (intravenous bevacizumab) to HSPPG-96 combined with bevacizumab in recurrent GBM patients (Aim 3).