Targeting T cell dysfunction in glioblastoma: A proof-of-concept Phase 0/I trial of anti-TIGIT antibody AB154 in combination with anti-PD1 antibody AB122

靶向胶质母细胞瘤中的 T 细胞功能障碍：抗 TIGIT 抗体 AB154 与抗 PD1 抗体 AB122 联合的概念验证 0/I 期试验

• 批准号: 10346649
• 负责人: David A. Hafler
• 金额: $ 69.51万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-15 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10346649
• 关键词: Acceleration; Adult; Advanced Malignant Neoplasm; Aftercare; Antibodies; Antigen Presentation; Antigen-Presenting Cells; Automobile Driving; Biological; Biological Markers; Blood; Blood specimen; Brain; Brain Neoplasms; CD8-Positive T-Lymphocytes; CTLA4 gene; Cells; Central Nervous System Neoplasms; Chronic; Clinical; Clinical Trials; Clonal Expansion; Clonality; Clone Cells; Coculture Techniques; Combination immunotherapy; Data; Development; Disease; Enrollment; Environment; Evaluation; Excision; Exposure to; Frequencies; Functional disorder; Glioblastoma; Human; Immune; Immune System Diseases; Immune checkpoint inhibitor; Immune response; Immune system; Immunofluorescence Immunologic; Immunotherapy; In Vitro; Infiltration; Inflammatory; Interferon Type II; Laboratories; Lead; Life; Ligands; Malignant Neoplasms; Malignant neoplasm of brain; Modeling; Monoclonal Antibodies; Myeloid Cells; Neuraxis; Operative Surgical Procedures; PD-1 blockade; Pathway interactions; Patients; Peripheral; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phase; Phase 0/1 Clinical Trial; Phase 0/1 Trial; Placebos; Play; Primary Brain Neoplasms; Prior Therapy; Prognosis; Prognostic Factor; Randomized; Recurrence; Recurrent disease; Recurrent tumor; Regulatory T-Lymphocyte; Resolution; Role; Safety; Sampling; Schedule; Seminal; Signal Transduction; Solid Neoplasm; Specimen; T-Cell Proliferation; T-Lymphocyte; Testing; Toxic effect; Tumor-Derived; Validation; Work; anti-CTLA4; anti-PD-1; anti-PD1 antibodies; anti-PD1 therapy; antigen-specific T cells; bench to bedside; blood treatment; chemoradiation; cohort; design; effector T cell; efficacy study; immunosuppressed; improved; in vitro Assay; in vivo; melanoma; neoantigens; novel; prevent; programmed cell death protein 1; receptor; response; single-cell RNA sequencing; trait; transcriptomics; trial design; tumor; tumor microenvironment

ABSTRACT Glioblastoma (GBM), the most common primary brain tumor in adults, is associated with a poor prognosis and short survival in spite of aggressive management. T cell dysfunction is a crucial component in the immunosuppressed state observed in the GBM tumor microenvironment and remains a significant barrier for the development of successful immunotherapies. Recent work suggests modulation with the immune-checkpoint inhibitors α-PD-1 or α-CTLA-4 do not provide significant clinical benefit in GBM, as opposed to other cancers. These data suggest that multiple co-inhibitory receptors are involved in the GBM tumor microenvironment driving T cell dysfunction. While investigating T cell dysfunction in human inflammatory disease, we first identified a key role for engagement of TIGIT on T cells by CD155 as a major co-inhibitory pathway; we then demonstrated a role for TIGIT in maintaining functional stability of Tregs, in that TIGIT signaling prevents conversion of Tregs into proinflammatory cells. Moreover, we and others have found that TIGIT and its ligand CD155 are highly expressed in GBM. Our new preliminary data using single-cell RNAseq shows that, among GBM tumor-infiltrating T cells, Tregs express the highest levels of TIGIT. Anti-TIGIT therapies are now entering clinical trials in cancer and recently, α-TIGIT mAb tiragolumab was given FDA breakthrough designation. In this proposal, we will elucidated mechanisms of T cell dysfuction in GBM by conducting a phase 0/1 clinical trial of α-TIGIT and α-PD- 1 mAbs as checkpoint inhibitors for treatment of recurrent GBM. The trial design allows for establishing the safety of this combination, while providing tumor samples and blood specimens for a robust evaluation of in human effects of α-TIGIT & α-PD-1 either alone or in combination, with transcriptomic single-cell resolution. Our mechanistic hypothesis is that while anti-PD-1 enhances both effector and regulatory T cell proliferation, the addition of α-TIGIT to α-PD-1 will destabilize Treg function and optimize the immune response. To investigate this hypothesis, our trial utilizes a “window-of-opportunity” design, within a bench-to-bedside-to-bench approach. Prior to surgery for resection of recurrent tumor, patients will be randomized to receive placebo, or α-PD-1, or α- TIGIT either alone or in combination. Single-cell RNAseq (10x) will be performed on baseline blood, post- treatment blood and tumor specimens from the trial patients. We will compare clonality and functional traits of tumor-infiltrating Tregs and effector T cells, and frequency of proinflammatory and suppressive tumor-derived myeloid cells. Multiplexed immunofluorescence (4i) will be used for spatial validation. We will analyze circulating T cells clonally related to tumor-infiltrating T cells to identify peripheral correlates and develop a non-invasive biomarker of emerging immune response. We will then model effects of PD-1 and TIGIT blockade on T regs in vitro using healthy donors T regs and compare to effects observed in the trial. Through this comprehensive approach, our study will determine whether PD-1 and TIGIT receptor engagement on T cells in the GBM tumor microenvironment induces immune dysfunction not allowing for immune survelliance in this CNS tumor.

抽象的 胶质母细胞瘤 (GBM) 是成人中最常见的原发性脑肿瘤，与不良预后相关 尽管采取积极的管理，但生存期很短。 T细胞功能障碍是一个重要组成部分 在 GBM 肿瘤微环境中观察到的免疫抑制状态仍然是免疫抑制的重要障碍 开发成功的免疫疗法。最近的研究表明用免疫检查点进行调节 与其他癌症相比，α-PD-1 或​​ α-CTLA-4 抑制剂对 GBM 没有显着的临床益处。 这些数据表明多种共抑制受体参与 GBM 肿瘤微环境驱动 T细胞功能障碍。在研究人类炎症性疾病中的 T 细胞功能障碍时，我们首先确定了一个关键因素 TIGIT 通过 CD155 作为主要共抑制途径参与 T 细胞的作用；然后我们展示了一个 TIGIT 在维持 Tregs 功能稳定性方面的作用，因为 TIGIT 信号传导可阻止 Tregs 的转换 进入促炎细胞。此外，我们和其他人发现 TIGIT 及其配体 CD155 高度 以 GBM 表示。我们使用单细胞 RNAseq 的新初步数据表明，在 GBM 肿瘤浸润中 T 细胞、Tregs 表达最高水平的 TIGIT。抗 TIGIT 疗法现已进入癌症临床试验 最近，α-TIGIT mAb tiragolumab 获得 FDA 突破性认定。在本提案中，我们将 通过进行 α-TIGIT 和 α-PD 的 0/1 期临床试验，阐明了 GBM 中 T 细胞功能障碍的机制 1 mAb 作为检查点抑制剂，用于治疗复发性 GBM。试验设计可以确定安全性 这种组合，同时提供肿瘤样本和血液样本，用于对人类进行强有力的评估 α-TIGIT 和 α-PD-1 单独或组合的作用，具有转录组单细胞分辨率。我们的 机制假设是，虽然抗 PD-1 药物可以增强效应 T 细胞和调节性 T 细胞的增殖，但 将 α-TIGIT 添加到 α-PD-1 中会破坏 Treg 功能的稳定性并优化免疫反应。调查 根据这一假设，我们的试验采用了“机会之窗”设计，采用从实验室到临床到实验室的方法。 在切除复发肿瘤的手术之前，患者将被随机分配接受安慰剂、α-PD-1 或​​ α- TIGIT 可以单独使用，也可以组合使用。单细胞 RNAseq (10x) 将在基线血液上进行 来自试验患者的治疗血液和肿瘤标本。我们将比较克隆性和功能特征 肿瘤浸润性 T 细胞和效应 T 细胞，以及促炎性和抑制性肿瘤来源的频率 骨髓细胞。多重免疫荧光 (4i) 将用于空间验证。我们将分析循环 T 细胞与肿瘤浸润 T 细胞克隆相关，以识别外周相关性并开发非侵入性 T 细胞 新兴免疫反应的生物标志物。然后我们将模拟 PD-1 和 TIGIT 阻断对 T reg 的影响 使用健康供体 T reg 进行体外试验，并与试验中观察到的效果进行比较。通过这次全面的 方法，我们的研究将确定 PD-1 和 TIGIT 受体是否与 GBM 肿瘤中的 T 细胞结合 微环境会导致免疫功能障碍，导致中枢神经系统肿瘤无法进行免疫监视。