Background: Monoclonal antibodies and checkpoint blocking approaches have achieved remarkable success in cancer immunotherapy in clinical practices. Besides the success of anti-PD-1 and anti-PD-L1 antibodies (such as Keytrude and Tecentriq), two bispecific antibodies, Catumaxomab and Blinatumomab have been approved to treat cancer patients, and many more bispecific antibodies are currently in pre-clinical or clinical development. To meet the increasing market needs for fast, reliable and cost effective mouse tumor model systems, we developed a panel of humanized tumor models, designated as MiXenoTM platform. MiXenoTM could be used in a broad spectrum of applications in immuno-oncology drug discovery, including targeted cancer immune-therapy.

Method: CrownBio has a collection of about 200 xenograft models, including subcutaneous, orthotropic and systemic models, which covers majority of cancer type. Gene expression and mutation status are often profiled in these models. To engage both host immune system and tumor antigens, we have developed some specific MixenoTM tumor models by inoculating tumor cells over-expressing specific anti-tumor antigens (e.g. EGFR, CD47, Braf or PD-L1) into PBMC-humanized immunocompromised mice. Reconstitution of human immune component with human PBMCs in these tumor-bearing mice provides a useful tool to evaluate the targeted immune-therapeutics including bispecific T cell engagers.

Results: To validate the MiXenoTM models for targeted cancer immunotherapy, several xenograft models have been profiled and selected based on their tumor antigens or gene expression. Models with over-expression of a variety of tumor antigens (e.g. EGFR, CD47, Braf, PD-L1, etc.) were used to develop specific MixenoTM tumor models. The immune and tumor cells were engrafted either simultaneously or sequentially. Graft versus host disease (GvHD) can be managed by optimizing the immune cell constitution and tumor cell engraftment. Some models were also validated using stand of care I/O drugs and characterized by immune-phenotyping.

Conclusions: MiXenoTM tumor models with specific tumor antigen targeting strategy are valid model systems to evaluate the human immuno-modulatory drugs including bispecific antibodies. Further studies are needed to expand model collections and to extend their applications in I/O space.

Citation Format: Lan Zhang, Haochen Wu, Fei Chen, Lianqi Zhao, Xiaoyu An, Weibin Tan, Xiaoyan Fu, Meng Qiao, Qian Shi, Wenqing Yang. Establishment and application of a panel of PBMC-humanized mouse tumor models in immune-oncology and targeted cancer immunotherapy [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 5677.