2018 ALK Positive This grant was funded by ALK Positive Mark Awad, MD, PhD Dana-Farber Cancer Institute Boston MA Research Summary Dr. Awad’s team has discovered that a subset of ALK-positive lung cancers is “immuno-reactive” – patients produce antibodies against the modified ALK protein. However, the role of these antibodies in the progression of ALK-positive lung cancer is not known. Dr. Awad’s team will determine whether patients with antibodies against the modified ALK protein respond differently to ALK tyrosine kinase inhibitors than those patients who do not produce antibodies. His team will next characterize the antibody response to determine which parts of the ALK protein trigger an immune response, with the ultimate goal of producing personalized ALK vaccines. Technical Abstract 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. Key words Acquired resistance Anaplastic lymphoma kinase (ALK) Immunotherapy Metastatic Non-small cell lung cancer (NSCLC) PD-1/PD-L1 Stage IV Targeted therapy Tyrosine kinase inhibitors (TKIs)
