A three dimensional human immune-tumor cell model reveals the importance of isotypes in antibody-based immunotherapy

Monoclonal antibodies (mAb) have revolutionized clinical medicine, especially in the field of cancer immunotherapy. The challenge now is to improve the response rates in the patients, as immunotherapy still fails for many patients. Strategies to enhance tumor cell death is a fundamental aim, but relevant model systems for human tumor immunology are lacking. Herein, we have developed a novel pre-clinical human immune – three-dimensional (3D) tumor model (spheroids) to map the efficiency of tumor-specific isotypes for improved tumor cell killing. Different anti-CD20 Rituximab (RTX) isotypes alone or in combination, were evaluated for mediating complement-dependent cytotoxicity and antibody-dependent phagocytosis by human monocytic cells in 3D spheroids, in parallel with monolayer culture, of human CD20 + B-cell lymphoma. We show that the IgG3 variant of RTX has the greatest tumoricidal effect over other isotypes, mediating strong infiltration of monocytic effector cells into 3D spheroids. Hence, the human immune-3D tumor model is an attractive ex vivo system to help filter out mAbs for best efficacy in cancer immunotherapy.