Abstract 3178: Discovery and characterization of small molecules to enhance NK cell cytotoxicity against solid tumors

Abstract Adoptive cell therapies (ACT), such as CAR-T and NK therapy, have transformed hematologic cancer treatment but show limited efficacy against solid tumors. NK cell therapies in particular have an excellent safety profile due to their specific, innate recognition of cancer cells, but fail to elicit adequate and sustained tumor clearance in vivo. To address this hurdle, we developed a high-throughput phenotypic small molecule screen to identify novel compounds that can enhance NK cell cytotoxicity against tumor cells. We screened 300, 000 compounds for their ability to enhance NK cytotoxicity against ovarian cancer cells (OVCAR-3). Our primary screen and subsequent hit validation identified 11 lead compounds that increase NK cell killing of OVCAR-3 cells (>10% increase over vehicle-treated control). We performed secondary screening using a flow cytometry-based assay on 5 of these 11 compounds to date, confirming that 3 significantly enhance NK cytotoxicity against OVCAR-3. After completing the secondary screening of the remaining 6 compounds, we will identify the most promising lead compound(s) through a series of secondary and orthogonal assays to characterize the biological activity and toxicity profile of validated hits. We will then pursue medicinal chemistry efforts to increase potency of our best lead compound, coupled with mechanistic studies for how the compound promotes NK cytotoxic activity. Ultimately, we hope to translate our findings into NK cell therapy clinical trials to achieve greater efficacy against solid cancers. Citation Format: Indrani Das, Olubukola Abiona, Riufu Liu, David N. Wald. Discovery and characterization of small molecules to enhance NK cell cytotoxicity against solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3178.