LAUSR

Targeted and immune therapies have transformed outcomes for melanoma patients, nevertheless, significant challenges remain to maximize their clinical benefit. BRAF/MEK targeted therapy (TT) is associated with very high initial response rates that are typically short-lived, while in contrast Immune Checkpoint Inhibitors (ICI) provide more durable responses but have lower initial response rates. Hence, it has been proposed that sequencing ICIs with TT would lead to a higher frequency of durable responses. However, there are many unanswered questions regarding the choice of immunotherapy, the best sequencing strategy and the mechanism leading to this synergy. To address these questions, we have optimized a syngeneic mouse melanoma model, YUMMER1.7-PV1 that is sensitive to both TT and ICIs. Importantly, this model recapitulates the known three therapeutic response phases of targeted therapies: initial response, followed by drug tolerance and then resistance. Investigation of the tumor immune microenvironment (TIME) at these three drug-induced phases, demonstrates that the immune suppressive microenvironment present during the acquired resistant phase is primed at the drug tolerance phase. Utilizing this model, we have explored the time-dependent therapy-induced changes in both tumor cells and the TIME during various TT and ICI sequencing strategies. This information will determine the optimal sequencing strategy of targeted therapy and immunotherapy that will deliver better outcomes for melanoma patients. Citation Format: Riyaben Patel, Anna Trigos, Nicole Haynes, Emily Lelliott, Grant McArthur, Karen E. Sheppard. Sequencing of targeted- and immune-therapy: delineating time dependent changes in both melanoma cells and the immune microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5941.