3D model for CAR-mediated cytotoxicity using patient-derived colorectal cancer organoids

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2019
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de Groot, Marnix HP
Zhang, Congcong
Mosa, Mohammed H.
Michels, Birgitta E.
Röder, Jasmin
Darvishi, Tahmineh
Wels, Winfried S.
Farin, Henner F.
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The EMBO journal. 2019, 38(12), e100928. ISSN 0261-4189. eISSN 1460-2075. Available under: doi: 10.15252/embj.2018100928
Zusammenfassung

Immunotherapy using chimeric antigen receptor (CAR)-engineered lymphocytes has shown impressive results in leukemia. However, for solid tumors such as colorectal cancer (CRC), new preclinical models are needed that allow to test CAR-mediated cytotoxicity in a tissue-like environment. Here, we developed a platform to study CAR cell cytotoxicity against 3-dimensional (3D) patient-derived colon organoids. Luciferase-based measurement served as a quantitative read-out for target cell viability. Additionally, we set up a confocal live imaging protocol to monitor effector cell recruitment and cytolytic activity at a single organoid level. As proof of principle, we demonstrated efficient targeting in diverse organoid models using CAR-engineered NK-92 cells directed toward a ubiquitous epithelial antigen (EPCAM). Tumor antigen-specific cytotoxicity was studied with CAR-NK-92 cells targeting organoids expressing EGFRvIII, a neoantigen found in several cancers. Finally, we tested a novel CAR strategy targeting FRIZZLED receptors that show increased expression in a subgroup of CRC tumors. Here, comparative killing assays with normal organoids failed to show tumor-specific activity. Taken together, we report a sensitive in vitro platform to evaluate CAR efficacy and tumor specificity in a personalized manner.

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ISO 690SCHNALZGER, Theresa, Marnix HP DE GROOT, Congcong ZHANG, Mohammed H. MOSA, Birgitta E. MICHELS, Jasmin RÖDER, Tahmineh DARVISHI, Winfried S. WELS, Henner F. FARIN, 2019. 3D model for CAR-mediated cytotoxicity using patient-derived colorectal cancer organoids. In: The EMBO journal. 2019, 38(12), e100928. ISSN 0261-4189. eISSN 1460-2075. Available under: doi: 10.15252/embj.2018100928
BibTex
@article{Schnalzger2019-06-17model-47046,
  year={2019},
  doi={10.15252/embj.2018100928},
  title={3D model for CAR-mediated cytotoxicity using patient-derived colorectal cancer organoids},
  number={12},
  volume={38},
  issn={0261-4189},
  journal={The EMBO journal},
  author={Schnalzger, Theresa and de Groot, Marnix HP and Zhang, Congcong and Mosa, Mohammed H. and Michels, Birgitta E. and Röder, Jasmin and Darvishi, Tahmineh and Wels, Winfried S. and Farin, Henner F.},
  note={Article Number: e100928}
}
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