Oncotarget

Priority Research Papers:

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

Keiichi Sakakibara _, Takuji Sato, Donald W. Kufe, Daniel D. VonHoff and Takumi Kawabe

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Oncotarget. 2017; 8:78277-78288. https://doi.org/10.18632/oncotarget.20968

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Abstract

Keiichi Sakakibara1, Takuji Sato1, Donald W. Kufe2, Daniel D. VonHoff3 and Takumi Kawabe1

1 CanBas Co., Ltd., Numazu, Shizuoka, Japan

2 Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA

3 Translational Genomics Research Institute (TGen), Phoenix, Arizona, USA

Correspondence to:

Keiichi Sakakibara, email:

Keywords: platinum agent, immunogenic cell death, immune checkpoint inhibitor, Anti-PD-1, CD8+ T cell

Received: June 27, 2017 Accepted: August 26, 2017 Published: September 16, 2017

Abstract

CBP501, a calmodulin-binding peptide, is an anti-cancer drug candidate and functions as an enhancer of platinum uptake into cancer cells. Here we show that CBP501 promotes immunogenic cell death (ICD) in combination with platinum agents. CBP501 enhanced a clinically relevant low dose of cisplatin (CDDP) in vitro as evidenced by upregulation of ICD markers, including cell surface calreticulin exposure and release of high-mobility group protein box-1. Synergistic induction of ICD by CDDP plus CBP501 as compared to CDDP alone was confirmed in the well-established vaccination assay. Furthermore, cotreatment of CDDP plus CBP501 significantly reduced the tumor growth and upregulated the percentage of tumor infiltrating CD8+ T cell in vivo. Importantly, the antitumor effect of CDDP plus CBP501 was significantly reduced by anti-CD8 antibody treatment. Based on this novel effect of CBP501, we analyzed the combination treatment with immune checkpoint inhibitors in vivo. Mice treated with CBP501 in combination with CDDP and anti-PD-1 or anti-PD-L1 showed an additive antitumor effect. These results support the conclusion that CBP501 enhances CDDP-induced ICD in vitro and in vivo. The findings also support the further clinical development of the CBP501 for enhancing the antitumor activity of immune checkpoint inhibitors in combination with CDDP.


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