Assessing efficacy & MoA of mono & combo immunotherapies in preclinical humanized models

The breakthrough of immune checkpoint-targeting therapies has unveiled new hopes for cancer therapy. However, subsets of patients who do not see robust responses to immunotherapy remain. To address this hurdle, combination therapies – coupling agents with distinct mechanisms of action (MoA) – appear promising to enhance treatment success against various cancers. However, a major challenge in the development of novel combination therapies is the unmet need for preclinical models to predict efficacy and tolerability. Immunocompetent models featuring humanized immune checkpoints enable the assessment of human-targeted therapies in well-established syngeneic tumor models, allowing investigation with fully functional crosstalk among syngeneic tumor, immune, and stromal cells. While these models enable profiling evaluation of agents directed toward human targets, results still reflect mouse biology. Alternatively, immunodeficient mice reconstituted with a human immune system offer the possibility to investigate the efficacy and MoA of agents directed against human targets, with the advantage of exploring human biology using human tumor cell lines in a mouse model. This article discusses examples of applicability and complementarity of syngeneic and BRGSF– human immune system (HIS) models to assess the efficacy and MoA of immunotherapies, either in combination with inhibitory immune checkpoints or as monotherapy.