Phenotypic Human Primary Cell-based Tumor Microenvironment Models for Evaluation of Drug Combinations for Immune Oncology

Phenotypic Human Primary Cell-based Tumor Microenvironment Models for Evaluation of Drug Combinations for Immune Oncology
Version:
033016

File Name/Number:
2016 Keystyone Poster

Year:
2016

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.
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The Diversity PLUS panel of 12 BioMAP systems has been validated to test agents and combinations with respect to predicting efficacy and safety.
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Additional panels relevant to oncology consist of co-cultures of human fibroblasts or endothelial cells, a cancer cell line, and immune cells.
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These host tumor microenvironment (TME) models mirror tumor-associated immune suppression biology relevant for immuno-oncology drug testing.
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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.
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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.
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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.
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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.