Preclinical modelling of immune checkpoint blockade (P2012)

Harnessing the power of the immune system to identify and eliminate cancer is a promising area of development in cancer therapy. Increasing T-cell activation, in particular, is now a clinically validated approach to the treatment of cancer. Cytotoxic T lymphocyte antigen 4 (CTLA-4, CD152) and PD-L1 (B7-H1, CD274) are part of a complex system of receptors and ligands that are involved in limiting T-cell activation through the delivery of inhibitory signals. MedImmune is currently developing tremelimumab (anti-CTLA4) and MEDI4736 (anti-PD-L1), for the treatment of advanced or metastatic solid tumours. Both of these antibodies antagonise T-cell inhibition signals with the aim of enhancing anti-tumor T cell activity. We have established and characterised a panel of syngeneic mouse tumor models and employed these to explore the activity of anti-mouse CTLA-4 and PD-L1 antibodies using pharmacodynamic (PD) and tumor growth inhibition (TGI) endpoints. Published studies characterising the immunogenic nature of some existing cancer therapeutics provide reason to believe that a combination strategy, utilising checkpoint blockade together with current standard of care, or novel therapeutics, could result in increased activity. We have gone on to explore the value of such combinations in preclinical mouse models.