2018 ALK Positive This grant was funded by ALK Positive Justin Gainor, MD Massachusetts General Hospital Boston MA Research Summary ALK-positive lung cancers do not respond to immune checkpoint inhibitors such as PD1 or PD-L1 inhibitors. Dr. Gainor’s project aims to understand why these tumors are resistant to conventional immunotherapy. Are there cancer-cell-specific, tumor-microenvironment-specific, patient-immune-cell-specific mechanisms, or a combination of these factors that contribute to the lack of response to immunotherapy? His team will identify potential biomarkers that may help predict which ALK-positive lung cancers will respond to PD1/PD-L1 inhibitors. His ultimate goal is to use the findings from his project to develop novel immunotherapy strategies such as T-cell-based therapies customized to individual ALK patients. Technical Abstract ALK rearrangements define a distinct molecular subset of NSCLC and confer sensitivity to treatment with ALK tyrosine kinase inhibitors (TKIs). These agents have produced dramatic improvements in clinical outcomes among ALK-rearranged (ALK+) patients, yet acquired resistance remains a major challenge. Thus, there is an urgent need for alternative therapeutic approaches for this disease. Recently, immune checkpoint inhibitors targeting negative regulators of the immune response (e.g., PD-1/PD-L1) have emerged as powerful new therapies in NSCLC. In preliminary analyses, we and others have observed that ALK+ lung cancers are generally less responsive to immune checkpoint inhibitors. We hypothesize that distinct immune-based strategies may therefore be needed for ALK+ lung cancers. To inform these strategies, we will investigate 1) tumor-intrinsic factors associated with immunogenicity in ALK+ tumors (e.g., neoantigens, tumor mutation burden), 2) tumor-immune cell interactions (e.g., PD-L1 expression, alternative checkpoint expression, antigen presentation), and 3) endogenous T cell responses against ALK in the peripheral blood. Together, these studies may lay the groundwork for development of biomarkers informing optimal delivery of PD-(L)1 therapy in ALK+ lung cancers, while also promoting the development of novel combinations and approaches, including autologous cellular therapies directed against ALK. Key words Anaplastic lymphoma kinase (ALK) Immunotherapy Metastatic Non-small cell lung cancer (NSCLC) PD-1/PD-L1 Stage IV Targeted therapy Tyrosine kinase inhibitors (TKIs)
