Engineered in vitro tumor models for cell-based immunotherapy

Ando, Yuta; Mariano, Chelsea; Shen, K. Robert

doi:10.1016/j.actbio.2021.03.076

Cited by 19 publications

(12 citation statements)

References 192 publications

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“…With live-cell imaging and cell tracking, the platform can also be extended to investigate endothelial-immune interaction in cell-based therapies, with a broader set of cell types including natural killer (NK) cells, dendritic cells (DCs), macrophages, engineered T cells, etc. [57]. Furthermore, immunotherapies, particularly those through antigen recognition by T cell receptor (TCR), involve major histocompatibility complex (or human leukocyte antigen, or HLA).…”

Section: Discussionmentioning

confidence: 99%

Engineering a Vascularized Hypoxic Tumor Model for Therapeutic Assessment

Ando

Zhao

et al. 2021

Cells

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Solid tumors in advanced cancer often feature a structurally and functionally abnormal vasculature through tumor angiogenesis, which contributes to cancer progression, metastasis, and therapeutic resistances. Hypoxia is considered a major driver of angiogenesis in tumor microenvironments. However, there remains a lack of in vitro models that recapitulate both the vasculature and hypoxia in the same model with physiological resemblance to the tumor microenvironment, while allowing for high-content spatiotemporal analyses for mechanistic studies and therapeutic evaluations. We have previously constructed a hypoxia microdevice that utilizes the metabolism of cancer cells to generate an oxygen gradient in the cancer cell layer as seen in solid tumor sections. Here, we have engineered a new composite microdevice-microfluidics platform that recapitulates a vascularized hypoxic tumor. Endothelial cells were seeded in a collagen channel formed by viscous fingering, to generate a rounded vascular lumen surrounding a hypoxic tumor section composed of cancer cells embedded in a 3-D hydrogel extracellular matrix. We demonstrated that the new device can be used with microscopy-based high-content analyses to track the vascular phenotypes, morphology, and sprouting into the hypoxic tumor section over a 7-day culture, as well as the response to different cancer/stromal cells. We further evaluated the integrity/leakiness of the vascular lumen in molecular delivery, and the potential of the platform to study the movement/trafficking of therapeutic immune cells. Therefore, our new platform can be used as a model for understanding tumor angiogenesis and therapeutic delivery/efficacy in vascularized hypoxic tumors.

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Section: Discussionmentioning

confidence: 99%

Engineering a Vascularized Hypoxic Tumor Model for Therapeutic Assessment

Ando

Zhao

et al. 2021

Cells

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“…However, the tumor spheroids most commonly used for MPS oncology studies are aggregates of cancer cell lines, either in monoculture or in combination with other cell types such as cancer-associated fibroblasts (CAFs) or endothelial cells (ECs), and in many instances lacking extracellular matrix. Immune components are typically incorporated with the addition of lymphocytes from peripheral blood mononuclear cells (PBMC), tumor infiltrating lymphocytes, CAR T, or CAR NK cells [ 28 , 29 , 30 , 31 , 32 ]. A unique approach to replicating the TIME in MPS is to collect organotypic spheroids directly from tumor tissues.…”

Section: Microphysiological Models For Cell Therapy Testingmentioning

confidence: 99%

Engineered Microphysiological Systems for Testing Effectiveness of Cell-Based Cancer Immunotherapies

Shelton

Chen

Kamm

et al. 2022

Cancers

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Cell therapies, including adoptive immune cell therapies and genetically engineered chimeric antigen receptor (CAR) T or NK cells, have shown promise in treating hematologic malignancies. Yet, immune cell infiltration and expansion has proven challenging in solid tumors due to immune cell exclusion and exhaustion and the presence of vascular barriers. Testing next-generation immune therapies remains challenging in animals, motivating sophisticated ex vivo models of human tumor biology and prognostic assays to predict treatment response in real-time while comprehensively recapitulating the human tumor immune microenvironment (TIME). This review examines current strategies for testing cell-based cancer immunotherapies using ex vivo microphysiological systems and microfluidic technologies. Insights into the multicellular interactions of the TIME will identify novel therapeutic strategies to help patients whose tumors are refractory or resistant to current immunotherapies. Altogether, these microphysiological systems (MPS) have the capability to predict therapeutic vulnerabilities and biological barriers while studying immune cell infiltration and killing in a more physiologically relevant context, thereby providing important insights into fundamental biologic mechanisms to expand our understanding of and treatments for currently incurable malignancies.

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“…[1][2][3] To continue its development, it is necessary to optimize and standardize protocols for upscaling clinical cell manufacture. 4,5 To effectively treat a malignancy, a single dose of engineered T cells could require several hundreds of thousands of therapeutic patient-derived T cells, that must retain the desired phenotype and function to ensure the effectiveness of treatment. 6,7 To successfully expand T cells ex vivo, before or aer the genetic modication, they are rst articially stimulated to imitate the in vivo function of antigen-presenting cells (APCs) to subsequently proliferate under immunological synapses.…”

Section: Introductionmentioning

confidence: 99%