Abstract 1595: Transforming tumor terrain: Effect of datopotamab deruxtecan (Dato-DXd) on the tumor microenvironment in three-dimensional explant lung tumor models

Abstract Introduction: Antibody-drug conjugates (ADCs) targeting Trop-2 (human trophoblast cell surface antigen 2) are a promising class of therapeutics with potential to enhance therapeutic outcomes for non-small cell lung cancer. Dato-DXd, a Trop-2 targeted ADC, has demonstrated encouraging activity, leading to further interest in testing combinatorial approaches. However, a greater understanding of its effects on the tumor microenvironment (TME) are needed to identify optimal combinations. Herein we examine tumor-stromal interactions in response to Dato-DXd in ex vivo three dimensional-lung tumor models (3D-LTMs). Methods: 3D-LTMs were generated utilizing freshly isolated, remnant human lung tumor specimen from patients undergoing tumor resection (Institutional Review Board approved protocol) and continuously perfused with culture media to provide nutrient circulation. Starting on day 3 of culture, 4, 6, or 8 mg/kg Dato-DXd or vehicle control was added to circulating media. Dato-DXd used in this study was purchased from a 3rd party commercial vendor (MedChemExpress). On day 14 of culture (day 11 of ADC treatment) histologic and flow cytometry analyses were performed. Results: An increased trend in the percentage of apoptotic cells (18.5±1.5 vs. 13±1.5; p=0.13) was noted with 6 mg/kg Dato-DXd when compared to vehicle control. Additionally, a significant reduction in the percentage of tumor cells (p=0.025) and a significant increase in non-viable tumor cells (p=0.047) was observed with this dose when compared to vehicle treated tissues. No differences in fibroblasts, CD45+ immune cells, CD8+ T cells, endothelial cells, or non-viable fibroblasts was observed between 6 mg/kg Dato-DXd and control. When an 8 mg/kg dose was utilized a significant increase in total CD45+ immune cells (p=0.0007) and CD8+ T cells (p=0.012) and an increasing trend in endothelial cells (p=0.099) was observed when compared to vehicle control. No significant changes in apoptosis, tumor cells, fibroblasts, or non-viable tumor cells or fibroblasts were observed when comparing this dose to control. When proportions were normalized to reduce variability across tissues, an increase in apoptotic cells was observed in 3 of 5 samples assessed at 4 mg/kg, and 4 of 5 samples at 6 and 8 mg/kg. An increase in immune cells (CD45+) was observed in 3 of 5 samples at 6 and 8 mg/kg. An increase in CD8+ T cells was observed in 3 of 5 samples at 8 mg/kg. Conclusion: We observed a notable trend towards an increase in immune cell populations (e.g. CD8+ T cells) following Dato-DXd treatment in 3D-LTMs. These preliminary findings indicate an enhanced anti-tumor immune response following treatment with Dato-DXd. Collectively, data suggest that Dato-DXd induces significant alterations in the TME which may facilitate the evaluation of rational drug combinations to amplify the anti-tumor response. Citation Format: Kayla F. Goliwas, Siva C. Chabattula, Ahmed Ismail, James M. Donahue, Benjamin Wei, Thomas S. Winokur, Jessy S. Deshane, Yanis Boumber, Aakash Desai. Transforming tumor terrain: Effect of datopotamab deruxtecan (Dato-DXd) on the tumor microenvironment in three-dimensional explant lung tumor models [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 1595.