Abstract 4089: Antitumor activity of eribulin in combination with anti-PD1 antibody in a mouse syngeneic breast cancer model

Abstract

Abstract Eribulin is a synthetic analog of halichondrin B, which is isolated from the marine sponge natural product, as the first halichondrin class of microtubule dynamics inhibitors. Its clinical formulation is currently approved for advanced breast cancer (BC) and advanced liposarcoma in numerous countries. Eribulin shows antitumor activity through cell death induction by an antimitotic effect, and modulation of tumor microenvironment that include vascular remodeling, and reversal of EMT in some of preclinical subcutaneous xenograft models. Effects of eribulin on tumor microenvironment led us to test combination of eribulin with anti-PD1 blockades, and Phase2 clinical study of eribulin in combination with pembrolizumab for metastatic BC patients is in progress. In this study, we investigated antitumor activity of eribulin in combination with anti-PD1 mAb in preclinical mouse BC model using 4T1 cells. Because parent 4T1 cells express P-glycoprotein (Pgp) and eribulin is a substrate of Pgp, we established Pgp-knockout (Pgp-KO) mouse 4T1 BC cells to examine combination antitumor activity of eribulin with anti-PD1 antibody. We used a clone 31 of Pgp-KO 4T1 (#31) cells, which maintains similar tumor phenotypes to parent 4T1 orthotropic transplantation (OT) models, such as growth rate and formation of metastasis. Eribulin inhibited in vitro proliferation of Pgp-KO 4T1 (#31) cells with a lower concentration compared to parent 4T1 cells. Eribulin were intravenous administered at 1 mg/kg with either Q7Dx2 or Q4Dx3 in the combination with anti-PD1 mAb, 200 µg/head, Q3Dx10 in the Pgp-KO 4T1 (#31) OT model (6 mice per a treatment group). Anti-PD1 mAb did not clearly show in vivo antitumor activity. Treatments of eribulin by Q4Dx3 showed enhanced antitumor activity in the combination compared to each single treatment, and all tumors became non-palpable in the combination group. On the other hand, weekly treatments of eribulin did not enhance antitumor activity in the combination with anti-PD1 mAb, although eribulin single treatment significantly inhibited in vivo tumor growth of Pgp-KO 4T1 (#31) tumors. These preclinical results provide preclinical rationale for clinical testing of eribulin in combination with anti-PD1 blockades in patients with BC, and further preclinical analysis of MOA of combination antitumor activity of eribulin with anti-PD1 antibody is warranted. Citation Format: Taro Semba, Kimiyo Tabata, Yoichi Ozawa, Saori Watanabe Miyano, Junji Matsui, Yasuhiro Funahashi. Antitumor activity of eribulin in combination with anti-PD1 antibody in a mouse syngeneic breast cancer model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4089.