Abstract B97: Response to checkpoint inhibition by GEMM breast cancer allograft

Abstract

Abstract Background. Cancer patient's response to immunotherapy, e.g. checkpoint inhibitors, differ greatly, likely due to their genetic composition (e.g. neo-mutation) or immunological profile of tumors. Experimental models may facilitate the identification of responders or of the approach to enhance response. Syngeneic mouse tumor models have been widely used as experimental model for testing surrogate immunotherapy, but limited by the fact that only a few are available and respond to the current checkpoint inhibitors. Allografts of mouse spontaneous tumors (MuPrimeTM) may be used as new type of I/O model with advantages: 1) its primary natures with “stem cell diseases” and relevant tumor microenvironment as seen in PDX1-5; 2) diverse cancer types and deriving from wider range of available spontaneous mouse tumors. Method. We created a MuPrime, MBR6004, by allografting the breast adenocarcinoma derived from GEMM-MMTV-PyVT in FVB/N mice1. We then characterized the model by examine it subcutaneous and orthotopic growth, and its ability to metastasis. We also transcriptome-sequenced and immune-profiled the tumor, and assessed its response to different treatments, including I/O therapy. Results. MBR6004 was found to over-express HER2 but negative for ER and PR. It maintains original primary tumour histopathology, grows robustly, and is confirmed to express its original transgene. It is also resistant to docetaxel. The orthotopic implantation resulted in lung metastasis. We can detected and quantitatively confirmed tumor-infiltrating immune cells, e.g. TIL, CTL, Treg, immune-suppression macrophage, NK, etc. We confirmed that the tumor cell expressed relatively low PD-L1, but inducible, per flow analysis. Our preliminary data indicated that it partially respond to anti-mouse PD1 and anti-mouse CTLA-4 antibodies when mice are preconditioned. Currently, we are investigating whether the responses are associated with the reduced Treg and increased CD8+ TIL in tumors, and also whether the combination therapy can enhance its tumor response synergistically. Conclusion. Our data seem to suggest that MuPrime could be another type of I/O model alternative to commonly used syngeneic cell line derived models at present.