Amplifying lymphocyte response against primary peritoneal malignancy cells through a personalized immunocompetent organoid microfluidic platform 4186

Abstract Description It is known that current adoptive cellular therapies (ACT) may fail due to insufficient targeting of neoantigens formed by heterogeneous tumors and poor proliferative capacity of immune cells. To improve ACT, we developed a novel biomimetic device where patient-derived tumor organoids, enriched with antigen presenting cells, are cocultured with autologous peripheral blood mononuclear cells (PBMCs) in a microfluidic tumor-on-a-chip system (TOC). As PBMCs circulate through the device, they are exposed to dispersed tumor polyclonal neoantigens, leading to formation of patient- and tumor-specific organoid interacting lymphocytes (OILs). Using 30 surgical specimens from mesothelioma (10) and appendiceal adenocarcinoma (20) cases, we assessed the cytotoxic potential of OILs. Controls included patient-matched Tumor Infiltrating Lymphocytes (TILs) and uncirculated PBMCs. Utilizing flow cytometry, single-cell secretome analysis, media cytokine analysis, ELISA, and spatial proteomics, we observed that OILs produced significantly more granzyme B, granzyme A, and IFN-γ than controls (p < 0.05), were more polyfunctional, and had significantly (p < 0.01) increased tumor killing upon in vitro reintroduction. Funding Sources Supported by the Appendix Cancer Pseudomyxoma Peritoneil Research Foundation, the Mesothelioma Research Foundation, and the Wake Forest Comprehensive Cancer Center. Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)