Development of B-cell-based vaccine for Glioblastoma

开发基于 B 细胞的胶质母细胞瘤疫苗

• 批准号: 10579894
• 负责人: Catalina Lee Chang
• 金额: $ 35.87万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-15 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10579894
• 关键词: APC Vaccine; Animals; Antibodies; Antibody Formation; Antigen Presentation; Antigens; Authorization documentation; Autologous; B cell differentiation; B-Cell Activation; B-Cell Antigen Receptor; B-Cell Development; B-Lymphocytes; Brain; CD8-Positive T-Lymphocytes; CD86 gene; CD8B1 gene; Cell Therapy; Cells; Cellular Immunity; Characteristics; Circulation; Clinic; Cross Presentation; Data; Dendritic Cells; Ensure; Evaluation; Future; Generations; Glioblastoma; Glioma; Goals; Humoral Immunities; IgG1; Immune; Immunity; Immunologics; Immunosuppression; Immunotherapeutic agent; Immunotherapy; Infiltration; Interferon Type II; Interleukin-15; Investigational New Drug Application; Knowledge; MHC Class I Genes; Mediating; Memory; Metabolic; Mus; Myelogenous; PD-L1 blockade; Patients; Phase I Clinical Trials; Prevention; Process; Production; Radiation; Research; Research Proposals; Specificity; T cell infiltration; T memory cell; T-Cell Activation; T-Lymphocyte; TNFRSF5 gene; Testing; Therapeutic; Therapeutic antibodies; Toxicology; Translating; Treatment Protocols; Tumor Antigens; Tumor Immunity; Vaccine Production; Vaccines; Work; anti-PD-L1; authority; cancer immunotherapeutics; clinical application; cost; cytokine; cytotoxic; cytotoxicity; design; efficacy study; experimental study; immune checkpoint blockade; in vivo; migration; novel; peripheral blood; phase 1 designs; preclinical efficacy; preclinical study; preclinical toxicity; prevent; research clinical testing; secondary lymphoid organ; tumor; tumor eradication; tumor growth; vaccine immunotherapy

PROJECT SUMMARY/ABSTRACT Immunotherapy has revolutionized the treatment of many tumors. However, most GBM patients have not, so far, benefited from immunotherapeutic treatment. With the goal of exploring ways to boost 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 IFNγ stimulation. BVax migrate to key secondary lymphoid organs and are proficient at antigen cross-presentation, which promotes both the survival and functionality of CD8+ T cells. A combination of radiation, BVax, and PD-L1 blockade conferred tumor eradication in 80% of treated tumor-bearing animals. This research proposal aims to understand the immune mechanisms underlying this protection and prevention of tumor growth. We will focus on two processes: generation of CD8+ T-cell memory formation (Aim 1) and Ab production (Aim 2). We hypothesize that both effector functions elicit protective anti-GBM immunity. We have been successful at generating GBM patient-derived BVax that activated autologous CD8+ T cells, which shows a strong ability to kill autologous glioma cells. This demonstrates that BVax can be produced from patient's peripheral blood. We now aim to further characterize and optimize BVax treatment protocol to inform future clinical application of this therapeutic approach (Aim 3). Overall, our study provides a novel alternative to current immunotherapeutic approaches that can be readily translated to the clinic.

项目总结/摘要 免疫疗法彻底改变了许多肿瘤的治疗。然而，大多数GBM患者 迄今为止，他们还没有从免疫治疗中受益。目的是探索 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 + 用CD40激动、BAFF和IFN γ刺激活化B细胞。BVax迁移到关键辅助服务器 淋巴器官，并精通抗原交叉呈递，这促进了两个 CD8 + T细胞的存活和功能。放射、BVax和PD-L1阻断的组合 在80%的经治疗的荷瘤动物中实现了肿瘤根除。本研究提案 旨在了解这种保护和预防肿瘤的免疫机制， 增长我们将重点关注两个过程：CD8 + T细胞记忆形成的产生（目的1）和 Ab生产（目标2）。我们假设这两种效应器功能都能引起保护性抗GBM 免疫力 我们已经成功地产生了GBM患者来源的BVax，其激活了自体CD8+细胞， T细胞，它显示出很强的杀伤自体胶质瘤细胞的能力。这表明BVax 可以从患者的外周血中产生。我们现在的目标是进一步表征和优化 BVax治疗方案，为该治疗方法的未来临床应用提供信息（目标3）。 总的来说，我们的研究为目前的免疫治疗方法提供了一种新的替代方案， 很容易翻译到诊所。