Abstract 4397: Leveraging patient-derived organoids to investigate bystander effects of antibody-drug conjugates in solid tumor backgrounds

Abstract Background: Antibody-drug conjugates (ADCs) have demonstrated significant clinical benefit, yet their efficacy can be influenced by heterogeneous target expression and bystander killing. Understanding these dynamics in physiologically relevant models is critical for optimizing ADC design and patient selection. Methods: We established and expanded patient-derived organoids (PDOs) from solid tumor backgrounds using our automated CX.ai platform, enabling high-throughput and standardized culture conditions. Target abundance for HER2 and c-MET was assessed via immunohistochemistry (IHC). Co-culture systems were optimized to include disease and healthy PDOs at defined ratios. Experimental assays incorporated mosaic PDO populations treated with ADCs (trastuzumab deruxtecan, telisotuzumab adizutecan, ADCs) and controls (antibody alone, warhead alone). Readouts included live-cell imaging, fixed-cell labelling, and high-content analysis to quantify PDO shrinkage, cell death, and target expression. Results: Preliminary data indicate feasibility of generating mosaic PDO systems and detecting differential responses to ADCs. Optimization of co-culture conditions and imaging-based metrics (nuclear count reduction, PDO object shrinkage) are underway to correlate target expression heterogeneity with bystander killing. Conclusions: PDO-based platforms combined with automated culture and advanced image analysis provide a robust system to study ADC bystander effects in heterogeneous tumor contexts. These findings will inform ADC development strategies and biomarker-driven patient selection. Citation Format: Oksana Sirenko, Nikki Carter. Leveraging patient-derived organoids to investigate bystander effects of antibody-drug conjugates in solid tumor backgrounds abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4397.