Abstract 2735: Cancer immunotherapy with agonistic anti-4-1BB scFv producing and secreting Bifidobacterium in syngeneic mouse model

Abstract

Abstract Agonistic antibodies against immune checkpoint molecules, such as 4-1BB, reportedly demonstrate antitumor effects at the early clinical phase, whereas immune-related adverse events hamper further development. A single chain variable fragment (scFv), which is expected to have better penetration into tissues, is clinically being investigated, however, poor distribution into tumor tissues due to rapid clearance is a serious issue. In order to improve drug delivery and decrease adverse events, we have developed in situ Delivery and Production System (i-DPS) by genetically engineering a non-pathogenic anaerobic Bifidobacterium. We previously reported that the modified Bifidobacteria localized and proliferated only in the hypoxic area of the tumor engrafted in the mouse post i.v. injection, thus producing anti-tumor molecules persistently and selectively at the tumor site (AACR2010). Here we present i-DPS with agonistic anti-murine 4-1BB scFv. We created a recombinant Bifidobacterium producing and secreting anti-murine 4-1BB scFv. The anti-murine 4-1BB scFv increased IFN-γ production by 171% over the control group (PBS(-)) in the mouse splenocytes activated by ant-CD3 antibody in vitro. Anti-tumor effects of Bifidobacteria producing the anti-murine 4-1BB scFv were demonstrated in the syngeneic model of CT-26 in Balb/c mouse (61.7% tumor growth inhibition (TGI) at 1×109 cfu/mouse, i.v. on day 14). We further evaluated the anti-tumor effects of i-DPS for anti-murine 4-1BB scFv (1×109 cfu/mouse, i.v.) in combination with PD-1 antibody (i.p.), and confirmed that the combination therapy significantly suppressed the tumor growth on day 21 (TGI: combination, 60.7%; anti-murine 4-1BB scFv, 38.8%; anti-mPD-1 mAb, 8.9%). In conclusion, i-DPS for anti-4-1BB scFv will provide a new promising modality for the immune-therapy targeting hypoxic solid tumors. Citation Format: Tomio Matsumura, Koichiro Shioya, Yasuyoshi Kanari, Yuko Shimatani, Shiro Kataoka, Shun'ichiro Taniguchi, Takaaki Nakamura. Cancer immunotherapy with agonistic anti-4-1BB scFv producing and secreting Bifidobacterium in syngeneic mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2735.