Project Summary Abstract: Overall Skin cancers are the most common cancers in the US, including melanoma and cutaneous squamous cell carcinoma (cSCC). Despite substantial progress, most patients with advanced melanoma do not benefit from treatment, while the most potent therapies of melanoma also cause serious adverse events. In addition, we still need safe, efficient, and cost-effective therapies of cSCCs in immunocompetent and immunodeficient patients that could transform treatment and outcomes for these at-risk patient populations. The overall goal of the Melanoma and Skin Cancer Program (MSCP SPORE) is to develop novel translational research to overcome the hurdles of current therapies of melanoma and cSCCs. Each of the three Projects results from seminal and innovative findings made by the investigators of the MSCP SPORE, which are translated into new combinatorial immunotherapy trials for patients with melanoma and skin cancers. Project 1 will assess the clinical and immunological activity of anti-LAG3 alone and in combination with anti-PD1, for the first time, in treatment-naïve MPs who have not received prior ICB. Project 2 will evaluate the efficacy, and immunogenicity of CMP-001 (CMP), a type A CpG, in PD1 naïve metastatic melanoma in the context of a phase II/III randomized clinical trial with intratumoral CMP and nivolumab (CMP/nivo) vs. nivo. Project 3 will test a novel microneedle array (MNA) device to deliver both a potent chemotherapeutic agent to induce immunogenic cell death and an innate immune stimulant into accessible cSCCs. This approach will be tested both in immunocompetent and immunosuppressed cancer patients.The MSCP SPORE will use innovative strategies to determine the mechanisms of response and resistance to the proposed therapies. The investigators will be supported by shared-facility cores to provide state-of-the-art expertise and economies-of-scale in 1) sample collection and processing, translational pathology, data annotation, biospecimen repository, and immunomonitoring (Core 1); and 2) biostatistics and bioinformatics (Core 2), supporting rigor and reproducibility across all research projects. The Career Enhancement Program (CEP) and Development Research Program (DRP) will attract talented basic, translational, and clinical investigators into melanoma research. The MSCP SPORE leverages Hillman Cancer center (HCC) resources and institutional commitment with state-of-the-art research and clinical facilities, clinical regulatory services to support clinical trial coordination, and translational research. The MSCP SPORE includes outstanding External and Internal Advisory Boards (EAB, IAB), an Executive Committee that is highly experienced in the successful management of SPOREs and Patient Advocates. The organizational structure of the MSCP SPORE will facilitate thorough following of progress and managing of potential hurdles for each project. The MSCP SPORE will share data with the scientific community and other SPO...