Abstract 4982: BNC105 induces tumor micro-environment changes which enhance the efficacy of checkpoint inhibitor therapy in preclinical models

Abstract

Abstract BNC105 is a Phase II stage drug that specifically targets tubulin causing rapid depolymerisation. The therapeutic window of BNC105 has been shown to be superior compared to similar compounds in its class with highly specific action on tumor vasculature and minimal off target activity. BNC105 shows evidence of strong anti-cancer efficacy in vitro and in animal models not only through destruction of tumour microvasculature but also through strong suppression of cancer cell proliferation. Complementary studies in models of chronic lymphocytic leukaemia have shown that BNC105 also activates pro-apoptotic proteins, which mediate cancer cell death. Recent studies have been conducted to assess changes in the tumour microenvironment that make BNC105 amenable to combination with immune checkpoint inhibitors. Strong synergy with BNC105 has been seen with anti-PD-1 (97%TGI in combination compared to 40% with BNC105 and 74% with anti-PD-1 as monotherapies) and anti-CTLA-4 (70%TGI in combination compared to 27% with BNC105 and 14% with anti-CTLA-4 as monotherapies) using syngeneic MC38 and CT26 colorectal murine tumor models respectively. We hypothesised that the rapid BNC105 induced tumor microvasculature destruction and onset of tumor hypoxia and necrosis leads to an efflux of tumor antigens being presented to the immune system. This has the potential to elicit an immune response against tumors with a lower mutational load than those that would otherwise activate the immune system using checkpoint inhibitors alone. An increase in tumoral IFNgamma can be associated with the presence of antigen-stimulated lymphocytes within the tumor. IFNgamma levels, CD3+ and CD8+ cells were assessed in tumors treated with BNC105 to elucidate the changes in the recruitment of T cell populations within the tumor microenvironment. A more rapid rate of maturation of dendritic cells upon presentation of antigen is also a potential mechanism associated with changes in the tubulin content of the dendritic cell. The elucidation of the mechanism whereby the disruption of micro-vasculature caused by BNC105 further validates the complementary functional role of BNC105 in immune activation with checkpoint inhibitors. These findings support the investigation of combining BNC105 with immune checkpoint inhibitors with the view of progressing such combinations to clinical evaluation. Citation Format: Daniel J. Inglis, Donna M. Beaumont, Annabell F. Leske, Michaela A. Scherer, Tina C. Lavranos. BNC105 induces tumor micro-environment changes which enhance the efficacy of checkpoint inhibitor therapy in preclinical models. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4982.