Abstract 2747: Anti-glypican-3 monoclonal antibody (codrituzumab/GC33/RO5137382) treatment enhances tumor infiltration of PD-L1-positive macrophages, and combination therapy with anti-PD-L1 monoclonal antibody promotes antitumor effects
Authors: Endo Mika , Kinoshita Yasuko , Adachi Kenji , Narita Yoshinori , Amano Jun , Kato Atsuhiko , Watanabe Takeshi , Kayukawa Yoko , Miyazaki Yoko , Ohtomo Toshihiko 
Published: August 2018

Introduction: Codrituzumab/GC33/RO5137382 (GC33) is a humanized monoclonal antibody that targets glypican-3 (GPC3), an oncofetal protein expressed on the cell surface of hepatocellular carcinoma (HCC). GC33 interacts with CD16/FcγR3 and triggers antibody-dependent cellular cytotoxicity. Because anti-PD-L1/PD-1 agents have shown marked antitumor effect in various cancer types including HCC, we investigated if GC33 plus anti-PD-L1 mAb combination can augment antitumor efficacy in a mouse hepatoma syngeneic model transfected with human GPC3, named Hepa1-6/hGPC3.

Methods: The Hepa1-6/hGPC3 cells were subcutaneously inoculated into C57BL/6J mice. After tumor mass was established, anti-mouse GPC3 mAb (mGC33; once-weekly), anti-mouse PD-L1 mAb (anti-mPD-L1 mAb; once-weekly), or a combination was administered on the first day of treatment (Day 0). Tumor tissues were collected on Day 21 for immunohistochemical (IHC) of F4/80 and PD-L1. To analyze tumor infiltrating lymphocytes (TILs), mGC33, anti-mPD-L1 mAb, or combination was administered to the Hepa1-6/hGPC3 mice. After 3 and 8 days from the 2nd dosing, TILs were analyzed to quantify the CD45-, CD3ε-, CD4-, or CD8α-positive TILs and CD11b+F4/80+ macrophages by flow cytometry.

Results: In the Hepa1-6/hGPC3 model, combination therapy demonstrated a marked antitumor effect compared to the corresponding dose of mGC33 or anti-mPD-L1 mAb alone. Pathological complete responses were observed only in combination groups. The necrosis was more marked with combination therapy than with mGC33 or anti-mPD-L1 mAb alone. Though F4/80-positive cells existed mainly in the stroma in the vehicle group, these cells infiltrated the tumor periphery after mGC33 treatment. Most tumor-infiltrating immune cells, including macrophages and multinucleated giant cells, were PD-L1-positive. The combination increased CD45-, CD3ε-, and CD8α-positive T lymphocytes, but not CD4-positive T lymphocytes on Days 3 and 8 after the 2nd dosing. TILs were not increased in mice treated with either mGC33 or anti-mPD-L1 mAb.

Conclusions: In this mouse model, mGC33 plus anti-mPD-L1 mAb combination therapy showed more potent antitumor efficacy than either monotherapy. mGC33 treatment enhanced tumor infiltration of PD-L1-positive immune cells, such as macrophages and multinucleated giant cells. Because anti-mPD-L1 mAb can block the binding between PD-L1 on macrophages and PD-1 on T cells, the CD8-positive T lymphocytes may be increased by combination therapy. These results suggest that the combination therapy of GC33 and anti-PD-L1 mAb may be clinically useful as a treatment for HCC.

Citation Format: Mika Endo, Yasuko Kinoshita, Kenji Adachi, Yoshinori Narita, Jun Amano, Atsuhiko Kato, Takeshi Watanabe, Yoko Kayukawa, Yoko Miyazaki, Toshihiko Ohtomo. Anti-glypican-3 monoclonal antibody (codrituzumab/GC33/RO5137382) treatment enhances tumor infiltration of PD-L1-positive macrophages, and combination therapy with anti-PD-L1 monoclonal antibody promotes antitumor effects [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 2747.