Abstract 908: BRAF inhibition and nanoparticle-delivered cytokine therapy for melanoma: A novel rational combined approach

Abstract

Abstract Although the advent of BRAF inhibitors plus MEK inhibitors has revolutionized BRAF-mutant melanoma therapy, most patients relapse within 16 months due to the persistence of minimal residual disease (MRD), a key obstacle in cancer therapy. In our inducible genetically engineered mouse model (iBIP), doxycycline withdrawal results in BRAFV600E extinction causing tumors to shrink, but not completely disappear, achieving a status of MRD. Time-course microarray analysis revealed a set of immune hallmarks with acute and strong initial activation after BRAFV600E extinction, then a decrease through to MRD, suggesting that the MRD might be immune suppressive/evasive. Systems biology analysis pinpointed the family of interferon inducible chemokines CXCL9/10/11 as central players in the orchestration of the process: CXCL9/10/11 are strongly induced within 8 hours of BRAFV600E extinction, but dissipate just prior to MRD, paralleling the more general immune signature. Data obtained in human samples and in other immunocompetent mouse models also show both a strong CXCL9/10/11 induction after BRAF inhibition and an immune evasive/suppressive microenvironment after eventual tumor relapse. Our preliminary data indicates resident macrophages as the main population responsible for CXCL9/10/11 production.. These data led us to hypothesize that sustaining CXCL9/10/11 expression might support superior tumor immune infiltration and activation to neutralize or eradicate the MRD. In a pilot study, we have observed significant tumor rejection in vivo with combined BRAF extinction plus intratumoral recombinant CXCL9 (rCXCL9) therapy in immunocompetent mice, which suggests that CXCL9 can therapeutically convert immunologically “cold” MRD back to “hot”. In order to improve the pharmacokinetics of cytokine therapy, we are currently developing a nanoparticle-based delivery that extends stability and half-life of rCXLC9 in vitro, with in vivo experiments as the next step. In this work, we utilized a confluence of in silico and in vivo data to guide the rational identification of a molecularly-driven cancer treatment based on immune drivers with predicted molecular synergy. Citation Format: Gabriele Romano, Roger Liang, Paradiso Francesca, John Miller, Francesca Taraballi, James Costello, Lawrence Kwong. BRAF inhibition and nanoparticle-delivered cytokine therapy for melanoma: A novel rational combined approach [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 908.