Abstract B92: The tubulin-targeting agent BNC105 potentiates the efficacy of immune checkpoint inhibitors in preclinical models of colorectal cancer

Abstract

Abstract BNC105 is a tubulin depolymerisation agent. Its activity includes effects on both cancer cells and on solid tumor microvasculature. BNC105 shows evidence of strong anti-cancer efficacy in vitro and in animal models. In solid tumors its efficacy is driven by selective destruction of tumor vasculature (Vascular Disrupting Agent - VDA) and direct action on tumor cells through suppression of their proliferation. In non-proliferating blood cancers (e.g. Chronic Lymphocytic Leukaemia) BNC105 activates pro-apoptotic proteins, which mediate cancer cell death. BNC105P may be useful in the treatment of human cancers both as a monotherapy and also in combination therapies. Two separate in vivo studies were conducted to assess the potential therapeutic utility of combining BNC105 with antibodies that target PD-1 or CTLA4. The in vivo models utilised were xenografts of the murine colorectal cancer cell lines MC38 and CT26. C57/BL6 mice were inoculated subcutaneously with MC38 cells and treatment commenced when tumors reached a volume of approximately 100-150mm3. BNC105 was administered at 10 mg/kg i.v. on Day 1, 8 and 15 andanti-PD-1 antibody (Clone RMP1-14) was administered at 3.5mg/kg i.p. on Day 1, 4, 8, 12 and 16. Tumor growth inhibition was evident as early as Day 8 of the treatment period especially in the combination group compared to control group (p<0.05). On Day 17 of the treatment period, animals treated with BNC105 as a monotherapy experienced 40% inhibition of tumor growth, anti-PD-1 treated animals experienced 74% inhibition in tumor growth. Animals treated with the combination of BNC105+anti-PD-1 therapy experienced 97% inhibition in tumor growth. Balb/c mice were inoculated subcutaneously with CT26 cells. When tumors reached an average volume of approximately 100 - 150mm3 animals were randomised into 5 groups of 10 mice per group. BNC105 (10mg/kg) was administered on Days 1 and 8 and the anti-CTLA4 antibody (Clone 9D9) was administered at 10mg/kg i.p. on Days 2, 5, and 9.. Animals treated with the BNC105+anti-CTLA4 combination experienced greater inhibition of tumor growth compared to animals treated with either BNC105 or anti-CTLA4 alone. On Day 11 of the treatment period, animals treated with BNC105 as a monotherapy experienced 27% inhibition in tumor growth and anti-CTLA4 treated animals experienced 14% inhibition of tumor growth. Animals treated with the combination of BNC105+anti-CTLA4 experienced 70% inhibition in tumor growth. The synergistic relationship for each of the combinations was calculated as previously described (Cancer Biol Ther 2011; 12:837-45). BNC105 displayed synergy with both anti-PD-1 and CTLA4. These findings support the investigation of combining BNC105 with immune checkpoint inhibitors in further preclinical models with the view of progressing such combinations to clinical evaluation. Citation Format: Tina C. Lavranos, Donna Beaumont, Daniel Inglis, Michaela Scherer, Chloe Hawkins, Annabell F. Leske, Gabriel Kremmidiotis. The tubulin-targeting agent BNC105 potentiates the efficacy of immune checkpoint inhibitors in preclinical models of colorectal cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B92.