Clinical Neuroimmunology of Vaccines in Brain Tumors

在像胶质母细胞瘤(GBM)这样的脑瘤中，未能开发出有效的疫苗和实现免疫 检查点抑制被归因于这种特殊的抗原性肿瘤内异质性 疾病。为了克服这一点，成功的GBM免疫治疗将需要增加的抗肿瘤T细胞 大小和功能(效力)和同时针对多种抗原的T细胞(多样性)。我们有 确定了实现这些目标的3个战略。首先，我们将确认相邻的新抗原主要 具有通用破伤风P30Ⅱ类表位的组织相容性复合体I类表位多肽 显著提高T细胞反应的效力，并揭示T细胞对MHC I抗原的反应 在其他方面是非免疫原性的，导致从头免疫反应能够诱导抗肿瘤效果。 其次，我们将给予P30在肿瘤微环境中刺激P30特异性的CD4+T细胞的帮助。帮助 在效应阶段提供给肿瘤中的CD8+T细胞已被证明可以改善大小和 CD8+肿瘤浸润性淋巴细胞的持久性。第三，我们将使用一种新颖的、临床可用的检查站 激动剂CD27)和程序性细胞死亡蛋白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性，改善 活化T细胞的存活、效应器功能和迁移能力。然而，由于CD27刺激可以导致 抑制PD-1在T细胞上的表达，我们还将探索PD-1的阻断作为一种限制这种逃逸的方法 作用机制，进一步提高疗效。我们建议多抗原P30-连结的I类新抗原 用新型检查点激动剂CD27和PD-1阻断接种将增加效力和多样性 减少新抗原特异性CD8+T细胞反应，从而提高抗肿瘤疗效。因此，尽管出现了低点 在GBM中的突变负荷，我们的策略应该能够使强大的新抗原特异性T细胞应答 靶点的广度，以产生对异质肿瘤的疗效。我们的具体目标是： 1.确定多抗原、联合新抗原接种是否可提高异种小鼠的存活率。 脑内胶质瘤； 2.确定在肿瘤部位添加II类抗原是否提高了这些肿瘤的疗效； 3.为了确定CD27是否单独或与PD-1阻断联合使用，增加了细胞的效力和多样性 肿瘤特异性T细胞反应与异种肿瘤的抗肿瘤疗效。

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.