OVERCOMING LOCAL AND PERIPHERAL IMMUNE SUPPRESSION IN GLIOMA TO FACILITATE EFFEC

该项目的长期转化目标是克服 免疫抗性降低了神经胶质瘤患者免疫治疗的功效，特别是 成胶质细胞瘤（GBM）。在上一个周期中，我们完成了I期临床试验和II期临床试验。 对手术后用实验性疫苗免疫的复发性GBM患者进行的临床试验 切除术这些试验表明，自体胶质瘤源性热休克蛋白肽 复合物-96（HSPPC-96）疫苗是安全的，可引起CD 4+和CD 8+肿瘤特异性T细胞应答 与历史对照相比，增加复发性GBM患者的存活率。在 在先前的SPORE循环中，我们还鉴定了有助于神经胶质瘤免疫抗性的蛋白质， 包括在神经胶质瘤细胞表面上表达的B7-同源物1（B7-H1），诱导CD 8 + T- PI（3）K对细胞凋亡有正调控作用。我们的观察解释了PI（3）K/B7-H1 途径可以直接抑制T细胞对肿瘤的杀伤。在本项目的下一个周期中，我们计划测试 假设PI（3）K/B7-H1通路激活的免疫抑制肿瘤作用也可以 间接介导，通过扩增调节性T细胞（Treg）库（Aim 1）和通过 B7-H1蛋白在低度恶性肿瘤患者肿瘤浸润巨噬细胞（Aim 2）上的表达 星形细胞瘤（LGA）、间变性星形细胞瘤（A）和GBM。为了确定临床影响， PI（3）K/B7-H1通路激活对胶质瘤免疫治疗的反应，我们将启动一项研究， 一项比较标准治疗（静脉注射贝伐单抗）与HSPPG-96的随机试验 与贝伐单抗联合治疗复发性GBM患者（目的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).