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.

摘要