Core 1: Mouse Model and Tissue Biobank Core

Murine and Clinical Tumors (MCT) Core services. Project Summary The simultaneous combination of anti-PD-L1 with BRAFV600MUT and MEK inhibitors (so-called “triplet” therapy), in early clinical data, appears beneficial and has recently been approved for patients with BRAFV600MUT melanoma (13). This is first mutation-immune co-targeted therapy to be approved, but the data on this triplet appear mixed, with other trials not meeting key endpoints (14), suggesting that simultaneous combination is not optimal. Importantly, retrospective clinical data analysis and in vivo therapeutic modeling using syngeneic models of murine melanoma showed that a regimen of anti-PD-1/L1 (± anti-CTLA-4) lead-in before MAPKi combination augments the efficacy of triplet therapy by enhancing MAPKi durability (and overcoming innate resistance to immune checkpoint blockade) (12). Thus, the realization that immune factors drive resistance to MAPKi therapy opens the door to immune-based strategies, such as adoptive cell therapy (ACT) (Project 1, Aim 3), as combinatorial agents to prevent MAPKi resistance. Building on this recent progress, this Murine and Clinical Tumors (MCT) Core will offer Projects 1 and 2 model and clinical tumors to obtain multi-scale (spatiotemporal) profiles of the tumor immune microenvironment (TIME) early and late on single-agent (MAPKi or anti-PD-1/L1) therapy (Project 1, Aim 1). These “early” data will provide inputs to the agent-based models (ABMs) being developed in Project 1, Aim 2, and “late” data will help validate predictions. Profiles from more successful combination strategies will be compared against less successful combination strategies to teach the ABM on optimized TMEs. This core will also offer clinical tissues for translational validation (Project 1, Aim 4) and tumor models to test predicted novel combination therapies (Project 2, Aim 3).