Introduction: We previously reported that FF-10832, a liposomal gemcitabine, exerted anti-tumor activity superior to that of gemcitabine with high stability, long plasma half-life, and preferential tumor accumulation in preclinical tumor models. Beneficial gemcitabine immune-modulating effects in tumor microenvironments have also been reported. We investigated the immune-modulating effects of FF-10832 by evaluating its anti-tumor activities combined with immune checkpoint blockade.
Methods: Murine syngeneic tumor models were created by subcutaneous implantation of MBT-2 (bladder) or EMT6 (breast) tumor cells and tumor volume evaluated during and after treatments. Treatments included 2 or 4 mg/kg of FF-10832 or 240 mg/kg of gemcitabine intravenously once a week, and 10 mg/kg of an immune checkpoint inhibitor intraperitoneally twice a week for 3 weeks.
Results: In the MBT-2 tumor model, although tumor growth was slightly inhibited by anti-PD-L1 mAb (clone: 10F.9G2) alone, only one out of nine mice showed complete response. Although FF-10832 decreased tumor growth during treatment (3 weeks), remission was incomplete, and tumor growth continued after treatment was discontinued. In contrast, in combination, tumor growth was inhibited even after treatment withdrawal; three out of nine mice achieved complete remission, and median survival improved (vehicle control and anti-PD-L1 mAb: 25 days; FF-10832: 28 days; combination: >49 days). This combination effect was comparable to that of gemcitabine combination. Previously, FF-10832 has also shown anti-tumor effects in a gemcitabine-insensitive BxPC-3 xenograft tumor model, so the potential benefit in combination with checkpoint inhibitors was evaluated in a gemcitabine-insensitive EMT6 tumor model. FF-10832 significantly inhibited tumor growth relative to that of gemcitabine in this model, but all mice showed tumor re-growth after treatment withdrawal. Anti-CTLA-4 mAb (clone: 9H10) alone showed complete response in only one out of eight mice. Strikingly, FF-10832 in combination with anti-CTLA-4 mAb exerted superior anti-tumor activity compared to that with gemcitabine, as shown by tumor regression in all mice and complete regression in seven out of eight mice. Further analysis to clarify the mode of action underlying the combination effect is ongoing now. These results indicate that the effect of immune checkpoint inhibitors is enhanced by FF-10832 regardless of tumor sensitivity to gemcitabine.
Conclusion: Although immune checkpoint blockade is thought to be a breakthrough for cancer treatment, only a limited patient population has achieved favorable outcomes. Our results suggested that FF-10832 enhances the anti-tumor activity of immune checkpoint blockade, which could significantly improve treatment outcomes.
Citation Format: Tadaaki Ioroi, Takashi Komori, Takeshi Matsumoto, Susumu Shimoyama, Takayuki Kobayashi, Hidetoshi Murao, Shinichi Watanabe, Shinji Hagiwara, Takefumi Hara. FF-10832 combined with immune checkpoint blockade shows favorable anti-tumor activity [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 3953.