Generation of syngeneic, mutation-driven melanomas in an autoimmune-prone mouse to improve therapeutic efficacy without immunotoxicity - PROJECT ABSTRACT Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of melanoma, providing durable, curative responses to a proportion of patients with advanced and metastatic disease. Nonetheless, there remains several obstacles that impact the clinical utility of ICI treatment, with most significantly a lack of understanding of which patients are at risk for treatment resistance and/or immune-mediated side effects. Over half of all patients receiving ICIs display resistance, and biomarkers to predict benefit from ICI treatment remain limited. To combat therapeutic resistance, combination approaches that target multiple immunoregulatory markers have been clinically approved. While combinations improve treatment efficacy, they also precipitate an increase in the frequency of severe side effects, known as immune-related adverse events (irAEs). These irAEs can impact nearly every organ system and lead to significant morbidity, discontinuation of cancer-curing treatments, and even death. Therapies used to combat irAEs, such as corticosteroids and cytokine inhibitors, have been increasingly suggested to limit the efficacy of ICI treatment, highlighting the need for irAE-specific options that uncouple side effects from anti-tumor immunity to improve treatment outcomes for patients with melanoma. One major limitation for understanding optimal treatment combinations is the lack of models that assess both therapeutic safety and efficacy in the same system. This is due to many preclinical melanoma models being developed in autoimmune-resistant or immunodeficient mice that do not develop irAEs following exposure to ICIs, or other immune-based and targeted treatments. Additionally, the ability to identify systemic interactions between tumor-directed and host immunity cannot be assessed using current in vitro and ex vivo approaches, due to the heterogeneity and inaccessibility of irAE-affected tissue. We will engineer syngeneic models of melanoma, initiated by oncogenic drivers, in autoimmune-prone non-obese diabetic (NOD) mice. A series of NOD melanoma cell lines will be evaluated for their genetic, transcriptional, and immune phenotypes to select for heterogeneity in melanoma models, consistent with diverse clinical features. Using these models, we will assess the efficacy and safety of ICI treatments, either with or without targeted therapies to the oncogenic drivers employed for melanomagenesis (namely mutant Braf and Nras) and will define novel anti-irAE treatments that do not compromise ICI therapeutic efficacy. Together, this first-in-class model system of melanoma will enhance our ability to understand and treat complex clinical problems, such as treatment resistance and toxicity, and lead to improved therapeutic strategies with enhanced safety and efficacy for patients with melanoma. By advancing mammalian mouse models through combining the etiology of melanomagenesis alongside diverse host immune responses that reflect clinical conditions, such as irAE susceptibility, we will enhance the translational applicability of preclinical systems to overcome the bottleneck in therapeutic innovation.
