Abstract 4564: Synergistic anti-tumor efficacy of combination therapy with APS001F, a cytosine deaminase (CD) expressing Bifidobacterium, 5-fluorocytosine (5-FC) and anti-mPD-1 antibody in syngeneic mice model
Authors: Shioya Koichiro , Seki Yuji , Matsumura Tomio , Shimatani Yuko , Taniguchi Shun'ichiro , Fujimori Minoru 
Published: July 2017

Abstract
Immune checkpoint blockers like anti-PD-1 antibody are leading the new generation in anti-cancer drug development. A lot of scientific evidences have demonstrated that immune checkpoint antibodies have promising clinical response in patients with multiple cancer types. Nevertheless, limited fraction of patients responds to the antibody immunotherapy, and moreover, immune related serious adverse events caused by nonspecific reaction with immune checkpoint blockers result in treatment discontinuation. Many approaches have been attempted to improve therapeutic outcomes of antibody immunotherapy, particularly a combination of antibody treatment and other therapies is one of worth-trying ideas. APS001F is a live recombinant Bifidobacterium longum expressing cytosine deaminase (CD), which is an enzyme to catalyze the hydrolytic deamination of cytosine to uracil. Bifidobacterium is a non-pathogenic anaerobic bacterium derived from normal human intestinal flora. It can only survive and grow at low oxygen environment such as solid tumor. Intravenous administration of APS001F to patients leads to colonization of the B.longum and production of CD enzyme only inside the solid tumor. Locally expressed CD enzyme converts orally taken prodrug, 5-FC, into anti-tumor drug 5-FU, which increases 5-FU concentration specifically inside tumor and results in alleviation of side effects caused by attacking normal organs. The phase 1 clinical trial for APS001F is conducted in the US sponsored by us.
5-FU has been shown to alleviate Myeloid Derived Suppressor Cells (MDSC) in the tumor site and release immune suppression in tumor [1]. Furthermore, Van Der Kraak et. al. have reported that 5-FU upregulated PD-L1 expression on the surface of tumor cells [2]. These findings drove us to combine anti-PD-1 antibody with the APS001F therapy. At this present study, systemic administration of APS001F and 5-FC significantly suppressed tumor growth in CT26 bearing syngeneic mice model, which is consistent with our previous finding. Additionally, anti-murine PD-1 antibody combined with APS001F and 5-FC further suppressed tumor progression and some of individual samples achieved complete regression of CT26 tumors. The combination treatment effect of anti-murine PD-1 antibody and APS001F with 5-FC showed statistical significance in comparison with either treatment group, which encourages us to expect much effective results and less side effects in clinic.
Reference: 1. Vincent J. et. al., Cancer Res. 2010 Apr 15;70(8):3052-61, 5-Fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced T cell-dependent antitumor immunity. 2. Van Der Kraak et. al., J Immunother Cancer., 2016 Oct 18;4:65. 5-Fluorouracil upregulates cell surface B7-H1 (PD-L1) expression in gastrointestinal cancers.
Citation Format: Koichiro Shioya, Yuji Seki, Tomio Matsumura, Yuko Shimatani, Shun'ichiro Taniguchi, Minoru Fujimori. Synergistic anti-tumor efficacy of combination therapy with APS001F, a cytosine deaminase (CD) expressing Bifidobacterium, 5-fluorocytosine (5-FC) and anti-mPD-1 antibody in syngeneic mice model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4564. doi:10.1158/1538-7445.AM2017-4564