Clinical Neuroimmunology of Vaccines in Brain Tumors

脑肿瘤疫苗的临床神经免疫学

基本信息

批准号：
10348190
负责人：
Qijing Li
金额：
$ 40.07万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-15 至 2022-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10348190
关键词：
Adjuvant Affinity Agonist Antigen Targeting Antigens Antitumor Response Brain Neoplasms CD4 Positive T Lymphocytes CD40 Ligand CD8-Positive T-Lymphocytes CD8B1 gene Cell Death Clinical Complement Data Dose Epitope spreading Epitopes Etiology Failure Generations Glioblastoma Glioma Goals Heterogeneity Histocompatibility Antigens Class II Human I-antigen Immune response Immunotherapy Link MHC Class II Genes Major Histocompatibility Complex Malignant - descriptor Malignant Neoplasms Mediating Memory Modeling Mus Mutation Operative Surgical Procedures Peptides Phase Primary Brain Neoplasms Proteins Radiation Dose Unit Site T cell response T-Lymphocyte Tetanus Therapeutic Toxic effect Tumor Antigens Tumor-Infiltrating Lymphocytes Vaccination Vaccines checkpoint inhibition chemotherapy cytotoxic CD8 T cells disease heterogeneity effective therapy immunogenic immunogenicity improved innovation neoantigen vaccination neoantigens neoplastic cell neuroimmunology novel novel strategies novel therapeutics programmed cell death protein 1 programs ranpirnase recruit tumor tumor heterogeneity tumor microenvironment vaccine efficacy

项目摘要

In brain tumors like glioblastoma (GBM), failures to develop an effective vaccine and achieve immune checkpoint inhibition have been attributed to the extraordinary antigenic intratumoral heterogeneity of this disease. To overcome this, successful immunotherapy for GBM will require antitumor T cells with increased magnitude and functionality (potency) and T cells targeting multiple antigens simultaneously (diversity). We have identified 3 strategies to accomplish these goals. First, we will confirm that conjoining neoantigen major histocompatibility complex class I (MHCI) epitope peptides with the universal tetanus P30 class II epitope markedly increases the potency of T cell responses and unveils T cells responses against MHC I antigens that are otherwise non-immunogenic, resulting in de novo immune responses capable of inducing antitumor efficacy. Second, we will administer P30 in the tumor microenvironment to stimulate P30-specific CD4+ T cell help. Help provided to CD8+ T cells at the tumor during the effector stage has been shown to improve the magnitude and persistence of CD8+ tumor infiltrating lymphocytes. Third, we will engage a novel, clinically-available checkpoint agonist CD27) and program cell death protein 1 (PD-1) blockade. Stimulating CD27 on antigen-engaged, CD4+ and CD8+ T cells increases the immunogenicity and memory of low-affinity CD8 epitopes, and improves the survival, effector function, and migratory capacity of activated T cells. However, as CD27 stimulation can cause expression of inhibitory PD-1 on T cells, we will also explore PD-1 blockade as a way of limiting this escape mechanism and further enhancing efficacy. We propose that multi-antigen P30-conjoined class I neoantigen vaccination with the novel checkpoint agonist CD27 and PD-1 blockade will increase the potency and diversity of neoantigen-specific CD8+ T cell responses, resulting in improved antitumor efficacy. Thus, despite a low mutational burden in GBM, our strategy should enable potent neoantigen-specific T cell responses against a breadth of targets to engender efficacy against heterogeneous tumor. Our Specific Aims are: 1. To determine if multi-antigen, conjoined neoantigen vaccination improves survival in mice with heterogeneous intracerebral glioma; 2. To determine if the addition of class II antigen at the tumor site improves efficacy in these tumors; 3. To determine if CD27, alone or in combination with PD-1 blockade, increases the potency and diversity of tumor-specific T cell responses and antitumor efficacy against heterogeneous tumors.

对于胶质母细胞瘤 (GBM) 等脑肿瘤，未能开发出有效的疫苗并实现免疫系统检查点抑制归因于这种异常的抗原瘤内异质性为了克服这一问题，成功的 GBM 免疫疗法需要增加抗肿瘤 T 细胞。我们拥有强度和功能（效力）以及同时针对多种抗原的 T 细胞（多样性）。确定了实现这些目标的 3 种策略首先，我们将确认连接新抗原的主要作用。具有通用破伤风 P30 II 类表位的组织相容性复合物 I 类 (MHCI) 表位肽显着增强 T 细胞反应的效力，并揭示针对 MHC I 抗原的 T 细胞反应，否则是非免疫原性的，导致能够诱导抗肿瘤功效的从头免疫反应。其次，我们将在肿瘤微环境中施用 P30，以刺激 P30 特异性 CD4+ T 细胞的帮助。在效应阶段向肿瘤中的 CD8+ T 细胞提供药物已被证明可以改善肿瘤的大小和第三，我们将采用一种新型的、临床可用的检查点。激动剂 CD27) 和程序细胞死亡蛋白 1 (PD-1) 阻断刺激抗原结合的 CD27、CD4+。 CD8+ T细胞增加低亲和力CD8表位的免疫原性和记忆，并改善然而，CD27 刺激可能会导致活化 T 细胞的存活、效应功能和迁移能力。 T 细胞上抑制性 PD-1 的表达，我们还将探索 PD-1 阻断作为限制这种逃逸的方法我们提出多抗原P30联合I类新抗原。接种新型检查点激动剂 CD27 和 PD-1 阻断剂将增加效力和多样性新抗原特异性 CD8+ T 细胞反应，从而提高抗肿瘤功效，尽管效果较低。 GBM 中的突变负担，我们的策略应该能够针对 GBM 中的突变产生有效的新抗原特异性 T 细胞反应我们的具体目标是： 1. 确定多抗原、联合新抗原疫苗接种是否可以提高具有异质性的小鼠的存活率脑内神经胶质瘤; 2. 确定在肿瘤部位添加 II 类抗原是否可以提高这些肿瘤的疗效； 3. 确定 CD27 单独使用或与 PD-1 阻断剂联合使用是否会增加肿瘤特异性 T 细胞反应和针对异质肿瘤的抗肿瘤功效。