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

描述(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)的两年生存率为10%。大多数退伍军人没有提出可起诉的司机 他们癌症中的突变可以用靶向治疗来治疗。涉及检查站的免疫疗法 阻断(CPB)释放获得性免疫反应，已成为一种有前途的治疗方法 非小细胞肺癌的战略提供了一些戏剧性和持久的回应。然而，绝大多数患者都这样做。 没有持续、持久的回应。迫切需要了解耐久性的决定因素 回应这些有希望的疗法，使我们的长期目标成为更多的退伍军人成为长期的 幸存者。目前批准的用于非小细胞肺癌的体外循环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)。到目前为止，生物标志物主要集中在PD-L1 在肿瘤微环境中的表达和T细胞亚群，导致一个有用的分类，范围从 高度免疫原性到免疫平静的肿瘤，可能在某种程度上定义为敏感或耐药 转到CPB。然而，这些间接生物标记物并不定义效应器T细胞的T细胞库，它们是 应对CPB的最终调解人。激活特定T细胞反应的最末端步骤是 T细胞受体(TCR)与主要组织相容性：多肽复合体的结合。TCR的研究进展 测序让我们史无前例地接触到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细胞克隆可能会导致未来的试验 以一种个性化的免疫治疗方法扩大这些克隆，以潜在地延长 持续回应。我们假设：(1)基线肿瘤TCR谱系的多样性将显著 与患者相比，6个月后通过体外循环对PD-1抑制表现出DCB的患者更高 没有DCB(即其癌症在治疗前6个月进展)，(2)在 DCB患者血液与肿瘤T细胞克隆高度重叠，(3)异常 应答者将呈现独特的TCRα和β序列，识别患者体内表达的新抗原 肿瘤以人类白细胞抗原限制的方式。我们将通过以下目标来检验我们的假设：1： 要确定 肿瘤T细胞受体(TCR)多样性在PD-1长期临床受益患者中的作用 抑制力。2：评估肿瘤与外周血共享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。我们将在一项正在进行的议定书中实现这些目标 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- 机构，多学科协作团队，由具有肺部专业知识的免疫学家、内科科学家组成 癌症临床和转化性研究、病理学家和具有生物统计学和生物信息学的个人 专业知识来实现我们的目标。这项拟议的研究将首次确定一种肿瘤特异性T细胞 可为自体、抗原特异性、过继T细胞疗法与体外循环联合试验提供信息的曲目 退伍军人中患有非小细胞肺癌的高危人群。

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.