Abstract 2161: Improving the tumor microenvironment with liposomal gemcitabine, FF-10832, enhances the effects of immune checkpoint blockade

Abstract Cancer immunotherapy, including immune checkpoint blockade (ICB), is a type of cancer treatment that achieves tumor regression in various types of cancer. However, more than half of patients are resistant to ICB therapy. As the tumor microenvironment (TME) is different in each cancer patient, it is important to understand the state of immune cells in the tumor and develop strategies, including combination therapies. In the TME, immunosuppressive cells such as regulatory T cells (Treg), tumor associated macrophages (TAMs) and myeloid derived suppressor cells (MDSCs) work in correlation with ICB resistance. These immunosuppressive cells are promising targets for ameliorating resistance to ICB treatment and a lot of drugs targeting these cells have been developed. In particular, the therapy targeting TAMs have proved effective. We previously developed liposomal nanoparticle, FF-10832, encapsulating the cytotoxic anti-tumor drug, gemcitabine. Non-clinical studies demonstrated that FF-10832 was more stable than unencapsulated gemcitabine and preferentially distributed to solid tumor sites, resulting in an improved therapeutic index. A phase I clinical trial indicated that FF-10832 was well-tolerated in heavily pre-treated patients with advanced solid tumors at the recommended phase 2 dose (NCT03440450). Therefore, this study investigated the application of FF-10832 as an immunomodulator in combination therapy with ICB. Treatment of mouse models of solid tumor and in vitro analysis showed that FF-10832 is engulfed into the cytoplasm of TAMs in the tumor by phagocytosis. Combination therapy with FF-10832 and anti-PD-1 antibody resulted in significant tumor regression compared to gemcitabine monotherapy, altering the balance immunosuppressive cells in the TME. These results suggest that FF-10832 is a promising immunomodulator for TAM-targeted cancer immunotherapy. Combination therapy of FF-10832 and pembrolizumab is under investigation for non-small cell lung cancer and urothelial cancer in a phase 2a clinical trial (NCT05318573). Citation Format: Tadaaki Ioroi, Michie Morimoto, Hitomi Nishinakamura, Keisuke Watanabe, Shohei Koyama, Hiroyoshi Nishikawa, Mikinaga Mori, Susumu Shimoyama. Improving the tumor microenvironment with liposomal gemcitabine, FF-10832, enhances the effects of immune checkpoint blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2161.