PD-1/PD-L1

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.

Several ALK tyrosine kinase inhibitors (TKIs) are available for the treatment of ALK-rearranged non-small cell lung cancer (NSCLC), but resistance to all ALK TKIs (including crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib) has been reported and occurs through a variety of mechanisms. Once patients develop resistance to available ALK inhibitors, they are typically treated with cytotoxic chemotherapy rather than immunotherapy since response rates to PD-1 pathway inhibitors in this population are very low. However, our work in mouse models of ALK-positive NSCLC has demonstrated that a vaccine generated against the rearranged portion of ALK can both prevent the development of ALK-positive tumors and also more effectively treat them once they arise. In addition, we have recently found evidence of an anti-ALK immune response in patients, as a subset of them generate spontaneous ALK autoantibodies.

To more deeply characterize anti-ALK immunologic responses in patients, we propose (Aim 1) to determine if the presence of anti-ALK antibodies correlates with progression-free and overall survival among patients with ALK-positive NSCLC, and (Aim 2) to directly identify and validate antigenic ALK peptides in different HLA-haplotype backgrounds. Antigenic peptides that are identified through these studies will serve as the basis for a therapeutic ALK peptide vaccine clinical trial, for which funding has been secured independently.