Project 5: Microenvironment manipulation using anti-angiogenics to improve immunotherapy in melanoma

PROJECT SUMMARY/ABSTRACT Monoclonal antibody mediated blockade of checkpoint receptors like PD-1, CTLA-4, and LAG-3 have had unprecedented success in the treatment of melanoma patients. Despite these successes, many melanoma patients do not respond, and some subtypes of melanoma like acral, mucosal, and uveal melanoma remain remarkably resistant to immune based therapies. We and other have shown that the metabolic microenvironment in melanoma, driven by the metabolism of the tumor cells themselves, can create a barrier to immunotherapeutic success. Key among these are alterations to the vasculature and the generation of a hypoxic tumor microenvironment. We have employed anti-angiogenics as a means to correct tortuous vacsculature, reduce hypoxia, and allow for enhanced T cell infiltration into melanoma tumors. First piloted in mouse models, this Project takes advantage of a completed clinical trial in melanoma patients that have progressed on front-line PD1 +/- CTLA-4 blockade. Of note, several acral and mucosal melanoma patients are included in this trial. This trial employs axitinib, a VEGFR tyrosine kinase inhibitor, along with nivolumab in the immunotherapy refractory setting. This combination had an impressive disease control rate amongst refractory individuals, and was associated with alterations to the local tumor immune microenvironment. In this Project, we will deeply profile how the tumor microenvironment is modulated by axitinib and nivolumab, using single cell RNAseq and spatial transcriptomics. Further, we will correlate those alterations to measure of clinical responses seen in patients. Ultimately, the goal is to further our knowledge of immunotherapy resistance, uncover the molecular and cellular signatures that define success in axitinib+nivolumab co-therapy, and to use those data to define the targets for clinical investigation.