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）疫苗安全，可引起CD 4+和CD 8+肿瘤特异性T细胞反应 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）。 相关性（参见说明）： GBM患者的主动免疫治疗提供了特异性而无毒性的希望，但外周免疫治疗可能会导致GBM患者的死亡。 免疫应答并不总是与临床成功相关。在本提案中，我们将使用 逆转免疫抗性的新方法，以优化免疫治疗。 项目/生产现场（如果需要额外空间，请使用项目/生产现场表格页） 项目/

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). RELEVANCE (See instructions): Active immunotherapy for GBM patients offers the hope of specificity without toxicity, however peripheral immune responses have not always correlated with clinical success. In the present proposal we will use novel approaches to reverse the immunoresistance in an effort to optimize immunotherapy. PROJECT/PERFORIVIANCE SITE(S) (if additional space is needed, use Project/Perfomiance Site Fomnat Page) Project/