Abstract 1235: Complex in vitro tumor models screen NK therapy and reveal mode of action

Abstract NK cell therapy is an emerging and increasingly promising modality for various cancers. Whereas T cell-based adoptive cell therapy (e.g. tumor infiltrating lymphocytes or TILs, and CAR-T) is mainly limited to patient’s autologous cells due to concerns around allogeneic responses with MHC (major histocompatibility complex) mismatch, NK therapies do not suffer from this due to their low risk of introducing GvHD (Graft-versus-host disease), enabling the development of NK therapies using either patient-sourced NK cells or allogeneic, healthy donor-sourced cells. NK therapies have demonstrated early success in some hematologic cancer, however, the inadequate infiltration and persistence in the tumor microenvironment (TME) limits their application in solid tumors. Therefore, the ability to model solid tumors in vitro to screen efficacy and study mode of action would be highly beneficial to gaining early and actionable insights for clinical translation. Here, we developed several patient-derived xenograft (PDX) 3D in vitro non-small cell lung or colorectal cancer models using a proprietary hydrogel platform. The platform resembles the TME to enable consistent growth of tumor cells, fibroblast elongation, and immune cell interactions. An activated NK cell population (“NK therapy”), featuring CD56bright CD16+ (∼50%) and CD56bright CD16- (∼50%) phenotypes by flow cytometry, was highly potent in the 3D models. These NK therapy cells demonstrated a significant increase in tumor infiltration and tumor cytotoxicity compared to the non-activated NK (“NK control”) counterparts from the same donor. Interestingly, key cytokines like IFNg were downregulated in the NK therapy as compared to the NK control. These data demonstrate a robust and comprehensive in vitro analysis for NK therapy, offering a new preclinical tool for validating their effectiveness and mode of action. Citation Format: Bin Xue, Christopher Harrod, Long Le, Julia Schueler, Kolin C. Hribar. Complex in vitro tumor models screen NK therapy and reveal mode of action [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 1235.