Phenotypic Human Primary Cell-based Tumor Microenvironment Models for Evaluation of Drug Combinations for Immune Oncology
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- 2016 Keystyone Poster
We have developed complex in vitro co-cultures of human primary cells to model disease states in a standardized format to enable phenotypic drug screening.
The Diversity PLUS panel of 12 BioMAP systems has been validated to test agents and combinations with respect to predicting efficacy and safety.
Additional panels relevant to oncology consist of co-cultures of human fibroblasts or endothelial cells, a cancer cell line, and immune cells.
These host tumor microenvironment (TME) models mirror tumor-associated immune suppression biology relevant for immuno-oncology drug testing.
Drug effects on protein biomarkers in these models are measured and the resulting phenotypic signatures reveal how drugs will impact disease biology.
We evaluated multiple oncology drugs, including pembrolizumab (α-PD-1) and paclitaxel (anti-mitotic) alone and in combination, across the broad non-cancer Diversity PLUS panel and in the oncology systems.
Paclitaxel is highly active in Diversity PLUS and TME systems with decreased levels of tissue and tumor cell-specific markers. Paclitaxel increased levels of cytokines produced by immune cells but only in the TME models.
While pembrolizumab was inactive in non-TME systems, it showed similar activities in the TME systems with increased levels of granzyme B, IFNγ, IL-10, IL-17A and TNFα.
We observed potentiated anti-tumor activities with the combination relative to the monotherapies including increased IFNγ, IL-17A, and TNFα and decreased tumor cell markers.
In conclusion, phenotypic evaluation of drug combinations in complex human primary cellbased TME systems identifies therapeutic strategies warranting further clinical evaluation.