Role of PD-1/PDL-1 in Lung Carcinogenesis and Therapy

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DESCRIPTION (provided by applicant): The outcomes of stage III non-small cell lung cancer seem to reach a plateau following two decades of clinical research by optimally combining cisplatin-based chemotherapy and thoracic radiotherapy. Escalation of radiotherapy dose failed to improve outcome as demonstrated by the recent RTOG 0617 trial. Frequent failures with systemic recurrence following concurrent chemoradiation contribute to disappointing cure rate of locally advanced lung cancer. Encouraging clinical data have come from recent immunotherapeutic trials. Moreover, combining radiotherapy with immunotherapy has yielded potentially synergistic systemic/abscopal (i.e. distant) effects. Molecular studies have pointed to a crucial role for immunomodulating B7-H1 or PDL-1/PD-1 pathway in the control of T cell activation and in maintaining immunotolerance induced by tumor cells. PDL-1, a ligand of PD-1 is over-expressed on human tumors from different tissue origins whereas PD-1 receptor is expressed in T cells to prevent T-cell overactivation in physiological conditions. In certain types of cancer, higher level of PDL-1 has been correlated with poor prognosis. Tumor-induced PDL-1 utilizes multiple mechanisms to evade host immune surveillance, including 1) promoting T cell anergy, exhaustion, unresponsiveness and apoptosis, 2) inducing the expansion of regulatory T cells, and 3) enhancing tumor therapeutic resistance. Four therapeutic biologics targeting the human PD-1 are currently in clinical trials, with promising results [1]. PD-1/PDL-1-blocking mAbs are being evaluated to treat various advanced cancers [2]. Recent reports on clinical trials using BMS-936558 (a PD-1 inhibitor) and BMS-936559 (a PDL-1 inhibitor) showed significant objective responses (18% among patients with non-small-cell lung cancers). The clinical response is also durable, suggesting immune memory. Tumor PDL-1 over-expression correlates with anti-tumor responses in a small patient cohort, suggesting that PDL-1 could be a potential biomarker for PD-1 inhibitors. Integrating PD-1 inhibitors into the standard chemoradiation regimens for locally advanced non-small cell lung cancer potentially breaks immune tolerance against lung cancer cells and synergistically activates T cells as cancer antigens are released following cytotoxic chemoradiation treatment. These immune responses may impact distant microscopic metastases, which are sources for treatment failures in this population of patients. We hypothesize PD-1 and PDL-1 modulate lung carcinogenesis and therapeutic response to chemotherapy and radiotherapy and combining PD-1/PDL-1 inhibitors with chemoradiation regimens improves therapeutic outcomes of lung cancer patients: Aim 1: Determine the role of PD-1 and PDL-1 in carcinogenesis and therapeutic response of lung cancer; Aim 2: Determine the efficacy and toxicities of combining PD-1 or PDL-1-blocking antibody and thoracic radiotherapy in an orthotopic mouse model of lung cancer. The proposed studies will help us to understand the role of PD-1 and PDL-1 in lung carcinogenesis and therapeutic response of lung cancer.