Abstract 2981: Establishment and validation of humanized murine modeling platforms to facilitate immuno-oncology research

Abstract

Abstract Immuno-oncology (I/O) space is proven to be one of the fast-moving areas with numeral blockbuster drugs delivered to the market. However, lacking of more clinically relevant preclinical models appeared to hinder this process as the I/O field is getting more established and the therapeutic modalities becomes more complex. The traditional testing systems such as transplantable xenograft tumor models can no longer meet the requirements of I/O novel drug evaluation and the mouse models with tumor-immune microenvironment interactions are urgently needed. At Simcere, in order to overcome those technical barriers and to accommodate our fast-paced pipeline development, we attempted to establish our own I/O in vivo testing platforms. These platforms were tailored to Simcere's dynamic progress of the research programs. To date, a variety of humanized mouse model-based in vivo modalities have been established in house. These testing systems fall into 4 categories: the human immune system reconstitution mouse tumor model (either using hPBMC or hCD34 stem cell approach), the hTreg focused humanized mouse model, the hTreg interfered GVHD mouse model, and the transgenic mouse model with modified immune targets (I/O targeted model; co-developed with a patterner). Each of these model systems were characterized to gain a comprehensive understanding before they were applied to any programs. The model characterization data showed that, 1) A large population of hCD4 and hCD8 T cells was maintained in peripheral blood of the hPBMC reconstructed mice,and significant percentage of human T,B and other type of immune cells were maintained in the human stem cell reconstituted mice.Anti-PD-L1 or anti-TIGIT antibodies showed significant anti-tumor efficacy in these humanized tumor models; 2) In the hTreg focused humanized mice axis, the proportion and functions of hTregs in the spleen of the hTreg reconstituted mice treated with the Treg modulated drugs were significantly amended, indicating that the system can be used to dissect out drugs with Treg modulating functions; 3) A hTreg interfered mouse GVHD model was proven to be a useful tool to assess effects of exogenous or endogenous Tregs on progression of the disease in a chronic setting; 4) Collaborating with a business patterner, we generated genetically modified mouse models in which selected murine immune targets were replaced with human counterparts. One of these models have been used to evaluate our IND candidate molecules, where significant anti-tumor effects and meaningful PD modulation were observed. To conclude, we have developed four types of I/O in vivo platforms to facilitate development process of immune modulatory and cancer immunotherapy agents. A majority of these modalities have been validated and utilized to drive our internal I/O programs. Optimization and expansion of these platforms are currently ongoing. Citation Format: Yang Liu, Hai Huang, Danni Hao, Ran Pang, Mi Ye, Guojing Wu, Wenjing Li, Liting Xue, Zhenchuan Miao, Ming Yin, Wenqing Yang. Establishment and validation of humanized murine modeling platforms to facilitate immuno-oncology research [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 2981.