Identification and characterization of novel immunosensitizing therapeutics for melanoma (VAC3P.1060)

Abstract

Abstract Recent breakthroughs in the field of immunotherapy have revolutionized the treatment of melanoma patients. Specifically, immune checkpoint blockade of CTLA-4 and PD-1 have prolonged overall survival in a subset of melanoma patients. Despite dramatic and durable results in some cases, low overall response rates to these therapies leave the majority of melanoma patients without effective immunotherapeutic treatment options. In order to identify immunotherapies which might offer improved response rates with the potential to be rapidly translated to the clinic, we developed a high-throughput screen and tested over 2000 compounds, many of which are FDA-approved for various malignancies or other diseases. The screen revealed distinct families of multikinase inhibitors and DNA-damage repair inhibitors as novel melanoma immunosensitizing agents. We show that these two classes of drugs can reduce the expression of various immunosuppressive molecules (e.g. PD-L1, CD155) on the cell surface of a wide variety of genetically distinct human melanoma cell lines. Notably, the drugs also increased the expression of HLA and melanoma antigens in most cases. Importantly, preliminary data suggests that drug treatment sensitizes melanoma cells to T cell mediated cytotoxicity. Further preclinical studies are underway to verify drug targets, identify mechanisms of action, and establish in vivo anti-tumor activity.