[Advances in Immuno-Oncology Congress] Evaluation of Small Molecules for Immuno-Oncology Development Using BioMAP Early Screening Phenotypic Services
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- Advances in Immuno-Oncology Congress
Less than a dozen immuno-oncology (IO) drugs have been approved for the treatment of cancers recalcitrant or resistant to more traditional approaches such as hormone or chemotherapies. And although immune checkpoint inhibitors, in particular anti-PD-(L)1 antibodies, are now considered an integral standard-of-care across many cancer types, their efficacy remains limited to a small cohort of patients. The need for better IO therapies with
greater clinical success continues to fuel investigational programs in the pursuit of next-generation candidates with improved outcomes for a broader patient population. For clinical success, IO drugs must first target immune cells, restoring their cell killing ability. The desired outcome, cancer cell killing, is a secondary impact. One approach to address this drug discovery challenge is to screen compounds that elicit the key immune restorative response within the tumor microenvironment (TME). Ideally, a small molecule therapeutic would represent a distinct advantage over existing biologics, both in terms of administration as well as ability to optimize chemistry. In order to efficiently identify molecules with IO potential, a high throughput, physiologically relevant, screening approach that recapitulates the complexity of the TME is needed. BioMAP® Oncology Systems are co-cultures of human primary cell types (endothelial cells, fibroblasts, and PBMCs) and cancer cells that model immune suppressed TME biology. Compounds can be screened in these in vitro TME models to look for impacts on protein biomarkers relevant for immune responses, inflammation, matrix modulation and for impacts on cancer cells. These systems were validated for immune restorative activities using anti PD-(L)1 therapeutics pembrolizumab, nivolumab, and durvalumab. Specifically, increases in proinflammatory cytokine levels served as hallmark activities indicating a reversal of the immune suppressive influence of the cancer cell. In the StroHT29 BioMAP oncology system, we screened a library of 72 compounds targeting different molecules, the vast majority of which had not previously been identified as potential immuno-oncology candidates. Several small molecules that increased one or more cytokines were identified, indicating immune restorative potential consistent with IO potential. Interestingly, some of these small molecules inhibited immune responses consistent with oncology or autoimmune potential; others demonstrated anti-
inflammatory activities and influenced matrix biomarkers, indicating impacts on distinct compartments of the TME. This approach using human cell-based in vitro TME models represents a rapid and cost-effective manner to rapidly screen libraries of small molecules (both novel and repurposed) for immuno-oncology potential.