PI:
Helen Moore, Ph.D.
Project Summary
Advances in systemic immunotherapy for metastatic melanoma have revolutionized outcomes for the majority of patients, with more than half of all patients experiencing long term survival. Yet, this is of little consolation to the many patients who fail to respond to treatment. In particular, outcomes for patients with rare melanoma variants (acral and mucosal) have barely budged over the last decade with these therapies. Though originating from melanocytes, these rare melanoma variants share few characteristics with the sun-exposed cutaneous melanomas. They differ in their driver mutations, tumor mutational burden, tumor microenvironments, and most importantly response to treatment. Compounding this problem, these tumors represent approximately 3% of all melanomas. Human data are scarce and murine models with a competent immune system have not been developed for these rare variants. These rare melanomas disproportionately affect people of color, making the lack of efficacious therapies an important health equity issue. Strategies for both the identification of therapeutic targets and the testing of novel therapies are desperately needed.
To overcome these limitations, we have formed a team with the complementary expertise and capabilities needed to make progress on this problem. We have established a pipeline for tumor and immune monitoring through comparative oncology, studying naturally-occurring melanomas in canine patients. These melanoma variants, especially mucosal and acral, are the most common types of melanoma in canine patients. At our institution, we treat more than 10 times the number of canine patients with these melanomas than their human counterparts. Canines have even fewer treatment options than humans with mucosal and acral melanoma, as there are currently no approved, commercially-available immune checkpoint inhibitors for canines. To remedy this, our group has developed a novel immunotherapy treatment for these patients in the form of a lipid nanoparticle vaccine targeting the melanoma antigen GD3. From our initial treatment of more than 180 canine melanoma patients, we have identified this vaccination strategy’s potential to reprogram aspects of the tumor microenvironment and bridge both the innate and adaptive immune system toward an anticancer response. From these canine patients’ initial tumor samples and peripheral blood sampling we have identified key cellular players and pathways in the anticancer immune response to vaccination.
Pairing this real-world information with the available literature on the anti-melanoma immune response in human and canine patients, we have developed a mechanistic math model that, when complete, will be able to predict the response to therapy for each individual patient. It can pinpoint gaps in the coordinated immune response in individual patients and identify novel therapeutic targets. This model can also be used to optimize combination immune strategies to overcome resistance to treatment. In this proposed work, we will further refine and validate our mechanistic model using data from peripheral blood and tumor tissue sampling in canine patients receiving our novel lipid nanoparticle vaccine. This on-treatment tumor sampling is essential to correlating the peripheral blood cellular changes with those seen in the tumor microenvironment in response to therapy. This is difficult to capture in human studies and not currently possible to replicate in mouse preclinical models. From this analysis, we will then refine the key aspects of the model and calibrate this predictive model and run it in parallel for human patients with rare melanoma variants and immunotherapy-resistant melanoma who are receiving either standard immunotherapy or novel lipid nanoparticle vaccines. At conclusion of this project, we will have a validated, predictive mechanistic math model that can be used for personalized therapy selection in both human and canine subjects, can identify novel combination strategies to overcome resistance to therapy, and can identify novel targets for rare melanoma variants for further human clinical application.
Publications
UF Division of Hematology & Oncology Divisional News: Article