Defining biomarkers of immune activation during anti-PD1+Tvec therapy

The immune system is known to play a critical role in controlling, and in some cases eliminating, melanoma. We propose to study the efficacy of combining two immunotherapies that have proven efficacy against melanoma to test whether combining agents activating distinct arms of the immune system can provide overall stronger immune response and could potentially cure more patients. Talimogene laherparepvec (Amgen Inc), is an oncolytic virus that directly infects tumor cells and kills them while also releasing stimulators to draw in and activate immune cells. Anti-PD-1 antibody binds to an inhibitory marker on T cells and prevents T cell exhaustion and immune suppression. The concept is to bring T cells into the tumor using the vaccine and then to activate them using the anti-PD1. We will use a mutant mouse model to mimic the common BRAF mutation seen in melanoma, and use a BRAF inhibitor alongside the immunotherapies. We will define the synergy of combination therapy through survival studies. We will quantify immune cell populations by studying the tissue and blood of the mice. We will investigate cellular mechanisms of combination therapy and immune cell subtypes using flow functional immune assays and immune deficient mouse models. We also propose to define biomarkers predictive of response to treatment using microarray of frozen tumors and comparing mice with different outcomes. The purpose of this study is to provide valuable information for designing clinical protocols combining immunotherapies in patients and to help us understand which immune cell types and signaling pathways will be critical to success using these two agents together.