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Project 2: A Novel Cellular Tumor Vaccine Strategy for Glioblastoma

项目 2：针对胶质母细胞瘤的新型细胞肿瘤疫苗策略

基本信息

批准号：
10006178
负责人：
MICHAEL D GUNN
金额：
$ 52.12万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10006178
关键词：
Active Immunotherapy Adverse effects Adverse event Antigen Presentation Pathway Antigens Brain Neoplasms Cancer Vaccines Clinical Cytomegalovirus Cytotoxic T-Lymphocytes Data Dendritic Cells Development Dose Dose-Limiting Environment Future Generations Glioblastoma Goals Harvest Human Immunosuppression Immunotherapeutic agent Immunotherapy In Situ In Vitro Investigational Therapies Malignant Neoplasms Malignant neoplasm of brain Modeling Pathway interactions Patients Peptides Phase Primary Brain Neoplasms Procedures Proteins Protocols documentation RNA Safety Serum Spleen T cell response T memory cell T-Cell Proliferation T-Lymphocyte Testing Time Toxic effect Transfection Tumor Antigens Vaccination Vaccines anti-tumor immune response antigen-specific T cells base cancer vaccination cohort cost effective cytokine dosage effective therapy efficacy study first-in-human immunogenic improved improved outcome in vivo intravenous injection monocyte mouse model novel outcome forecast phase 1 study pre-clinical preclinical study research clinical testing response scale up success tumor tumor progression vaccination strategy vaccine safety vaccine trial

项目摘要

PROJECT SUMMARY – Project 2 Glioblastoma (GBM), the most common malignant brain tumor, has an extremely poor prognosis with a median overall survival of <21 months. Standard therapies for GBM are largely ineffective. Immunotherapies for GBM appear to have the greatest potential for success, but are limited by the fact that GBM tumors are poorly immunogenic. For this reason, effective treatment of GBM will likely require an active immunotherapy such as vaccination against GBM antigens. Unfortunately, stimulating effective anti-tumor T cell responses in the majority of patients has proven difficult. While standard tumor vaccination strategies stimulate tumor-specific cytotoxic T cell (CTL) responses in most patients, they provide very little benefit in terms of tumor progression and patient survival. We reasoned that the poor efficacy of current tumor vaccines may be due to the fact that they do not target the pathways by which endogenous CTL responses are generated. Using mouse models, we identified a novel cellular vaccine strategy that exploits an endogenous Ag presentation pathway. In this strategy, resident splenic DC are loaded with antigens (Ags) in situ by the intravenous injection of Ag-loaded monocytes. The administered monocytes migrate to the spleen, transfer Ag to DC for presentation to T cells, and stimulate robust T cell proliferation, CTL activity, and anti-tumor immune responses that are markedly superior to that seen with current vaccines. Our preclinical data suggests that this strategy may serve as a simple and efficacious immunotherapeutic platform for the treatment of human cancers. Here, we will, for the first time, test this novel cellular vaccine strategy in humans. After optimizing our protocol for the large-scale harvesting and Ag-loading of human monocytes, we will perform a Phase 1 safety and dose ranging study of monocyte vaccination in patients with GBM. In this study, increasing numbers of Ag-loaded human monocytes will be administered to cohorts of patients to determine if and when dose-limiting toxicity occurs and determine the dose of monocytes that stimulates the maximal Ag-specific T cell response. Once these safety and dosing parameters have been determined, we will perform an expanded Phase 1 study to confirm the safety of our optimal monocyte dose and determine its effects in terms of T cell response and potential clinical benefit. This project represents a first-in-man study to establish proof of principle for an entirely novel cellular vaccine strategy.

项目总结-项目2