Abstract 928: Preventing melanoma from healing itself after therapy-induced immune attack through IPRES blockade

Abstract

Abstract Over the past few years, therapeutics development for melanoma has led the oncology field, including the development of mutant BRAF-targeted therapies (e.g., BRAF inhibitor (BRAFi)) and immune checkpoint blockade therapies (e.g., anti-PD-1 or aPD-1, aPD-L1, etc). Based on the complementary qualities of aPD-1/L1 immunotherapy (long duration of response) and MAPKi (high rate of initial response), there are currently clinical trials testing the combination of the two. However, despite a more durable tumor suppression, resistance still eventually develops in patients treated by the combination (ref: KEYNOTE-022). My earlier study reported significant intra-patient and intra-tumoral heterogeneity which affect patient-specific responses to therapy. Furthermore, I also observed complex transcriptomic and tumor microenvironment reprogramming associated with resistance to targeted- or immuno-therapies in melanoma. However, the increased immune/stromal cells in the tumor under therapy has prevented us from definitively accounting the source of such reprogramming. To address this need, I utilized the novel single cell transcriptomic analysis to discover therapy-response-associated gene programs across different types of cells within a tumor. In murine mutant BRAF melanoma YUMM1.7, regressing/responding tumors on the 6th day of BRAFi treatment showed significant infiltration of the T cells and other immune cell population and, by the 15th day, the tumor showed activation of IPRES related processes. Combination of BRAFi and aPD-L1 in YUMM1.7 increased the proportion of lymphoid population in the tumor on the 7th day but only incrementally delayed the development of BRAFi resistance. Inhibition of IPRES-related processes (anti-VEGF and/or anti-TGFB) further delayed BRAFi resistance but no complete responses were observed. However, when we employed a UV-mutated subline of the same model, named the YUMMER (Bosenberg lab, Yale), combination of BRAFi, aPD-L1 and IPRES inhibition started to result in durable complete responses in our mouse model. We are now in midst of analyzing the differential response that we observed with this model; our current working hypothesis is that YUMMER induces higher level of antigen-specific antitumor response, which is augmented by the addition of immune checkpoint blockade and IPRES suppression. The results from our study will eventually pave the way to a novel therapeutic combination to overcome melanoma. Citation Format: Marco Piva, Lu Sun, Gatien Moriceau, Zhentao Yang, Antoni Ribas, Willy Hugo, Roger S. Lo. Preventing melanoma from healing itself after therapy-induced immune attack through IPRES blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 928.