Abstract A37: CBP501 induces tumor immunogenic cell death and CD8 T cell infiltration into tumor in combination with platinum, thereby increasing the efficacy of immune checkpoint inhibitors against tumors in mice

Abstract

Abstract Introduction: CBP501, a calmodulin-binding peptide, is an anti-cancer drug candidate that has completed two Phase II clinical trials for patients with malignant pleural mesothelioma and non-small cell lung carcinoma (NSCLC). CBP501 enhances the uptake of platinum agents by cancer cells specifically and induces immunogenic cell death within the clinically achievable dose levels of both CBP501 and cisplatin (CDDP) (EORTC 2015 abstract#C106). Here we treated tumor bearing mice with the combination of CBP501, platinum agents (CDDP and carboplatin), and immune checkpoint inhibitors and analyzed the tumor growth and behaviors of immune cells. Methods: Immuno-competent BALB/c mice were subcutaneously inoculated with CT26WT (5 x105 cells/mouse). A week later, mice were apportioned into 8 groups (6 mice/group) and treated with 2 dosing cycles for 3 anti-cancer agents, alone or in different combinations [CDDP: 4 mg/kg x 1/week, CBP501: 6.0 mg/kg x 1/week, anti-mPD1 mAb (RMP1-14) or anti-PD-L1 mAb (10F.9G2): 200 ug/mice x 2/week]. Results: In BALB/c mice bearing CT26WT tumor, CDDP- or immune checkpoint inhibitor-treated mice showed a minimal anti-tumor effect compared to the vehicle-treated mice. CDDP/immune checkpoint inhibitor-treated mice showed an additive anti-tumor effect. CBP501 significantly enhanced the anti-tumor effect of CDDP/immune checkpoint inhibitor combination. Flow cytometry analysis of single suspension cells from the tumor tissue showed that treatment of CDDP/CBP501 or CDDP/CBP501/anti-mPD1 mAb but not CDDP or anti-mPD1 mAb increased the percentage of tumor-infiltrating CD8+ T cell. Conclusion: An increase of tumor-infiltrating CD8+ T cells in CDDP/CBP501-treated mice supported the conclusion that CDDP/CBP501 treatment induced immunogenic cell death not only in vitro but also in vivo. It also supported the notion that CBP501 would not increase cytotoxicity of platinum agents to non-tumor cells. The fact that CBP501 enhanced anti-tumor activity of immune checkpoint inhibitors in combination with platinum agents (CDDP and carboplatin) would support further clinical development of CBP501. Citation Format: Keiichi Sakakibara, Takuji Sato, Donald W. Kufe, Daniel D. VonHoff, Takumi Kawabe. CBP501 induces tumor immunogenic cell death and CD8 T cell infiltration into tumor in combination with platinum, thereby increasing the efficacy of immune checkpoint inhibitors against tumors in mice. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr A37.