Project Summary/Abstract: Project 3 This project evaluates a novel combination immunotherapy approach applicable to a broad range of accessible skin cancers. Specifically, we will target both a potent chemotherapeutic agent to induce immunogenic cell death and an innate immune stimulant specifically to the 3D space of the tumor microenvironment (TME) of cutaneous squamous cell carcinomas (cSCCs). This strategy is enabled by a dissolvable microneedle array (MNA) device developed and produced in our laboratories. These studies represent the first tumor immunotherapy clinical trials utilizing spatially and kinetically controlled delivery of a synergistically acting combination therapy. This approach uniquely enables individualized patient-specific immunotherapy through low dose localized drug delivery, obviating obstacles related to tumor and antigen heterogeneity and reducing/preventing adverse effects associated with systemic exposure. Thus, the strategy could be applicable to a large patient population, including those who are immunosuppressed or have or are at risk for autoimmune diseases, as well as a broad range of skin cancers through a completely non-specific and generalizable MNA “band-aid”-like delivery platform. Our hypothesis is that in situ MNA-directed immunotherapy (MNA-IT) will kill tumor cells locally and induce a proinflammatory TME, enabling immune elimination of the treated tumor while potentially inducing durable systemic immunity. It is supported by both preclinical studies and results from our own clinical trials. To evaluate MNA-IT in patients with cSCCs, we will perform an iterative phase Ib/II clinical trial evaluating MNA-IT single and combination therapies utilizing dissolving MNAs to deliver doxorubicin, a STING agonist, or both directly to the TME of cSCCs. This will be evaluated in both immunocompetent patients and in immunosuppressed transplant recipients. We will evaluate safety, clinical, and pathologic responses, and explore therapy-induced changes in the TME and peripheral blood before, during, and after therapy. Through forward reaching pre-clinical studies, we will develop a “next-generation” combination MNA- IT to achieve sustained release of immune checkpoint inhibitors in the TME to support a sustained pro- inflammatory TME favoring the induction of systemic tumor immunity.