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Abstract B041: Establishment of orthotopic syngeneic models using bioluminescence imaging to recapitulate the tumor microenvironment for evaluation of immuno-oncology therapies

Background: The emergence of immuno-oncology (IO) therapies have shown promising benefit in various cancer types. The full potential of these therapies are still being realized, with the use of combinatorial treatments and overcoming resistance being areas of significant interest. Subcutaneous syngeneic models have been widely used to evaluate the efficacy and to understand the mechanisms of action of IO therapies. One main limitation of subcutaneous models is the lack of a clinically relevant tumor microenvironment (TME), which is known to play a pivotal role in the success of IO therapies. More clinically relevant TME can be established with orthotopic models where tumor cells are inoculated in a relevant organ-specific location to recapitulate the immune and stromal component interactions with the tumor, which can also facilitate metastatic spread. Using bioluminescent imaging (BLI), tumor development and progression, together with response to therapy, can be monitored in real-time. We have generated a panel of bioluminescent syngeneic cell lines that can be used to evaluate various therapies in both orthotopic and metastatic settings. Method: Bioluminescent variants of syngeneic cell lines were generated in house by transducing the cell lines with a lentiviral vector carrying the firefly luciferase gene. This panel represents a diverse range of cancer types including liver (Hepa 1-6 and HT22), breast (4T1), colon (CT26), brain (GL261) and pancreas (Pan02). These bioluminescent cells were orthotopically transplanted into immune competent mice, where primary tumor growth was measured by in life BLI, and metastasis assessed by ex vivo imaging. Results: Similar to subcutaneous syngeneic models, the success rate of tumor transplantation was very high as confirmed by in-life imaging and ex vivo imaging at termination. These models have first been evaluated using various checkpoint inhibitors to establish baseline responses. Various responses were observed when compared with subcutaneous model. For example, Hepa 1-6 showed very good response to anti-PD-1 antibody in both the subcutaneous and orthotopic setting. Interestingly, another liver cancer model, H22, responded to anti-CTLA4 antibody as a subcutaneous model but was refractory to the same dosing scheme in the orthotopic model. Conclusion: Syngeneic orthotopic mouse models offer a valuable platform for testing IO therapies with a more clinical relevant TME in comparison to a subcutaneous site. The establishment of a range of models covering diverse tumor types allows for interrogation of the therapeutic potential of novel anti-cancer agents across various cancers. Citation Format: Bryan Miller, Yanrui Song, Jason Davis, Rajendra Kumari, Davy Xuesong Ouyang, Henry Qixiang Li, Yinfei Yin. Establishment of orthotopic syngeneic models using bioluminescence imaging to recapitulate the tumor microenvironment for evaluation of immuno-oncology therapies [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B041. doi:10.1158/1535-7163.TARG-19-B041