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: 9979781
• 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 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9979781
• 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; Clone Cells; Complex; 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; Nonmetastatic; Outcome; Pathologist; Patients; Peptides; Physicians; Physiologic pulse; Protocols documentation; Research; Resistance; Role; Scientist; Survival Rate; T cell clonality; T cell receptor repertoire sequencing; T cell response; T cell therapy; T-Cell Antigen Receptor Specificity; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; T-cell receptor repertoire; Testing; Therapeutic; Time; Toxic effect; Transfection; Transgenic Organisms; Translational Research; Tumor Immunity; Veterans; War; adaptive immune response; anergy; biomarker discovery; driver mutation; drug efficacy; effective therapy; effector T cell; exceptional responders; exhaustion; fighting; health care economics; high risk; high risk population; immune checkpoint blockade; immunogenic; in silico; military veteran; multidisciplinary; neoantigens; neoplastic cell; peripheral blood; personalized approach; personalized immunotherapy; programmed cell death ligand 1; programmed cell death protein 1; 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）：肺癌是一种毁灭性的疾病，影响美国战争 退伍军人不成比例，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年存活率为10%。大多数退伍军人不存在可操作的驱动程序 他们的癌症中的突变可以用靶向治疗来治疗。免疫治疗，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 在NSCLC中的策略提供了一些显著和持久的反应。然而，绝大多数患者 没有持续的持久反应。迫切需要了解持久性的决定因素， 对这些有前途的疗法的反应，使我们的长期目标，更多的退伍军人成为长期 幸存者目前批准的用于NSCLC的CPB涉及阻断程序性死亡1（PD-1）的抗体， 活化的T细胞或其配体程序性死亡配体1（PD-L1）。迄今为止，生物标志物主要集中在PD-L1上 表达和T细胞亚群在肿瘤微环境中，导致一个有用的分类范围从 对免疫学上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 CPB。然而，这些间接生物标志物并不限定效应T细胞的T细胞库，其是免疫性的。 CPB反应的最终介质。激活特定T细胞反应的最远步骤是 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，其中包含特异性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细胞克隆可以导致未来的试验 以个性化的免疫治疗方法扩展这些克隆， 持续的反应。我们假设：（1）基线肿瘤TCR库多样性将显著增加， 与患者相比，在6个月时通过CPB表现出DCB至PD-1抑制的患者更高 没有DCB（即，其癌症在6个月治疗前进展），（2）在肿瘤细胞中的丰富的T细胞克隆， 血液将表现出与DCB患者的肿瘤T细胞克隆高度重叠，以及（3）异常 应答者将呈现独特的TCR α和β序列，其将识别在患者组织中表达的新抗原。 HLA限制性肿瘤我们将通过以下目标来测试我们的假设：1： 以确定 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 抑制作用2：评估肿瘤和外周血之间共有TCR序列的比例 在PD-1抑制前后的时间点作为DCB的决定因素。3：鉴定（neo）抗原 TCR在特殊应答者中的特异性。我们将在一项持续的议定书中实现这些目标， 了解非小细胞肺癌退伍军人免疫治疗反应的决定因素。 我们已经建立了一个多- 由免疫学家、具有肺部专业知识的医生科学家组成的机构性多学科协作团队 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。这项拟议中的研究将首次确定一种肿瘤特异性T细胞 可以为自体、抗原特异性、过继性T细胞疗法联合CPB试验提供信息， 这一高风险的退伍军人NSCLC人群。