We previously generated the MuPrime® mBR6004 model, by engrafting the breast adenocarcinoma derived from MMTV-PyVT transgenic mice (GEMM)1 into the syngeneic FVB/N mice2,3. The allograft grows robustly, maintains the histopathology features of the original GEMM, and metastasizes to the lungs in all examined cases when implanted orthotopically2. Additionally, histopathology shows that the models is HER2++, but ER-/PR-. We profiled drug responses to standard of care (SoC)2 and checkpoint inhibitors3. Interestingly, among all checkpoints inhibitors tested, our model is insensitive to PD1/PDL-1 inhibitors, but responds to CTLA-4 inhibitors3. To further explore the underlying mechanism of response, we performed extensive tumor immuno-profiling for the presence of infiltrating immune cells, e.g. TIL, CTL, Treg, immune-suppressive macrophages, NK, etc3. We observed a good pharmacodynamic (PD) correlation between the presence of tumor infiltrating T-cells, particularly CD8+ TIL, and NK and a positive response to therapy, regardless the treatment type. Given this preliminary observation, we attempted animal vaccination with tumor lysates prior to tumor engraftment or treatments. Interestingly, while vaccination had minimal effects on the engraftment take rate (100% take for all animals) and on the growth kinetics of the engraftments, it had profound effects on the tumor response to anti-PD1/anti-PDL-1 antibody treatments, significantly enhancing tumor response to these agents in a model that was otherwise unresponsive. Our results suggest that the immunological status of the animal, at least with regard to the specific anti-tumor immunity, is critically important to determine the response to checkpoint inhibitors. Our observations suggest that vaccination is critical for the overall success of immunotherapy (I/O) treatments utilizing checkpoint inhibitors as well other treatment strategies.
1. Guy, C.T., Cardiff, R.D. & Muller, W.J. Induction of mammary tumors by expression of polyomavirus middle T oncogene: a transgenic mouse model for metastatic disease. Molecular and cellular biology 12, 954-961 (1992).
2. Annie Xiaoyu An1, Jinping Liu1, Jie Cai1, Jean Pierre Wery1, and Henry Q.X. Li1,. Building mouse tumor derived allogragfts for immune-oncology research. (2015).
3. Zhun Wang1, A.X.A., 2*, Jinping Liu1, Gavin Jiagui Qu1, Likun Zhang, Jie Cai1, Bin Chen1, Davy Xuesong Ouyang1, Jean Pierre Wery1, and Henry Q.X. Li1,2. Response to checkpoint inhibition by GEMM breast cancer allograft EORTC-AACR-NCI Abstract (2015).
Citation Format: Zhun Wang, Xiaoyu An, Jinping Liu, Xuesong Ouyang, Jiagui Qu, Likun Zhang, Jie Cai, Jean-Pierre Wery, Henry Li. Prior vaccination is critical to PD1/PDL-1 treatment efficacy in a mouse breast cancer allograft. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3219.