Project 1: Evaluating stem-like T cells and improving efficacy of checkpoint inhibitors in NSCLC

项目1：评估干细胞样T细胞并提高非小细胞肺癌检查点抑制剂的疗效

• 批准号: 10459440
• 负责人: Rafi Ahmed
• 金额: $ 53.73万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-10 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10459440
• 关键词: Address; Aftercare; Blood; CD28 Antigens; CD28 gene; CD8-Positive T-Lymphocytes; Cancer Patient; Cells; Characteristics; Clinical; Combined Modality Therapy; Data; Deuterium; Effector Cell; Epigenetic Process; Excision; FRAP1 gene; Genetic Transcription; Goals; Immune checkpoint inhibitor; Immune response; Immunofluorescence Immunologic; Immunologic Factors; Immunologics; Immunotherapy; Investigation; Label; Location; Lung Neoplasms; Malignant neoplasm of lung; Measures; Monitor; Neoadjuvant Study; Neoadjuvant Therapy; Non-Small-Cell Lung Carcinoma; Operative Surgical Procedures; PD-1 blockade; Patients; Phenotype; Play; Population; Proliferating; Regimen; Resected; Role; Signal Transduction; Site; T cell receptor repertoire sequencing; T-Cell Proliferation; T-Lymphocyte; T-Lymphocyte Subsets; Techniques; Testing; Therapy trial; Tissues; Treatment outcome; Tumor Tissue; Universities; anti-cancer; base; checkpoint inhibition; clinical efficacy; cytokine; draining lymph node; efficacy study; exhaust; improved; in vivo; mTOR Inhibitor; mTOR inhibition; mouse model; neoplastic cell; novel; peripheral blood; predictive marker; programmed cell death protein 1; response; stem; stem-like cell; targeted treatment; tumor

Programmed cell death-1 (PD-1) targeted therapies have changed the landscape of lung cancer treatment1. While some impressive results have been generated, the mechanisms that dictate which patients will, or will not, respond to this treatment are not well defined. It is important to understand the immunological factors associated with clinical responses not only to improve current therapies but also to identify predictive biomarkers. We have recently identified a novel population of PD-1+ TCF-1+ CD28+ CD8 T cells with stem- cell-like features in a mouse model of T cell exhaustion6-8. The proliferative burst of CD8 T cells after PD-1 blockade comes from this stem-like CD8 T cell population, and is dependent on signals from costimulatory molecule CD28. Importantly, our preliminary data suggest that stem-like CD8 T cells are present in non-small cell lung cancer (NSCLC) patients. Based on our observations, we hypothesize that the stem- like CD8 T cells play a critical role in successful PD-1 targeted therapies in NSCLC patients. One of the major goals of this proposal is to identify and characterize these stem-like CD8 T cells in NSCLC patients. Another important point to be addressed in this proposal is if the presence of these stem-like CD8 T cells correlates with proliferative responses of CD8 T cells as well as clinical efficacy of the immunotherapies. The following Specific Aims are proposed to achieve our goals: Aim 1: To identify and characterize the phenotype, location, and function of stem-like CD8 T-cells in lung cancer patients. Aim 1a. Characterize the transcriptional, epigenetic, and functional characteristics of tumor infiltrating stem-like CD8 T cells in NSCLC; Aim 1b. Determine the clonal relationship between T-cell populations in tumor, draining lymph node, and blood using TCR sequencing. Aim 2: To study the efficacy and immune responses of combined inhibition of PD-1 and mTOR in a neo-adjuvant therapy trial in NSCLC patients. Aim 2a. To examine the clinical efficacy of the combined inhibition of PD-1 and mTOR in a neo-adjuvant therapy trial for patients with early stage NSCLC. Aim 2b. To examine the correlation between immune responses and clinical efficacy of the combination therapy. Aim 3: To evaluate T cell dynamics in lung cancer patients using in vivo deuterium labeling. Aim 3a. To measure proliferation in T cell populations in NSCLC patients using in vivo deuterium labeling. Aim 3b. To determine the CD8 T cell populations that proliferate in response to mTOR and PD1 blockade using in vivo deuterium labeling.

程序性细胞死亡-1（PD-1）靶向治疗改变了肺癌治疗的前景1。 虽然已经产生了一些令人印象深刻的结果，但决定哪些患者会，或将 对这种治疗的反应还没有很好的定义。重要的是要了解免疫因素 与临床反应相关，不仅可以改善目前的治疗， 生物标志物。我们最近发现了一种新的PD-1+ TCF-1+ CD 28 + CD 8 T细胞群， T细胞耗竭小鼠模型中的细胞样特征6 -8。PD-1后CD 8 T细胞的增殖爆发 阻断来自这种干细胞样CD 8 T细胞群，并且依赖于来自共刺激的信号。 分子CD 28。重要的是，我们的初步数据表明，干细胞样CD 8 T细胞存在于非小细胞肺癌中。 细胞肺癌（NSCLC）患者。基于我们的观察，我们假设干细胞样CD 8 T细胞 在NSCLC患者成功的PD-1靶向治疗中发挥关键作用。其中一个主要目标是 这项研究的目的是鉴定和表征NSCLC患者中的这些干细胞样CD 8 T细胞。另一个重点 在这个建议中要解决的是，如果这些干细胞样CD 8 T细胞的存在与增殖性T细胞相关， CD 8 T细胞的应答以及免疫疗法的临床功效。以下具体目标是 为实现我们的目标： 目的1：鉴定和表征CD 8干细胞样T细胞的表型、位置和功能。 肺癌患者。目标1a。表征转录，表观遗传和功能特征， NSCLC中肿瘤浸润干细胞样CD 8 T细胞;目的1b.确定T细胞之间的克隆关系 使用TCR测序检测肿瘤、引流淋巴结和血液中的细胞群。 目的2：研究PD-1和mTOR联合抑制在一种免疫系统中的疗效和免疫应答。 NSCLC患者的新辅助治疗试验。目标2a。检查联合治疗的临床疗效 在早期NSCLC患者的新辅助治疗试验中抑制PD-1和mTOR。目标2b。到 检查免疫应答与联合治疗的临床功效之间的相关性。 目的3：应用体内氘标记技术研究肺癌患者T细胞的动态变化。目标3a。到 使用体内氘标记测量NSCLC患者中T细胞群的增殖。目标3b。到 使用体内免疫测定法测定响应于mTOR和PD 1阻断而增殖的CD 8 T细胞群， 氘标记