Engineered in vitro tumor models for cell-based immunotherapy.

Tumor immunotherapy is rapidly evolving as one of the major pillars of cancer treatment. Cell-based immunotherapies, which utilize patient's own immune cells to eliminate cancer cells, have shown great promise in treating a range of malignancies, especially those of hematopoietic origins. However, their performance on a broader spectrum of solid tumor types still fall short of expectations in the clinical stage despite promising preclinical assessments. In this review, we briefly introduce cell-based immunotherapies and the inhibitory mechanisms in tumor microenvironments that may have contributed to this discrepancy. Specifically, a major obstacle to the clinical translation of cell-based immunotherapies is in the lack of preclinical models that can accurately assess the efficacies and mechanisms of these therapies in a (patho-)physiologically relevant manner. Lately, tissue engineering and organ-on-a-chip tools and microphysiological models have allowed for more faithful recapitulation of the tumor microenvironments, by incorporating crucial tumor tissue features such as cellular phenotypes, tissue architecture, extracellular matrix, physical parameters, and their dynamic interactions. This review summarizes the existing engineered tumor models with a focus on tumor immunology and cell-based immunotherapy. We also discuss some key considerations for the future development of engineered tumor models for immunotherapeutics. STATEMENT OF SIGNIFICANCE: Cell-based immunotherapies have shown great promise in treating hematological malignancies and some epithelial tumors. However, their performance on a broader spectrum of solid tumor types still fall short of expectations. Major obstacles include the inhibitory mechanisms in tumor microenvironments (TME) and the lack of preclinical models that can accurately assess the efficacies and mechanisms of cellular therapies in a (patho-)physiologically relevant manner. In this review, we introduce recent progress in tissue engineering and microphysiological models for more faithful recapitulation of TME for cell-based immunotherapies, and some key considerations for the future development of engineered tumor models. This overview will provide a better understanding on the role of engineered models in accelerating immunotherapeutic discoveries and clinical translations.