Enhancing Patient Lymphocyte Response to Peritoneal Malignancies Using a Personalized Immunocompetent Microfluidic Co-Culture Platform

Abstract Harnessing patient immune cells via adoptive cellular therapy is a promising cancer therapeutic strategy. However, major challenges remain for advanced solid malignancies, including difficulty isolating sufficient tumor infiltrating lymphocytes (TILs) and limited targeting of diverse neoantigens in heterogenous tumors. To address this, we have developed a tumor-on-a-chip platform with co-cultured patient-derived tumor cells, autologous peripheral blood mononuclear cells (PBMCs), and lymphoid tissue-derived antigen presenting cells. This approach generates organoid interacting lymphocytes (OILs) with enhanced anti-tumor activity. In peritoneal malignancies, OIL-induced cytotoxicity of patient-matched tumor cells surpasses both TILs and static-expanded PBMCs. We find that this improved performance was linked to increased CD8+ T and NK cells among OILs, and increased effector cytokine polyfunctionality, particularly Granzyme A. Our platform represents a versatile and scalable approach to generate patient-specific therapeutic lymphocytes even when TILs are insufficient, offering a promising avenue to treat diverse solid tumors associated with poor outcomes under current immunotherapies. Teaser A tumor-on-a-chip device primes patient immune cells with tumor recognition for personalized immunotherapy applications. Competing Interest Statement The authors have declared no competing interest. Footnotes ↵* indicates shared corresponding authorship