Clinical Neuroimmunology of Vaccines in Brain Tumors

脑肿瘤疫苗的临床神经免疫学

• 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
• 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

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.

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 检查点抑制归因于这种异常的抗原性肿瘤内异质性。 疾病为了克服这一点，GBM的成功免疫疗法将需要抗肿瘤T细胞， 强度和功能性（效力）以及T细胞同时靶向多种抗原（多样性）。我们有 确定了实现这些目标的三项战略。首先，我们要确认结合新抗原主要 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 显著增加T细胞应答的效力，并揭示T细胞对MHC I抗原的应答， 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应答。 其次，我们将在肿瘤微环境中施用P30以刺激P30特异性CD 4 + T细胞帮助。帮助 在效应子阶段提供给肿瘤处的CD 8 + T细胞已经显示出改善了肿瘤的大小， CD 8+肿瘤浸润淋巴细胞的持续存在。第三，我们将采用一种新颖的、临床可用的检查点， 激动剂CD 27）和程序性细胞死亡蛋白1（PD-1）阻断。刺激抗原结合的CD 27，CD 4 + 和CD 8 + T细胞增加低亲和力CD 8表位的免疫原性和记忆，并改善免疫原性。 活化T细胞的存活、效应子功能和迁移能力。然而，由于CD 27刺激可导致 我们还将探索PD-1阻断作为限制这种逃逸的一种方式， 机制，进一步提高疗效。我们认为多抗原P30-连接的I类新抗原 用新型检查点激动剂CD 27和PD-1阻断剂接种疫苗将增加效力和多样性 新抗原特异性CD 8 + T细胞应答，从而提高抗肿瘤疗效。因此，尽管低 GBM的突变负担，我们的策略应该能够有效的新抗原特异性T细胞应答， 靶点的宽度产生针对异质性肿瘤的功效。我们的具体目标是： 1.为了确定多抗原联合新抗原疫苗接种是否改善了异质性肿瘤小鼠的存活率， 脑内胶质瘤; 2.确定在肿瘤部位添加II类抗原是否改善这些肿瘤的疗效; 3.为了确定CD 27单独或与PD-1阻断剂组合是否增加了PD-I的效力和多样性， 肿瘤特异性T细胞应答和针对异质性肿瘤的抗肿瘤功效。