Influence of T Cell Clonality on PD-1 Blockade in Non-Small Cell Lung Cancer

T 细胞克隆性对非小细胞肺癌 PD-1 阻断的影响

• 批准号: 9350540
• 负责人: NITHYA RAMNATH
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9350540
• 关键词: Affect; Aftercare; Algorithms; American; Antigenic Specificity; Antigens; Apoptosis; Autoantigens; Autologous; Binding; Bioinformatics; Biological Markers; Biometry; Biopsy; Blocking Antibodies; Blood; CD8-Positive T-Lymphocytes; Cancer Etiology; Cells; Cessation of life; Classification; Clinical; Clinical Protocols; Clinical Research; Clonality; Clone Cells; Complex; Computer Simulation; Data; Disease; Distal; Exhibits; Foundations; Future; Goals; Health; High-Throughput Nucleotide Sequencing; Histocompatibility; Immune Tolerance; Immune system; Immunologics; Immunologist; Immunotherapy; In complete remission; Individual; Knowledge; Lead; Libraries; Ligands; Long-Term Survivors; Major Histocompatibility Complex; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Mediator of activation protein; Non-Small-Cell Lung Carcinoma; Outcome; PDCD1LG1 gene; Pathologist; Patients; Peptides; Physicians; Physiologic pulse; Population; Protocols documentation; Research; Resistance; Role; Scientist; Survival Rate; T cell response; T cell therapy; T-Cell Antigen Receptor Specificity; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; Time; Toxic effect; Transfection; Transgenic Organisms; Translational Research; Tumor Immunity; Veterans; War; actionable mutation; adaptive immune response; anergy; biomarker discovery; drug efficacy; effective therapy; exceptional responders; exhaustion; fighting; health care economics; high risk; high risk population; immune checkpoint blockade; immunogenic; multidisciplinary; neoplastic cell; peripheral blood; personalized approach; personalized immunotherapy; public health relevance; receptor; response; response biomarker; targeted treatment; treatment response; tumor; tumor microenvironment; tumor specificity

DESCRIPTION (provided by applicant): Lung cancer is a devastating disease that affects American War Veterans disproportionately and is the most common cause of cancer related death. Metastatic non-small cell lung cancer (NSCLC) has a 2 year survival rate of 10%. A majority of Veterans do not present actionable driver mutations in their cancers that can be treated with targeted therapies. Immunotherapy, involving checkpoint blockade (CPB) unleashes the adaptive immune response and has emerged as a promising therapeutic strategy in NSCLC providing some dramatic and durable responses. However, the vast majority of patients do not have a sustained durable response. There is a critical need to understand determinants of durable response to these promising therapies to enable our long term goal of more Veterans becoming long term survivors. Currently approved CPB for NSCLC involve antibodies that block programmed death 1 (PD-1) on activated T cells or its ligand programmed death-ligand1 (PD-L1). Biomarkers to date have focused on PD-L1 expression and T cell subsets in the tumor microenvironment, leading to a useful classification ranging from highly immunogenic to immunologically quiet tumors that may define to some degree sensitivity or resistance to CPB. However, these indirect biomarkers do not define the T cell repertoire of the effector T cells, which are the final mediators of response to CPB. The most distal step in activating a specific T cell response is the binding of the T cell receptor (TCR) to the major histocompatibility: peptide complex. Advances in TCR sequencing allow us unprecedented access to the T cell repertoire, which contains the diversity of specific T cell clones responsible for anti-tumor immunity. Identifying these specific T cell clones can lead to future trials that expand these clones in a personalized approach to immunotherapy to potentially lengthen the duration of sustained response. We hypothesize that: (1) baseline tumor TCR repertoire diversity will be significantly higher in patients who exhibit a DCB at 6 months to PD-1 inhibition through CPB, as compared with patients without DCB (i.e., whose cancer progresses before 6 months on-treatment), (2) abundant T cell clones in the blood will exhibit high degree of overlap with tumor T cell clones in patients with DCB and (3) Exceptional responders will present unique TCR α and β sequences that will recognize neoantigens expressed in patient’s tumor in an HLA restricted fashion. We will test our hypotheses through the following aims: 1: To determine the role of tumor T-cell receptor (TCR) diversity in patients with durable clinical benefit (DCB) to PD-1 inhibition. 2: To assess the proportion of shared TCR sequences between tumor and peripheral blood at time points before and after PD-1 inhibition as determinants of DCB. 3: To identify (neo) antigen specificity of TCR in exceptional responders. We will conduct these aims in an ongoing protocol to understand determinants of response to immunotherapy in Veterans with NSCLC. We have assembled a multi- institutional, multidisciplinary collaborative team of immunologists, physician scientists with expertise in lung cancer clinical and translational research, pathologists, and individuals with biostatistics and bioinformatics expertise to achieve our aims. The proposed research will, for the first time, identify a tumor-specific T cell repertoire that can inform trials of autologous, antigen-specific, adoptive T cell therapy combined with CPB in this high risk population of Veterans with NSCLC.

描述（由申请人提供）：肺癌是一种影响美国战争的毁灭性疾病 退伍军人比例不成比例，是癌症相关死亡的最常见原因。转移性非小细胞 肺癌（NSCLC）的 2 年生存率为 10%。大多数退伍军人没有提供可操作的司机 可以通过靶向治疗治疗的癌症突变。免疫疗法，涉及检查点 阻断（CPB）释放适应性免疫反应，并已成为一种有前途的治疗方法 非小细胞肺癌 (NSCLC) 的策略提供了一些显着且持久的反应。然而，绝大多数患者确实 没有持续持久的反应。迫切需要了解持久性的决定因素 对这些有希望的疗法的反应，使我们的长期目标成为更多退伍军人成为长期 幸存者。目前批准用于 NSCLC 的 CPB 涉及阻断程序性死亡 1 (PD-1) 的抗体 激活的 T 细胞或其配体程序性死亡配体 1 (PD-L1)。迄今为止的生物标志物主要集中在 PD-L1 肿瘤微环境中的表达和 T 细胞亚群，从而产生有用的分类，范围从 对免疫安静的肿瘤具有高度免疫原性，可能在某种程度上定义敏感性或耐药性 到CPB。然而，这些间接生物标志物并不能定义效应 T 细胞的 T 细胞库，这些 T 细胞库是 对 CPB 反应的最终中介。激活特定 T 细胞反应的最远端步骤是 T 细胞受体 (TCR) 与主要组织相容性：肽复合物的结合。 TCR 的进展 测序使我们能够前所未有地获得 T 细胞库，其中包含特定 T 细胞的多样性 负责抗肿瘤免疫的细胞克隆。识别这些特定的 T 细胞克隆可以为未来的试验带来帮助 以个性化的免疫治疗方法扩展这些克隆，从而有可能延长治疗的持续时间 持续的反应。我们假设：（1）基线肿瘤 TCR 库多样性将显着增加 与患者相比，6 个月时表现出 DCB 的患者通过 CPB 抑制 PD-1 的效果更高 没有 DCB（即，其癌症在治疗 6 个月前进展），(2) 体内有丰富的 T 细胞克隆 DCB 患者的血液将表现出与肿瘤 T 细胞克隆的高度重叠，并且 (3) 例外 应答者将呈现独特的 TCR α 和 β 序列，这些序列将识别患者体内表达的新抗原 HLA 限制性肿瘤。我们将通过以下目标来检验我们的假设：1： 确定 肿瘤 T 细胞受体 (TCR) 多样性在 PD-1 持久临床获益 (DCB) 患者中的作用 抑制。 2：评估肿瘤和外周血之间共享TCR序列的比例 PD-1 抑制之前和之后的时间点作为 DCB 的决定因素。 3：识别（新）抗原 TCR 在特殊反应者中的特异性。我们将在一项持续的协议中实现这些目标 了解非小细胞肺癌退伍军人对免疫治疗反应的决定因素。 我们已经组装了一个多 由具有肺专业知识的免疫学家、医师科学家组成的机构、多学科协作团队 癌症临床和转化研究、病理学家以及生物统计学和生物信息学人员 专业知识来实现​​我们的目标。拟议的研究将首次鉴定出肿瘤特异性 T 细胞 可以为自体、抗原特异性、过继性 T 细胞疗法与 CPB 相结合的试验提供信息 患有非小细胞肺癌的退伍军人的高危人群。