Evaluating a multimodality platform of tissue, blood and advanced imaging-based biomarkers to predict response to neoadjuvant immunotherapy and radiotherapy in melanoma

PROJECT SUMMARY Melanoma is the fifth most common cancer in the United States. While immunotherapy has improved treatment options, patients who do not respond to immune checkpoint inhibitors (ICI) continue to have poor prognosis. Developing a strategy to identify patients with high likelihood of response to treatment intensification with a novel combination of neoadjuvant ICI and radiotherapy (RT) could significantly improve outcomes. In this proposal, we plan to create a novel, multimodality platform to predict for responders to ICI+RT by leveraging a pilot, phase 2 clinical trial evaluating pathologic response and long-term outcomes after neoadjuvant ICI+RT, in mucosal melanoma, a subtype of melanoma enriched for immunotherapy refractory patients. As part of the “Preoperative Radiotherapy and Immunotherapy in Sinonasal and Anorectal Melanoma (PRISAM)” study, sinonasal and anorectal melanoma patients with non-metastatic disease receive 1-2 cycles of neoadjuvant ICI before starting neoadjuvant RT (with tissue-, blood-, and advanced imaging-based biomarkers collected before each change in treatment modality). This sequential therapy approach with serial biomarker collection provides a unique opportunity to prospectively evaluate how each treatment modality changes each patient’s tumor microenvironment and systemic response. In Aim 1 we focus on longitudinally evaluating tumor tissue using multiplex immunofluorescence and RNA expression analysis. We also plan to evaluate the systemic response to therapy by profiling peripheral mononuclear blood cells and T-cell receptor sequences as well as quantifying patient-specific circulating tumor DNA. In Aim 2, we plan to longitudinally evaluate multiparametric MRI sequences to characterize dynamic changes in cellularity and microvascular function using DWI/ADC and DCE- MRI. Our overall objective is to determine if baseline features as well as early ICI-induced changes measured by the various biomarker assays independently and/or together predict for pathologic response as well as overall outcomes. Ultimately, this proposal serves as a pilot study to evaluate the potential of our multimodality biomarker platform to predict for response to neoadjuvant ICI+RT. We anticipate the results will serve as a first step in the design of the next generation of neoadjuvant immunotherapy based clinical trials, whereby an optimized, longitudinal biomarker platform can help select the therapeutic pathway most likely to yield treatment response.