Development of a B Cell Based Vaccine for the Treatment of Newly Diagnosed Malignant Gliomas

开发用于治疗新诊断的恶性胶质瘤的 B 细胞疫苗

基本信息

批准号：
10626395
负责人：
Catalina Lee Chang
金额：
$ 30.18万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
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：
2018-08-17 至 2028-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10626395
关键词：
Agonist Animals Antibodies Antigen Presentation Antigens Appearance Autologous B cell therapy B-Cell Activation B-Lymphocytes Blood CD8-Positive T-Lymphocytes CD86 gene Cancer Patient Cancer Vaccines Cell Therapy Cells Cellular Immunity Cellular immunotherapy Characteristics Clinic Clinical Clinical Data Combined Modality Therapy Combined Vaccines Computer Analysis Cross Presentation Cytotoxic T-Lymphocytes Development Dose Effector Cell Ensure Flow Cytometry Glioblastoma Glioma Humoral Immunities Immune Immune checkpoint inhibitor Immune response Immune system Immunity Immunoglobulins Immunologics Immunophenotyping Immunotherapeutic agent Immunotherapy Infiltration Intervention Journals Left MHC Class I Genes Malignant Glioma Malignant Neoplasms Malignant neoplasm of brain Medicine Memory Metabolic Molecular Mus Mutation Newly Diagnosed Operative Surgical Procedures Outcome PD-L1 blockade Patients Penetrance Physiologic pulse Production Publishing Quality of life Radiation Recommendation Research Research Project Grants Research Proposals Safety Specificity T cell infiltration T-Cell Activation T-Lymphocyte TNFRSF5 gene Technology Testing Therapeutic Therapeutic Effect Time Translating Tumor Antigens Tumor Immunity Tumor-infiltrating immune cells Universities Vaccine Production Vaccines Work anti-PD-L1 cancer immunotherapeutics cost cytokine cytotoxicity design first-in-human improved innovation manufacture migration novel pre-Investigational New Drug meeting pre-clinical preclinical study prevent secondary lymphoid organ therapeutic vaccine transcriptomics translational approach treatment response tumor tumor eradication tumor microenvironment vaccine trial

项目摘要

PROJECT 3: SUMMARY Immunotherapy has significantly improved the clinical outcome of many cancer patients. However, most glioblastoma (GBM) patients have not, so far, benefited from immunotherapeutic intervention. To explore alternative ways to potentiate the anti-GBM immunity, we've developed a B-cell-based vaccine (BVax) that consists of 4-1BBL+ B cells activated with CD40 agonism, BAFF, and IFNg stimulation. In our preclinical study, BVax migrates to critical secondary lymphoid organs and is proficient at antigen cross-presentation, promoting the survival and functionality of tumor- infiltrating CD8+ T cells. In addition, BVax produces immunoglobulins (humoral immune response) reactive to the tumor. These immunoglobulins elicited a potent therapeutic effect. A combination of radiation, BVax, CD8 T cells and PD-L1 blockade conferred tumor eradication in 80% of treated tumor-bearing animals. This research proposal aims to translate BVax to the clinic to treat newly diagnosed malignant gliomas. To effectively implement this therapy in the clinic, we propose to perform IND-enabling studies to manufacture autologous BVax and CD8 T cells (Aim 1). Upon FDA approval, we aim to conduct a first-in-human BVax trial (Aim 2) and evaluate the effect on the immune response (Aim 3). We hypothesize that the proposed autologous cellular therapy is safe and effective at eliciting protective anti-GBM immunity via cellular and humoral immune responses. Overall, our study provides a novel alternative to current immunotherapeutic approaches.

项目 3：总结免疫疗法显着改善了许多癌症患者的临床结果。然而，大多数胶质母细胞瘤迄今为止，GBM 患者尚未从免疫治疗干预中受益。探索替代方法为了增强抗 GBM 免疫力，我们开发了一种基于 B 细胞的疫苗 (BVax)，由 4-1BBL+ B 细胞组成通过 CD40 激动、BAFF 和 IFNg 刺激激活。在我们的临床前研究中，BVax 迁移到关键的二级淋巴器官，精通抗原交叉呈递，促进肿瘤的存活和功能浸润 CD8+ T 细胞。此外，BVax 产生对肿瘤有反应的免疫球蛋白（体液免疫反应）。这些免疫球蛋白产生了有效的治疗效果。放射、BVax、CD8 T 细胞和 PD-L1 的组合封锁使 80% 接受治疗的荷瘤动物的肿瘤得到根除。本研究计划旨在翻译 BVax 到诊所治疗新诊断的恶性神经胶质瘤。为了在临床上有效实施这种疗法，我们提议进行 IND 支持研究以制造自体 BVax 和 CD8 T 细胞（目标 1）。经FDA批准后，我们的目标是进行首次人体 BVax 试验（目标 2）并评估其对免疫反应的影响（目标 3）。我们假设所提出的自体细胞疗法在引发保护性抗 GBM 免疫方面是安全有效的通过细胞和体液免疫反应。总的来说，我们的研究为当前的研究提供了一种新颖的替代方案免疫治疗方法。