While this type of therapy is promising, developing new checkpoint inhibitor therapeutics can be challenging due to the lack of physiologically relevant models.

For instance, some of the current models used for the clinical development of these inhibitors are syngeneic mouse models and humanized mouse models.² While these models provide valuable information in understanding immunological mechanisms and testing potential cancer immunotherapy drugs, they suffer from the inherent differences between the mouse immune system or human/mouse hybrid immune system and the human immune system.³

In vitro drug screens that use fully human ex vivo immuno-oncology assay models overcome the inter-species immune disparity. For example, co-culture assays of human T cells and human cancer cells can be used to observe the direct cytotoxic effects of T cells on cancer cells and evaluate inhibitor efficacy.⁴ The use of primary immune cells and patient-derived cells adds physiological relevance to the assay; however, these cells pose unique challenges such as natural donor variability issues and the experimental outcomes are often difficult to reproduce.⁵

Another alternative is the use of an artificial system comprising cancer cells engineered to overexpress immune checkpoint molecules that are co-cultured with non-cytotoxic T cells harboring a T cell activation signaling reporter gene. While this option solves the reproducibility problem, it loses physiological relevance due to the forced expression of the checkpoint molecules.⁶