Charles River is establishing a powerful translational immuno-oncology platform with the capability of progressing biologics or small molecule modulators of immune response from in vitro to in vivo assays using human and mouse variants of current check-point inhibitors and small molecules.
The platform includes validated (using chemotherapeutics, including anti-CTLA4, anti-PD1 and small molecule inhibitors of targets known to modulate immune responses including IDO inhibitors) primary human immune cell assays which profile T cell activation, cytokine release, T cell mediated cancer cell kill, expansion of T cell populations, T cell invasion and macrophage mediated T cell phagocytosis and is currently being expanded to determine the effect of activated immune cell populations on tumour cell spheroid cultures. We are in the process of developing a range of nuclear-restricted GFP expressing cell lines which will be used to support co-culture experiment.
Syngeneic mouse tumour models have frequently been used to profile immune responses in tumours, CRL have optimized and profiled existing check-point inhibitors to support immuno-oncology drug discovery using mouse and rat antibody variants of anti-CTLA4 and anti-PD1.
To confirm the translational development of our platform CRL have developed and optimized humanized mouse models using sub-cutaneous implanted patient derived xenografts (PDX) with human engraftment via CD34+ haematopoeitic stem cells in NOG mice which were treated with anti-CTLA4 and anti-PD1. Infiltration of human immune cells and PDL-1 expression was detected by flow cytometry (FC) and immunohistochemistry (IHC) in hematopoietic organs and tumor tissue, supporting the initial in vitro response in primary immune cells.