Syngeneic Models Take Center Stage In Immunotherapy
by Federica Parisi PhD, December 8, 2015 at 09:00 AM
Syngeneic models were developed over 50 years ago as early in vivo models for oncology drug development, consisting of allograft of murine tumor cells in hosts with a fully functional immune system. After an initial phase of great popularity they drifted out of the drug discovery landscape with the shift towards therapies directed against human targets, when they were replaced by models expressing human targets, such as genetically engineered mouse models (GEMM) or PDX.
Following the success of new immunotherapy agents (checkpoint inhibitors), syngeneic models have resumed center stage. Because they retain an intact immune system, they are considered particularly relevant models to study immunologically based therapies used either as single agents or in combination with other drugs that modulate the immune system’s ability to identify and destroy cancer cells.
With our greater understanding of the immunological makeup of the tumors and their responsiveness to checkpoint inhibitors, it has become clear that there is still a lot to learn. Beyond simply identifying syngeneic models as responder/non responder to immunotherapy, we are starting to ask how to best position these models for drug development and how can they help identify biomarkers of response in the patient population. This has proven to be a rather challenging aspect because the immune response to cancer involves several different cell types and immune-related factors (i.e. cytokines), with a variety of spatial and temporal manifestations. For this reason numerous biomarkers will likely be required to fully characterize efficacy of immunotherapies and predict eventual benefit. Analysis of peripheral blood and serum following immunotherapy, remains the standard approach, but the importance of obtaining tissue to study the immune response at the site of the tumor is becoming increasingly evident.
At Crown Bioscience we have sequenced and immuno-profiled a panel of syngenic model-derived tumors in the attempt to discover a genetic signature predictive of response and to better inform the selection of models for immunotherapy studies. We found a defined set of genes as potential predictive biomarkers of response for immunotherapy.
We tested the antitumor activity of the anti PD-1, PD-L1, and CTLA-4 antibodies, which by binding to these proteins on the surface of the tumor and immune cells, block the tumor dependent inhibition of the immune system and were able to identify which models responded best.
All syngeneic-derived tumors were screened for the presence of infiltrating immune cells, showing that the ratio between two subtypes of T cells (Teff/Treg) in the tumor microenvironment represents a better predictor of efficacy for the checkpoint inhibitors tested than mutational load.
At Crown we are committed to improving the selection of drug candidates by using the most clinically relevant models and services.
Contact us today to get immediate access to the genetic profiling data for our syngenic models and to get a copy of our award-winning poster titled “RNAseq and Immune Profiling Analysis of Syngeneic Mouse Models Treated with Immune checkpoint Inhibitors Enable Biomarker Discovery and Model Selection for Cancer Immunotherapy” presented during this year AACR meeting in Shanghai.