116 Novel targets for antibody–drug conjugate therapy

Abstract

the safe clinical profile of adenosine A2A receptor inhibitors (A2ARi) in Parkinson’s disease. Monoclonal antibodies (mAb) that block programmed death (PD)-1 or cytotoxic T lymphocyte antigen (CTLA-4) receptors have been associated with durable clinical responses against a variety of cancer types and hold great potential as novel cancer therapeutics. Metastasis is the main cause of cancer related deaths worldwide, and therefore we have studied experimental and spontaneous mouse models of melanoma and breast cancer metastasis to demonstrate the efficacy and mechanism of a combination of A2A receptor inhibitor in combination with various immune check point inhibitors. The combination of anti-PD-1 and A2A receptor inhibitor significantly reduces metastatic burden and prolongs the life of mice compared with either monotherapy alone. Importantly, the combination was only effective when the tumor expressed high levels of CD73, suggesting a tumor biomarker that at a minimum could be used to stratify patients that might receive this combination. The mechanism of the combination therapy was critically dependent on NK cells and interferon gamma, and to a lesser extent, CD8 T cells and the effector molecule, perforin. Consistent with the anti-metastatic role of NK cells, we observed significantly high number of NK cells in the lungs of tumor bearing mice after combination immunotherapy. Overall, our preclinical data provide a strong rationale to use A2ARi with anti-PD-1 mAb for the treatment of minimal residual and metastatic disease.