Overcoming Innate Immune Resistance in ALK-Rearranged Lung Cancer

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.