Combining Immune Therapy with Targeted Therapies to Improve Melanoma Survival

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Metastatic melanoma is one of the fastest growing tumor types in the US and our Veterans are at higher risk for developing melanoma. Recent therapeutic advances in immunotherapy utilizing immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced/metastatic melanoma. Antibodies targeting PD-1/PD-L1 (nivolumab, pembrolizumab, atezolizumab) and CTLA-4 (ipilimumab) evoke powerful anti-melanoma immune responses1,2,3. For metastatic disease, treatment with ipilimumab combined with nivolumab or nivolumab alone has demonstrated 5-year overall survival (OS) rates of 52% and 44%, respectively, with many patients experiencing exceptional response. Despite improvement in survival outcomes with ICIs, the majority of patients either fail to respond or develop resistance to ICIs. Novel therapeutic strategies are needed to improve outcomes for melanoma patients treated with ICI and to address acquired resistance. Development of new therapeutic approaches for melanoma patients who exhibit primary or acquired resistance to ICI therapy is the focus of our proposal. Our preliminary data from preclinical models indicate that combining the Ras mimetic, rigosertib (RGS) with ICI significantly reduces melanoma tumor growth, even in tumors that are poorly responsive to ICIs. RGS treatment results in a tumor immune microenvironment (TIME) enriched in CD8+T cells, dendritic cells (DCs) and natural killer cells, but does not reduce intratumoral myeloid-derived suppressor cells (MDSCs). RGS also increases CD40 expression on the melanoma tumor cells to facilitate immunogenic tumor cell death. In the absence of CD40 expression by tumor cells, or without CD8+T cells in the TIME, RGS’s anti-tumor activity is lost. We hypothesize that RGS-induced expression of CD40 in melanoma cells is a key component of RGS-enhanced anti-tumor immunity and that addition of a CD40 agonist to the RGS +ICI will enhance CD40- mediated immunogenic cell death. We also propose that addition of a CXCR1/2 antagonist to the RGS+ICI therapy will block MDSC recruitment to tumor, allowing prolonged CD8+T cell anti-tumor activity. Either of these approaches would further activate the anti-tumor immune response to induce tumor regression. We will pursue three specific aims to address this hypothesis. Aim 1: To determine the mechanism by which RGS induces expression of CD40 on tumor cells and to characterize the role of tumor cell CD40 in restoring response to ICI in immunocompetent mouse models of melanoma. Aim 2. To evaluate whether addition of a CD40 agonist antibody will enhance sensitivity of melanoma tumors to RGS + ICI and define mechanisms of response using mouse models and human organoid co-culture systems. Tumoral, immune, and transcriptome changes will be evaluated through multicolor flow cytometry and single cell(sc) RNAseq analysis to provide mechanistic insight on how this combined therapy modulates response to therapy. Aim 3: To determine whether RGS combined with a CXCR1/2 antagonist, can re-sensitize melanoma tumors to ICI therapy using similar approaches as for Aim 2. Significance: These studies will result in new therapeutic approaches to improve treatment of metastatic melanoma in our Veterans by enhancing response to ICI therapies or re-sensitizing ICI-resistant tumors to treatment with ICI.