OVERCOMING LOCAL AND PERIPHERAL IMMUNE SUPPRESSION IN GLIOMA TO FACILITATE EFFEC

克服神经胶质瘤的局部和外周免疫抑制以促进疗效

基本信息

批准号：
8514323
负责人：
ANDREW T PARSA
金额：
$ 33.75万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-05-01 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8514323
关键词：
Active Immunotherapy Anaplastic astrocytoma Antibodies Apoptosis Astrocytoma Autologous Autologous gp96 Heat Shock Protein Peptide Complex Vaccine Brain Neoplasms CD4 Positive T Lymphocytes CD8B1 gene Cell surface Cells Clinical Coculture Techniques Correlative Study Excision Flow Cytometry Glioblastoma Glioma Goals Grant Helper-Inducer T-Lymphocyte Homologous Gene IL2RA gene Immune response Immunosuppression Immunosuppressive Agents Immunotherapy In Vitro Infiltration Instruction Intravenous Measures Mediating Operative Surgical Procedures PTPRC gene Pathway interactions Patients Peripheral Phase I Clinical Trials Phase II Clinical Trials Primary Cell Cultures Proteins Recurrence Regulatory T-Lymphocyte Reproduction spores Sampling Site Specificity Specimen Surface T cell response T-Cell Proliferation T-Lymphocyte Testing Toxic effect Vaccines base bevacizumab cell killing heat shock protein-peptide complex-96 vaccine inhibitor/antagonist macrophage neoplastic cell novel strategies peripheral blood randomized trial response standard of care success trial comparing tumor

项目摘要

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/

该项目的长期翻译目标是克服免疫抗药性会降低免疫疗法对神经胶质瘤患者的功效，特别是 Glloblastoma（GBM）。在上一个周期中，我们完成了I期临床试验和II期手术后用实验疫苗免疫的复发性GBM患者的临床试验切除。这些试验表明自体神经胶质瘤的热休克蛋白肽复合物96（HSPPC-96）疫苗是安全的，唤起CD4+和CD8+肿瘤特异性T细胞反应与历史对照相比，复发性GBM患者的存活率增加。在以前的孢子周期我们还确定了有助于神经胶质瘤免疫抗药性的蛋白质，包括在神经胶质瘤Ceil表面表达的B7-词法1（B7-H1），诱导CD8+ T- 细胞凋亡，并由PI（3）K阳性调节。我们的观察结果解释了PI（3）K/B7-H1如何途径可以直接抑制肿瘤的T细胞杀死。在这个项目的下一个周期中，我们计划测试假设PI的免疫抑制肿瘤作用（3）K/B7-H1途径也可以是通过扩展调节T细胞（Treg）池（AIM 1）并通过间接介导的介导 B7-H1蛋白在肿瘤浸润巨噬细胞（AIM 2）中的表达低级患者（AIM 2）星形胶质细胞瘤（LGA），那间层状星形胶质细胞瘤（/^a）和GBM。确定 PI（3）K/B7-H1途径激活对神经胶质瘤免疫疗法，我们将启动A 随机试验比较了护理标准（静脉bevacizumab）与HSPPG-96 在复发性GBM患者中与贝伐单抗结合（AIM 3）。相关性（请参阅说明）： GBM患者的主动免疫疗法提供了没有毒性的特异性的希望，但是周围免疫反应并不总是与临床成功相关。在目前的建议中，我们将使用为了优化免疫疗法而扭转免疫力的新方法扭转免疫力。项目/穿越稳定站点（如果需要额外的空间，请使用项目/完善网站FOMNAT页面）项目/