To date, a total of 26 immune oncology (I-O) therapies have been approved, including six immune checkpoint inhibitors targeting 18 different cancer types. Compelling clinical reports have propelled this anti-cancer strategy to a high priority focus of multiple drug pipelines. However, while these I-O drugs have led to increased survival, current reports indicate that only 25% to 30% of patients, and as low as 10% for some cancers, have achieved good objective responses rates. Thus, there is a clear need for more, better and safer I-O therapies to be developed. Currently, more than 2,000 candidates aimed at over 300 targets are in pre-clinical or clinical development worldwide. While this indicates an enormous investment of resources, it also illustrates significant duplication of efforts. Innovative approaches are needed to identify first-in-class and best-in-class therapeutic strategies involving both monotherapies and combination approaches.
Phenotypic profiling is a preclinical technique that models complex biology to provide a robust and powerful assessment of how human cells respond to agents or combinations. We have pioneered the development of an in vitro human cell-based BioMAP® phenotypic platform to integrate translational biology into the drug discovery process. For oncology applications, BioMAP systems were developed using early passage human primary stromal or vascular plus immune cell types co-cultured with the HT29 cancer cell line to model the human tumor microenvironment (TME). By recapitulating the intra-tumoral immunosuppression seen in vivo, these BioMAP systems can detect an I-O-relevant immune restoration effects of both candidates and combinations that required for clinical efficacy. Three approved checkpoint inhibitors, pembrolizumab, nivolumab and durvalumab, all increased cytokine levels indicating restored immune function in these human TME model systems. Moreover, other anti-cancer drugs such as paclitaxel, gemcitabine and erlotinib also demonstrated I-O activity patterns. These results provide compelling evidence that I-O therapies can be effectively qualified during preclinical development and underscore the critical need for earlier and more translationally-relevant target validation and qualification of mono- and combination therapies.