Abstract 5584: Antitumor activity of liposomal formulation of eribulin combined with anti-PD-1
Authors: Niwa Yuki , Adachi Keito , Semba Taro 
Published: June 2022

Abstract
Eribulin (ERI) has been reported a microtubule dynamics inhibitor with unique tumor microenvironment modulations such as vascular remodeling and reversal of epithelial-mesenchymal transition activities. In the previous meeting (AACR2019), we reported that ERI has immunomodulatory activity and higher dose and frequent treatment of ERI (1.0mg/kg Q4D×3) shows combination antitumor activity with anti-PD-1. ERI-LF is a liposomal formulation of eribulin and has improved pharmacokinetics profile and improved antitumor activity compared to ERI in human xenograft models. Therefore, we expected that ERI-LF has greater immunomodulatory activity than ERI. In this study, we first compared antitumor activity of ERI-LF plus anti-PD-1 with that of ERI plus anti-PD-1 using a P-glycoprotein-knockout 4T1 (4T1#31) mouse breast cancer subcutaneous model. As a result, combination of 0.3mg/kg ERI (Q7D×2) with anti-PD-1 did not show significant stronger antitumor activity compared to each monotherapy, although it is an unfavorable condition for ERI that was treated with lower dose (0.3mg/kg) and longer interval (Q7D×2). In contrast, combination of ERI-LF (Q7D×2) with anti-PD-1 enhanced antitumor activity compared to each monotherapy in the dose range of 0.1-1.0mg/kg ERI-LF, suggesting ERI-LF has greater immunomodulatory activity than ERI. We next performed flow cytometry analysis for tumor-infiltrating lymphocytes (TILs) to reveal the mechanism of immunomodulatory activity of ERI-LF. Profile of TILs in 4T1#31 subcutaneous tumor demonstrated that 0.3mg/kg ERI-LF significantly increased the population of CD3+, CD4+, and CD8+ T cells and NK cells, and these changes were superior to that of ERI, demonstrating superior immunomodulatory activity of ERI-LF to ERI. When combined ERI-LF with anti-PD-1, the intratumoral TIL population of activated GzmB+CD8+ T and GzmB+ NK cells were significantly increased, demonstrating the mechanism of combination antitumor activity of ERI-LF with anti-PD-1. We finally verified the contribution of CD8+ T and NK cells to combination antitumor activity of ERI-LF with anti-PD-1 by using depletion antibodies for CD8+ T and NK cells. As a result, we confirmed that both CD8+ T cell singly depletion and NK cell singly depletion attenuated antitumor activity of ERI-LF plus anti-PD-1 combination. Furthermore, CD8+ T cell and NK cell combination depletion further attenuated antitumor activity of ERI-LF plus anti-PD-1 combination compared to each depletion, demonstrating that both CD8+ T and NK cells contribute antitumor activity of ERI-LF plus anti-PD-1 combination therapy. In summary, we demonstrated that ERI-LF has superior immunomodulatory activity than ERI and shows strong combination antitumor activity with anti-PD-1. Currently, Phase 1b/2 clinical trial of ERI-LF plus nivolumab in patients with selected solid cancer (NCT04078295) is underway.
Citation Format: Yuki Niwa, Keito Adachi, Taro Semba. Antitumor activity of liposomal formulation of eribulin combined with anti-PD-1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5584.