Grant: Project Grant

Non-small cell lung cancer (NSCLC) is the leading cause of cancer deaths with a 5-year survival of 1% for patients with stage IV disease. Recent clinical trials using novel precision medicine approaches such as therapeutic antibodies and antibody drug conjugates have not yielded encouraging results for NSCLC patients. On the other hand, immune checkpoint inhibitors such as pembrolizumab are approved in combination with chemotherapy for NSCLC with modest benefits, and only a small fraction of patients benefiting. Nectin-4 is a protein that is overexpressed in 60-70% NSCLC cells but not in healthy cells, and is responsible for disease aggressiveness. Therefore, this protein can serve as a target for diagnosis and treatment of NSCLC. No radioimmunoconjugates (antibody conjugates RIC) targeting Nectin-4 has been validated preclinically or evaluated in clinical trials. This work will focus on developing and testing new therapeutic RICs against Nectin-4 positive NSCLC. We will develop new fully human RICs that are tagged with potent radioisotopes actinium-225 (225Ac) or terbium-161 (161Tb), effective enough to eliminate primary and metastatic tumor cells that express this protein. These new therapeutics will be tested in a variety of mouse cancer models. We will investigate if these radiolabeled antibodies can prime cells in the tumor microenvironment, and take advantage of this by combining them with immune checkpoint inhibitor(s) for enhanced efficacy. These therapeutic RICs are expected to improve the survival of NSCLC patients when translated in clinical trials.