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 ? and ? 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.
The proposed research is relevant to Veterans health because the discovery of biomarkers for response to anti-PD-1 immunotherapy in metastatic NSCLC could help select patients with NSCLC who are most likely to benefit from PD-1 blockade, therefore decreasing toxicity and increasing drug efficacy, with significant immediate impact on both clinical outcomes and present-day healthcare economics