Abstract 1879: CIT-801: a bifunctional anti-PD1xIL15 agent demonstrated synergy and enhanced in vivo anti-tumor efficacy

Abstract

Abstract PD1/PD-L1 antibody has revolutionized cancer therapy. However, only a subset of cancer patients are responsive to anti-PD1 antibody treatment. Lack of immune effector cells in the tumor microenvironment (cold tumor) is considered a major reason for such a resistance. Interleukin 15 (IL15) is a cytokine critical for the survival and proliferation of T-cells and NK cells. We hypothesized that a combination of IL15 with anti-PD1 antibody might turn a cold tumor into a hot tumor and overcome tumor resistance to PD1 therapy, and therefore benefit a larger cancer patient population. We have constructed a homodimeric bifunctional agent (CIT-801) that is composed of an anti-PD1 antibody (CIT-100) and IL15 plus the sushi domain of IL15Rα. In vitro, this bifunctional anti-PD1xIL15 agent retained the ability of its anti-PD1 component to enhance T-cell activation in both mixed leukocyte reaction (MLR) and PD1 luciferase reporter assays. It also retained the ability of its IL15 component to stimulate the proliferation of T-cells. Moreover, the bifunctional agent was able to enhance the activation, proliferation and cytotoxicity of NK cells in vitro. In a syngeneic MC38 tumor model with human-PD1 knock-in mice, the bifunctional anti-PD1xIL15 agent strongly inhibited tumor growth, superior to anti-PD1 antibody treatment alone. In summary, anti-PD1xIL15 bifunctional compound CIT-801 has shown a great therapeutic potential and is worth further development. Citation Format: Yiwen Li, Yuxiang Hu, Welson Wang, Wei Wu. CIT-801: a bifunctional anti-PD1xIL15 agent demonstrated synergy and enhanced in vivo anti-tumor efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1879.