Evaluating CAR‐T Cell Therapy in a Hypoxic 3D Tumor Model

Ando, Yuta; Siegler, Elizabeth L.; Ta, Hoang P.; Cinay, Gunce E.; Zhou, Hao; Gorrell, Kimberly A.; Au, Hannah; Jarvis, Bethany M.; Wang, Pin; Shen, K. Robert

doi:10.1002/adhm.201900001

Cited by 70 publications

(77 citation statements)

References 101 publications

(119 reference statements)

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“…[14][15][16][17][18] However, they are labor-intensive and difficult to use. [14][15][16][17][18] However, they are labor-intensive and difficult to use.…”

Section: However Current Tools For Evaluating Car-t Functions Lack Smentioning

confidence: 99%

Dynamic Profiling of Antitumor Activity of CAR T Cells Using Micropatterned Tumor Arrays

et al. 2019

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Cancer immunotherapy based on the engineering of chimeric antigen receptors (CAR) on T cells has emerged as one of the most promising new therapies for patients with B‐cell malignancies. Preclinical assessments of essential CAR T cell functions such as trafficking and cytotoxicity are critical for accelerating the development of highly effective therapeutic candidates. However, current tools for evaluating CAR‐T functions lack sufficient precision. Here, a micropatterned tumor array (MiTA) is described that enables detailed and dynamic characterization of CAR T cell trafficking toward tumor‐cell islands and subsequent killing of tumor cells. It is shown that CAR T cells often merge into large clusters that envelop and kill the tumor cells with high efficiency. Significant differences are also measured between CAR T cells from different donors and between various CAR T cell constructs. Overall, the assay allows for multifaceted, dynamic, high‐content evaluation of CAR T trafficking, clustering, and killing and could eventually become a useful tool for immune‐oncology research and preclinical assessments of cell‐based immunotherapies.

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“…[14][15][16][17][18] However, they are labor-intensive and difficult to use. [14][15][16][17][18] However, they are labor-intensive and difficult to use.…”

Section: However Current Tools For Evaluating Car-t Functions Lack Smentioning

confidence: 99%

Dynamic Profiling of Antitumor Activity of CAR T Cells Using Micropatterned Tumor Arrays

et al. 2019

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“…The results showed that NK-92 cells modified by CAR can directly target the ubiquitous epithelial antigen (EpCAM), which can be effectively targeted in multiple organoids [118]. Another group explored the drug sensitivity and cytotoxicity of CAR-T cells by establishing different oxygen gradients in the 3D model of ovarian cancer [119]. The results showed that the OC 3D model can study CAR-T cytotoxicity better than the 2D model.…”

Section: Application Of Immunotherapymentioning

confidence: 99%

Organoid of ovarian cancer: genomic analysis and drug screening

et al. 2020

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Ovarian cancer is the most common malignant tumors of the female reproductive system, and its standard treatments are cytoreductive surgery and platinum-based adjuvant chemotherapy. Great advances have been achieved in novel treatment strategies, including targeted therapy and immunotherapy. However, ovarian cancer has the highest mortality rate among gynecological tumors due to therapeutic resistance and the gap between preclinical data and actual clinical efficacy. Organoids are a 3D culture model that markedly affects gene analysis, drug screening, and drug sensitivity determination of tumors, especially when used in targeted therapy and immunotherapy. In addition, organoid can lead to advances in the preclinical research of ovarian cancer due to its convenient cultivation, good genetic stability, and high homology with primary tumors.

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“…Similarly, a 3D microfluidic human ovarian cancer model was developed by embedding human epidermal growth factor receptor 2 (HER2) + ovarian cancer cells (SKOV3) in a micropatterned gelatin methacryloyl (GelMA) hydrogel and micromilled hypoxia device to establish an oxygen gradient across micropatterned cancer cells. [ 161 ] It consisted of perfusion channels for the delivery of HER2‐targeting 4D5 scFv CAR‐T cells and to study the infiltration as well as the cytotoxicity of CAR‐T cells under heterogeneous oxygen concentration conditions within the tumor. The enhanced cytotoxic activity of CAR‐T cells was observed under the physiologically relevant oxygen level, whereas immunosuppression was increased under the hypoxic condition as shown by increased PD‐L1 expression by the tumor cells under hypoxia culture.…”

Section: Other Relevant Immunocompetent Ooc Modelsmentioning

confidence: 99%

3D Immunocompetent Organ‐on‐a‐Chip Models

2020

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In recent years, engineering of various human tissues in microphysiologically relevant platforms, known as organs‐on‐chips (OOCs), are explored to establish in vitro tissue models that recapitulate the microenvironments found in native organs and tissues. However, most of these models have overlooked the important roles of immune cells in maintaining tissue homeostasis under physiological conditions and in modulating the tissue microenvironments during pathophysiology. Significantly, gradual progress is being made in the development of more sophisticated microphysiologically relevant human‐based OOC models that allow the studies of the key biophysiological aspects of specific tissues or organs, interactions between cells (parenchymal, vascular, and immune cells) and their extracellular matrix molecules, effects of native tissue architectures (geometry, dynamic flow, or mechanical forces) on tissue functions, as well as unravelling the mechanism underlying tissue‐specific diseases and drug testing. In this progress report, the different components of the immune system, as well as immune OOC platforms and immunocompetent OOC approaches that have simulated one or more components of the immune system, are discussed. The challenges to recreate a fully functional tissue system in vitro with a focus on the incorporation of the immune system are also outlined.

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Evaluating CAR‐T Cell Therapy in a Hypoxic 3D Tumor Model

Cited by 70 publications

References 101 publications

Dynamic Profiling of Antitumor Activity of CAR T Cells Using Micropatterned Tumor Arrays

Dynamic Profiling of Antitumor Activity of CAR T Cells Using Micropatterned Tumor Arrays

Organoid of ovarian cancer: genomic analysis and drug screening

3D Immunocompetent Organ‐on‐a‐Chip Models

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