Abstract 656: A patient-derived <i>ex vivo</i> platform for personalized evaluation of both direct and immune-mediated drug responses.

Abstract Patient-derived xenograft (PDX) models represent a milestone of preclinical oncology research, serving as a valuable in vivo system for evaluating drug efficacy in mice and informing potential personalized therapeutic strategies. However, widespread application of PDX models has been limited by prolonged and variable engraftment timelines, relatively low success rates, and substantial operational costs. Moreover, the gradual replacement of human tumor microenvironment (TME) with murine stromal components compromises the fidelity of PDX models, particularly for evaluating immunomodulatory agents, which requires an intact human immune context. While patient-derived organoids (PDOs) offer a faster and more efficient modeling alternative, their utility is limited by absence of a representative TME, difficulties in assay standardization, and inherent selection bias towards specific cancer cell clones. These limitations raise concerns regarding their ability to provide reliable prediction on efficacy to complex treatment regimens, thereby motivating the development of more holistic ex vivo approaches. In the current study, we established an ex vivo tissue culture platform utilizing freshly resected patient tumors to evaluate anti-tumor efficacy of test articles across a panel of patient tumors. Tumor samples obtained from surgery were processed immediately into uniform sections by tissue slicing and cultured in a trans-well system exposed to various stimulants and/or test articles. Post incubation, the cultured tumor tissues were subjected to multiple downstream analyses, including tumor killing assessment, immune cell profiling, biomarker analysis, immunohistochemistry (IHC) and immunofluorescence (IF). The culture medium was analyzed to profile secreted cytokines and chemokines. An illustrative application: tumor tissues collected from lung cancer patients were evaluated on this platform to compare anti-PD1 responses. Tumor collected from anti-PD1 responsive patient revealed pronounced tumor suppression characterized by a 25% increase in CD8+CD103+ T cells and a 22% reduction in CD163+ macrophages by flow cytometry, enhanced caspase-3 staining, decreased Ki-67 and TGF-β signals via IF, and elevated expression levels of cytokines associated with immune suppression and TAM recruitment as measured by Luminex, collectively distinguishing this profile from that of non-responders. This ex vivo tissue culture system dramatically expands the utility of clinical specimens while maintaining native architecture and cellular heterogeneity. It enables rapid and direct assessment of therapeutic responses and shows strong correlation with in vivo outcomes, bridging a critical gap between traditional in vitro assays and subsequent in vivo studies. This approach may accelerate the pipeline for anti-cancer drug discovery and development. Citation Format: Jie Wen, Hao Cheng, Nan Yang. A patient-derived ex vivo platform for personalized evaluation of both direct and immune-mediated drug responses [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 656.