Abstract A112: Observed separation of survival curves by WBC in CBP501-treated patients leads to experimental identification of macrophage functions suppressed by CBP501

Abstract

Abstract The CBP501 calmodulin-binding peptide is an anti-cancer drug candidate that has completed a Phase II clinical trial for patients with non-small cell lung carcinoma (NSCLC). CBP501 was also previously identified as a unique G2 checkpoint-directed agent and as an enhancer of cisplatin (CDDP) uptake. In a post-trial analysis of the NSCLC patients, it was found that the survival was statistically significantly different between subpopulations with normal white blood cell counts (WBC) (WBC < 8000) and high WBC (WBC > 8000). Notably, treatment by CDDP with or without CBP501 had no effect on the neutrophil oxidative burst or phagocytosis Here, we show that CBP501 inhibits several functions of macrophages. The LPS-stimulated production of several cytokines (IL-6. TNF-alpha and IL-10) by macrophages were suppressed by CBP501 treatment in vitro. The population of potential cancer stem-like cells was reduced by CBP501 in co-cultures of macrophages and tumor cell lines. In human macrophages isolated from peripheral blood-derived monocytes or THP-1 monocytic cells, phagocytic activity induced by IgG-conjugated beads was suppressed by in vitro CBP501 treatment. The neutrophil extracellular traps (NETs), which are supposed to be cleared by macrophages, were increased by CBP501 in response to leukocyte stimulation. Thrombotic tendency was increased in LPS- and CBP501-treated mice. These results suggest that the inhibition of macrophages by CBP501 could explain the observed dramatic separation of survival curves by WBC in patients with NSCLC. Many reports (Roy Noy and Jeffrey W. Pollard Immunity. 2014) indicate that tumor associated macrophages (TAMs) promote metastasis. To see if CBP501 might affect this relationship between macrophage activity and metastasis, we performed in vivo mouse study of mice bearing subcutaneous Lewis lung carcinomas. Results showed reduced metastasis to the lung upon CBP501 administration. Further investigation is underway to clarify the role of CBP501 in modulating the earlier characterized TAM-promoted metastasis. Citation Format: NAOKI MINE, Sayaka Yamamoto, Naoya Saito, Takuji Sato, Keiichi Sakakibara, Donald W. Kufe, Daniel D. Von Hoff, Takumi Kawabe. Observed separation of survival curves by WBC in CBP501-treated patients leads to experimental identification of macrophage functions suppressed by CBP501. [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 A112.