Engineered in vitro tumor models for cell-based immunotherapy

Abstract

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.

Figure 1.

A brief overview of cell-based immunotherapy. In a process known as adoptive cell transfer, cells are extracted from patient blood, engineered, and reinfused into the patient. Engineered immune cells circulate in the bloodstream until they eventually arrive in the tumor site, resulting in cancer killing or T cell recruitment and activation.

Figure 2.

(a) A representation of a multicellular tumor spheroid (ref [102]). (b) Tumor spheroids naturally form a gradient of soluble factors, with a core that is oxygen-deficient and rich in metabolic waste products. (c) Culture conditions (2-D versus spheroid culture) change phenotypic expression of patient-derived glioblastoma cells (ref [107]). (d) PBMC-induced tumor apoptosis was monitored by evaluating spheroid volume (top) and expression of cleaved caspase-3/−7 (bottom) (ref [110]).

Figure 3.

(a) A schematic of tumor organoid formation. Organoids can be formed from digested tumor tissue or through self-assembly of differentiated stem cells. (b) Tumor organoids recapitulate in vivo histology (ref [195]).

Figure 4.

(a) A side section of a typical microfluidics device. A channel connects the immune and tumor chamber, allowing for crosstalk between the two cell types. (b) TCR-engineered T cells (blue) showed tumor (green)-specific cytotoxicity (red) over time, compared to control T cells (ref [151]). (c) Endothelial cells (red) lining the surfaces of a microfluidics channel interacted with tumor cells (green) extravasating (ref [143]).

Figure 5.

(a) Multicellular structures like spheroids and organoids can be embedded in a hydrogel-filled chamber of a microfluidics device. (b) A microfluidics device with TCR-engineered T cells (blue) and tumor spheroids (green) was imaged over time to assess the degree of T cell-induced cytotoxicity (red) (ref [151]). (c) 3-D tumor micropatterns cultured under a gradient of hypoxia were treated with CAR T cells to resolve spatial and temporal cytotoxicity patterns (ref [165]).

Figure 6.

Engineered tumor models assessing tumor immunology and immunotherapy require smart designs. Special considerations should be made in cell-cell interactions of different cell types, connectivity of cell-secreted factors, biomechanics such as fluid pressure and ECM stiffness, and accurate depiction of a 3-D architecture.