Heat Shock Protein Vaccine Dev: Glioma immunoresistance and PI(3)K/Akt/mTOR pathw

热休克蛋白疫苗开发：胶质瘤免疫抵抗和 PI(3)K/Akt/mTOR 通路

• 批准号: 8258660
• 负责人: ANDREW T PARSA
• 金额: $ 29.56万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8258660
• 关键词: 1-Phosphatidylinositol 3-Kinase; Address; Antibodies; Antigens; Apoptosis; Archives; Autologous; Autologous gp96 Heat Shock Protein Peptide Complex Vaccine; Binding; Biological Assay; Blocking Antibodies; CD8-Positive T-Lymphocytes; CD8B1 gene; Caspase; Cell Line; Cell Surface Proteins; Cells; Cessation of life; Clinic; Clinical; Clone Cells; Coculture Techniques; Data; Effectiveness; Environment; Flow Cytometry; Glioblastoma; Glioma; Goals; Heat shock proteins; Homologous Gene; Human; Immune response; Immunosuppressive Agents; Immunotherapy; In Vitro; Incubated; Infiltration; Interferon Type II; Interferons; Interleukin-13; Ligands; Link; Malignant Glioma; Mediating; Membrane; Modality; Monitor; Natural Killer Cells; Pathway interactions; Patients; Peripheral; Peripheral Blood Lymphocyte; Phase; Phenotype; Predisposition; Production; Progression-Free Survivals; Proteins; Recurrence; Regulatory T-Lymphocyte; Resected; Resistance; Ribosomal Protein S6 Kinase; Running; Safety; Serum; Specimen; Staining method; Stains; System; T-Lymphocyte; TNFSF10 gene; Testing; Translating; Tumor Immunity; Tumor Necrosis Factor-alpha; Vaccinated; Vaccination; Vaccine Therapy; Vaccines; Xenograft procedure; anergy; caspase-8; cell killing; clinically relevant; cytokine; cytotoxicity; design; expectation; glioma cell line; inhibitor/antagonist; killings; mTOR protein; neuro-oncology; oncology service; programs; receptor; response; therapy design; tumor

The long-term goal of this project is to optimize immunotherapy for patients with malignant glioma. Several trials have shown the feasibility, safety, and anecdotal efficacy of glioma vaccines. However the general applicability of effective glioma immunotherapy has yet to be clearly documented. Vaccine therapies designed to provoke a cellular immune response may depend upon both tumor specific CD8+ T-cells and cytokine-stimulated natural killer (NK) cells. Tumor-specific cytotolytic CD8+ T-cells (CTLs) can undergo anergy or apoptosis in response to proteins expressed by gliomas, while NK cells may be rendered ineffective by proteins that confer resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated killing. B7-Homologue 1 (B7-H1), also known as programmed death ligand 1 (PD-L1), is a recently discovered cell surface protein that inhibits anti-tumor immunity by inducing T-cell apoptosis, impairing cytokine production, and diminishing the cytotoxicity of activated T-cells. FADD-containing inhibitor of caspase-8 cleavage short protein (FLIPS) may confer resistance to TRAIL-mediated NK cell killing. We believe that tumor specific proteins such as B7-H1 and FLIPS can limit the efficacy of glioma immunotherapy. In our preliminary results, we show that B7-H1 and FLIPS are positively regulated by the PI(3)K/Akt/mTOR pathway, and that glioma cells with this pathway activated are immunoresistant. In addition we show that an autologous patient-specific vaccine containing glioma-derived heat shock protein peptide complex-96 (HSPPC-96) appears to be safe, while evoking a tumor specific T-cell response and an increase in circulating NK cells. To translate our experimental findings into the clinic, we will test the hypothesis that activation of the PI(3)K/Akt/mTOR pathway in glioma suppresses innate (NK cell) and adaptive (T-cell) anti-glioma immune responses. In order to test our hypothesis in a clinically relevant in vitro system, aims #1 and #2 utilize glioma cells directly from glioblastoma multiforme (GBM) patients and passaged as xenografts, prior to culturing to assess the impact of PI(3)K/Akt/mTOR pathway on resistance to NK and T cell killing. In aim #3 we will study gliomas taken directly from patients to assess the relationship between PI(3)K/Akt/mTOR pathway activation and T-cell infiltration, and in aim #4 we will test our hypothesis within the context of an ongoing HSPPC-96 phase l/ll vaccine trial for glioma patients.

该项目的长期目标是优化恶性神经胶质瘤患者的免疫疗法。一些 试验表明，神经胶质瘤疫苗的可行性，安全性和轶事功效。但是将军 有效的神经胶质瘤免疫疗法的适用性尚未清楚地记录。疫苗疗法 旨在引发细胞免疫反应可能取决于肿瘤特异性CD8+ T细胞和 细胞因子刺激的天然杀手（NK）细胞。肿瘤特异性的细胞溶解CD8+ T细胞（CTL）可以进行 响应于神经胶质瘤表达的蛋白质的反应或凋亡，而NK细胞可能会渲染 无效的蛋白质无效，蛋白质赋予与肿瘤坏死因子相关凋亡的配体的抗性 （小径）杀害。 B7-词法1（B7-H1），也称为编程死亡配体1（PD-L1），是一个 最近发现的细胞表面蛋白通过诱导T细胞凋亡抑制抗肿瘤免疫力， 损害细胞因子的产生，并降低活化的T细胞的细胞毒性。含FADD的抑制剂 caspase-8裂解短蛋白（翻转）的裂解可能会赋予跟踪介导的NK细胞杀死的耐药性。我们 相信肿瘤特异性蛋白（例如B7-H1和翻转）可以限制神经胶质瘤的功效 免疫疗法。在我们的初步结果中，我们表明B7-H1和翻转由 PI（3）K/AKT/MTOR途径，并且激活该途径的神经胶质瘤细胞具有免疫性。在 此外，我们表明一种含有神经胶质瘤衍生的热休克蛋白的自体患者特异性疫苗 肽复合物96（HSPPC-96）似乎是安全的，同时唤起肿瘤特异性T细胞反应和A 循环NK细胞的增加。为了将我们的实验发现转化为诊所，我们将测试 胶质瘤中PI（3）K/AKT/MTOR途径的激活抑制先天细胞（NK细胞）和 自适应（T细胞）抗脱脂瘤免疫反应。为了检验我们在临床相关的体外相关假设 系统，AIMS＃1和＃2直接利用胶质母细胞瘤多形胶质瘤（GBM）患者和 在培养之前，以异种移植的形式传递，以评估PI（3）K/AKT/MTOR途径对电阻的影响 杀死NK和T细胞。在AIM＃3中，我们将直接从患者中研究神经胶质瘤，以评估 PI（3）K/AKT/MTOR途径激活与T细胞浸润之间的关系，在AIM＃4中，我们将测试 我们在正在进行的HSPPC-96期L/LL疫苗试验试验中为神经胶质瘤患者进行的假设。