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: 10180142
• 负责人: Catalina Lee Chang
• 金额: $ 36.37万
• 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/10180142
• 关键词: APC Vaccine; Address; Agonist; 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; Blood Circulation; Brain; CD8-Positive T-Lymphocytes; CD86 gene; CD8B1 gene; Cell Therapy; Cells; Cellular Immunity; Characteristics; 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 memory cell; T-Cell Activation; T-Lymphocyte; TNFRSF5 gene; Testing; Therapeutic; Therapeutic antibodies; Toxicology; Translating; Treatment Protocols; Tumor Antigens; Tumor Immunity; Tumor-infiltrating immune cells; Vaccine Production; Vaccines; Work; anti-PD-L1; base; cancer immunotherapeutics; clinical application; cost; cytokine; cytotoxic; cytotoxicity; design; efficacy study; experimental study; immune checkpoint blockade; in vivo; novel; peripheral blood; phase 1 designs; preclinical efficacy; preclinical study; preclinical toxicity; prevent; research clinical testing; secondary lymphoid organ; therapeutic vaccine; 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.

项目摘要/摘要 免疫疗法彻底改变了许多肿瘤的治疗方法。然而，大多数GBM患者 到目前为止，还没有从免疫治疗中受益。其目标是探索如何 增强抗GBM免疫，我们已经开发出一种基于B细胞的疫苗(BVAX)，它由4-1BBL+组成 B细胞用CD40激动剂、碱性成纤维细胞生长因子和干扰素γ刺激激活。BVAX迁移到密钥辅助服务器 淋巴器官，并精通抗原交叉呈递，这促进了 CD8+T细胞的存活和功能。放射、BVAX和PD-L1阻断的组合 在接受治疗的荷瘤动物中，80%的人获得了肿瘤根除。这项研究建议 旨在了解这种保护和预防肿瘤的免疫机制 成长。我们将专注于两个过程：CD8+T细胞记忆形成的产生(目标1)和 AB生产(目标2)。我们假设这两种效应器功能都能诱导保护性的抗GBM。 豁免权。 我们已经成功地产生了能激活自体CD8+的GBM患者来源的BVAX T细胞，显示出很强的杀伤自体胶质瘤细胞的能力。这证明了BVAX 可以从患者的外周血液中产生。我们现在的目标是进一步描述和优化 BVAX治疗方案，告知这一治疗方法的未来临床应用(目标3)。 总体而言，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法，可以 很容易被转送到诊所。