Abstract 3415: Mutant BRAF small molecule inhibition enhances oncolytic herpes virus immunotherapy through increased immune cell recruitment and activation in melanoma

Abstract

Abstract Small molecule inhibitors of the MAPK pathway have demonstrated rapid responses in melanoma patients, but their use is hindered by the frequent development of acquired resistance. Oncolytic viruses are a novel class of immunotherapeutics which selectively replicate inside cancer cells, causing lysis and subsequent activation of anti-tumor immunity. BRAF and MEK inhibitors have previously been shown to synergise with oncolytic viruses to kill melanoma cells, but the consequences of these interactions on immune responses have not been assessed. Here, we show that the combination of PLX4720 (BRAFV600E inhibitor) and intratumoral oncolytic herpes virus HSV1716 led to a significant tumor reduction and improved survival over single-agent treatment in a murine BRAFV600E melanoma model. The combination led to a significant increase of PD-L1+ neutrophils and monocytes at an early time point following therapy administration, suggesting an inflammatory switch in the tumor microenvironment. Importantly, the combination led to a significant increase in cytotoxic CD8+ cells at a later time point, which was accompanied by an increase in CD25+ Foxp3+ T-regulatory (Treg) cells. Addition of an anti-CD25 antibody to the PLX4720/HSV1716 doublet led to complete eradication of melanoma tumors in vivo. Current efforts are focused on deciphering T-cell dynamics during this therapy using a novel technology, Timer of cell kinetics and activity (Tocky). Tocky uses a fluorescent Timer protein which spontaneously changes its emission spectrum from blue to red, reporting real-time activation of the T-cell receptor and subsequent activation of immune cells in vivo. Using Tocky, we are identifying specific immune subsets that are stimulated following therapy and the real-time dynamics of antigen recognition and subsequent cell activation. These findings form the basis of future testing of drug-virus combinations in an effort to identify potent cytotoxic, as well as immuno-modulatory, strategies and their detailed mechanism of action. Citation Format: Galabina Bozhanova, Victoria Jennings, Malin Pedersen, Joan Kyula, Emmanuel Patin, Jehanne Hassan, Masahiro Ono, Kevin Harrington, Alan Melcher. Mutant BRAF small molecule inhibition enhances oncolytic herpes virus immunotherapy through increased immune cell recruitment and activation in melanoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3415.