Neoantigen immunotherapy in brain tumors using anti-CD27 to deplete regulatory T cells selectively

使用抗 CD27 选择性耗尽调节性 T 细胞的脑肿瘤新抗原免疫疗法

• 批准号: 10248316
• 负责人: JOHN H. SAMPSON
• 金额: $ 19.99万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-24 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10248316
• 关键词: Address; Affinity; Agonist; Antibodies; Antigen Targeting; Antigens; Binding; Brain Neoplasms; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cancer Vaccines; Cells; Clinical; Clone Cells; Cytomegalovirus; Data; Dose; Effectiveness; Epitopes; Failure; Glioblastoma; Goals; Heterogeneity; Human; IL2RA gene; Immune response; Immunosuppression; Immunotherapeutic agent; Immunotherapy; Interleukin 2 Receptor; Link; Malignant Neoplasms; Malignant neoplasm of brain; Memory; Mus; Mutation; Operative Surgical Procedures; Patients; Radiation Dose Unit; Regulatory T-Lymphocyte; Safety; Surface; T cell response; T-Cell Activation; Testing; Therapeutic; Tumor Immunity; Vaccination; Vaccine Antigen; Vaccine Design; Vaccines; Work; base; checkpoint inhibition; chemotherapy; cytotoxic; effector T cell; immunogenic; immunogenicity; improved; melanoma; mouse model; neoantigen vaccination; neoantigen vaccine; neoantigens; novel; novel therapeutics; patient population; programmed cell death protein 1; receptor; response; success; tumor; tumor heterogeneity; vaccination outcome

ABSTRACT – Project 1 In brain tumors like glioblastoma (GBM), failures to develop an effective vaccine and achieve immune checkpoint inhibition have been attributed to both the remarkable immunosuppression and extraordinary antigenic intratumoral heterogeneity. A major contributor to immunosuppression in GBM is elevated regulatory T-cells (TRegs) which dramatically suppress T cell effector function and diminish the efficacy of antitumor vaccination. Efforts to deplete TRegs by targeting the interleukin-2 receptor α (CD25) have been unsuccessful to date, due to cytotoxic effects on effector T cells, which are required to promote antitumor immunity. To overcome this hurdle, Project 1 builds novel preliminary data demonstrating the ability of a clinically available CD27 agonist antibody (αCD27) to simultaneously deplete TRegs and enhance vaccine-induced immune responses. Specifically, the Project tests the hypothesis that class I neoantigens linked to universal class II epitopes will be well-tolerated and rendered more immunogenic by the ability of the clinically available CD27 agonist antibody to deplete TRegs and simultaneously enhance vaccine-induced immune responses in patients with GBM. Aim 1 will evaluate the safety and therapeutic potential of a neoantigen and Cytomegalovirus antigen vaccine in combination with dose-escalating αCD27 in patients with GBM. Cumulative results will provide critical data on the feasibility and immunogenicity of neoantigen vaccination in patients with GBM to determine if a larger trial is warranted. Aim 2 will determine if αCD27 simultaneously depletes TRegs and increases vaccine-induced immune responses. It is expected that αCD27 will reduce TRegs in this patient population while improving vaccine-induced CD8+ and CD4+ T cell responses. If successful, this work will develop a therapeutic strategy for patients with GBM that has enhanced efficacy by addressing the issues of host immunosuppression and intratumoral heterogeneity.

摘要-项目1 在胶质母细胞瘤（GBM）等脑肿瘤中，未能开发有效的疫苗并实现免疫 检查点抑制归因于显著的免疫抑制和异常的免疫抑制。 抗原的瘤内异质性。GBM中免疫抑制的一个主要因素是调节性免疫抑制的升高。 T细胞（TReg），其显著抑制T细胞效应子功能并降低抗肿瘤药物的功效。 预防针通过靶向白细胞介素-2受体α（CD 25）来消除TReg的努力一直不成功， 迄今为止，由于对效应T细胞的细胞毒性作用，这是促进抗肿瘤免疫所必需的。到 为了克服这一障碍，项目1建立了新的初步数据，证明临床可用的 CD 27激动剂抗体（α CD 27）可同时耗竭TReg并增强疫苗诱导的免疫 应答具体而言，该项目检验了I类新抗原与通用II类新抗原相关联的假设， 表位将是良好耐受的，并且通过临床上可获得的CD 27免疫原性的能力而变得更具免疫原性。 激动剂抗体以消耗TReg并同时增强患者中疫苗诱导的免疫应答 关于GBM目的1将评估新抗原和巨细胞病毒的安全性和治疗潜力 抗原疫苗联合剂量递增的α CD 27治疗GBM患者。累积结果将 提供GBM患者新抗原疫苗接种可行性和免疫原性的关键数据， 确定是否需要进行更大规模的试验目的2将确定α CD 27是否同时耗竭TReg， 增加疫苗诱导的免疫反应。预计α CD 27将降低该患者的TReg 同时改善疫苗诱导的CD 8+和CD 4 + T细胞应答。如果成功，这项工作将 为GBM患者制定治疗策略，通过解决以下问题提高疗效： 宿主免疫抑制和肿瘤内异质性。