Efficacy of anti-CD147 chimeric antigen receptors targeting hepatocellular carcinoma

Hsiang chi Tseng; Wei Xiong; Saiaditya Badeti; Yan Yang; Minh Ma; Ting Liu; Carlos A. Ramos; Gianpietro Dotti; Luke Fritzky; Jie gen Jiang; Qing Yi; James Guarrera; Wei Xing Zong; Chen Liu; Dongfang Liu

doi:10.1038/s41467-020-18444-2

Efficacy of anti-CD147 chimeric antigen receptors targeting hepatocellular carcinoma

Hsiang chi Tseng, Wei Xiong, Saiaditya Badeti, Yan Yang, Minh Ma, Ting Liu, Carlos A. Ramos, Gianpietro Dotti, Luke Fritzky, Jie gen Jiang, Qing Yi, James Guarrera, Wei Xing Zong, Chen Liu, Dongfang Liu

Research output: Contribution to journal › Article › peer-review

120 Scopus citations

Abstract

Chimeric antigen receptor (CAR) therapy is a promising immunotherapeutic strategy for treating multiple refractory blood cancers, but further advances are required for solid tumor CAR therapy. One challenge is identifying a safe and effective tumor antigen. Here, we devise a strategy for targeting hepatocellular carcinoma (HCC, one of the deadliest malignancies). We report that T and NK cells transduced with a CAR that recognizes the surface marker, CD147, also known as Basigin, can effectively kill various malignant HCC cell lines in vitro, and HCC tumors in xenograft and patient-derived xenograft mouse models. To minimize any on-target/off-tumor toxicity, we use logic-gated (log) GPC3–synNotch-inducible CD147-CAR to target HCC. LogCD147-CAR selectively kills dual antigen (GPC3⁺CD147⁺), but not single antigen (GPC3^-CD147⁺) positive HCC cells and does not cause severe on-target/off-tumor toxicity in a human CD147 transgenic mouse model. In conclusion, these findings support the therapeutic potential of CD147-CAR-modified immune cells for HCC patients.

Original language	English (US)
Article number	4810
Pages (from-to)	4810
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-18444-2
State	Published - Sep 23 2020

Keywords

Animals
Basigin/genetics
Carcinoma, Hepatocellular/drug therapy
Cell Line, Tumor
Disease Models, Animal
Female
Hep G2 Cells
Humans
Immunotherapy, Adoptive/methods
Killer Cells, Natural
Liver/pathology
Liver Neoplasms/drug therapy
Male
Mice
Mice, Knockout
Mice, Transgenic
Receptors, Chimeric Antigen/drug effects
Xenograft Model Antitumor Assays

ASJC Scopus subject areas

General
General Physics and Astronomy
General Chemistry
General Biochemistry, Genetics and Molecular Biology

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10.1038/s41467-020-18444-2

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title = "Efficacy of anti-CD147 chimeric antigen receptors targeting hepatocellular carcinoma",

abstract = "Chimeric antigen receptor (CAR) therapy is a promising immunotherapeutic strategy for treating multiple refractory blood cancers, but further advances are required for solid tumor CAR therapy. One challenge is identifying a safe and effective tumor antigen. Here, we devise a strategy for targeting hepatocellular carcinoma (HCC, one of the deadliest malignancies). We report that T and NK cells transduced with a CAR that recognizes the surface marker, CD147, also known as Basigin, can effectively kill various malignant HCC cell lines in vitro, and HCC tumors in xenograft and patient-derived xenograft mouse models. To minimize any on-target/off-tumor toxicity, we use logic-gated (log) GPC3–synNotch-inducible CD147-CAR to target HCC. LogCD147-CAR selectively kills dual antigen (GPC3+CD147+), but not single antigen (GPC3-CD147+) positive HCC cells and does not cause severe on-target/off-tumor toxicity in a human CD147 transgenic mouse model. In conclusion, these findings support the therapeutic potential of CD147-CAR-modified immune cells for HCC patients.",

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author = "Tseng, {Hsiang chi} and Wei Xiong and Saiaditya Badeti and Yan Yang and Minh Ma and Ting Liu and Ramos, {Carlos A.} and Gianpietro Dotti and Luke Fritzky and Jiang, {Jie gen} and Qing Yi and James Guarrera and Zong, {Wei Xing} and Chen Liu and Dongfang Liu",

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year = "2020",

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doi = "10.1038/s41467-020-18444-2",

language = "English (US)",

volume = "11",

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T1 - Efficacy of anti-CD147 chimeric antigen receptors targeting hepatocellular carcinoma

AU - Tseng, Hsiang chi

AU - Xiong, Wei

AU - Badeti, Saiaditya

AU - Yang, Yan

AU - Ma, Minh

AU - Liu, Ting

AU - Ramos, Carlos A.

AU - Dotti, Gianpietro

AU - Fritzky, Luke

AU - Jiang, Jie gen

AU - Yi, Qing

AU - Guarrera, James

AU - Zong, Wei Xing

AU - Liu, Chen

AU - Liu, Dongfang

PY - 2020/9/23

Y1 - 2020/9/23

N2 - Chimeric antigen receptor (CAR) therapy is a promising immunotherapeutic strategy for treating multiple refractory blood cancers, but further advances are required for solid tumor CAR therapy. One challenge is identifying a safe and effective tumor antigen. Here, we devise a strategy for targeting hepatocellular carcinoma (HCC, one of the deadliest malignancies). We report that T and NK cells transduced with a CAR that recognizes the surface marker, CD147, also known as Basigin, can effectively kill various malignant HCC cell lines in vitro, and HCC tumors in xenograft and patient-derived xenograft mouse models. To minimize any on-target/off-tumor toxicity, we use logic-gated (log) GPC3–synNotch-inducible CD147-CAR to target HCC. LogCD147-CAR selectively kills dual antigen (GPC3+CD147+), but not single antigen (GPC3-CD147+) positive HCC cells and does not cause severe on-target/off-tumor toxicity in a human CD147 transgenic mouse model. In conclusion, these findings support the therapeutic potential of CD147-CAR-modified immune cells for HCC patients.

AB - Chimeric antigen receptor (CAR) therapy is a promising immunotherapeutic strategy for treating multiple refractory blood cancers, but further advances are required for solid tumor CAR therapy. One challenge is identifying a safe and effective tumor antigen. Here, we devise a strategy for targeting hepatocellular carcinoma (HCC, one of the deadliest malignancies). We report that T and NK cells transduced with a CAR that recognizes the surface marker, CD147, also known as Basigin, can effectively kill various malignant HCC cell lines in vitro, and HCC tumors in xenograft and patient-derived xenograft mouse models. To minimize any on-target/off-tumor toxicity, we use logic-gated (log) GPC3–synNotch-inducible CD147-CAR to target HCC. LogCD147-CAR selectively kills dual antigen (GPC3+CD147+), but not single antigen (GPC3-CD147+) positive HCC cells and does not cause severe on-target/off-tumor toxicity in a human CD147 transgenic mouse model. In conclusion, these findings support the therapeutic potential of CD147-CAR-modified immune cells for HCC patients.

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KW - Carcinoma, Hepatocellular/drug therapy

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KW - Female

KW - Hep G2 Cells

KW - Humans

KW - Immunotherapy, Adoptive/methods

KW - Killer Cells, Natural

KW - Liver/pathology

KW - Liver Neoplasms/drug therapy

KW - Male

KW - Mice

KW - Mice, Knockout

KW - Mice, Transgenic

KW - Receptors, Chimeric Antigen/drug effects

KW - Xenograft Model Antitumor Assays

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JF - Nature Communications

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ER -

Efficacy of anti-CD147 chimeric antigen receptors targeting hepatocellular carcinoma

Abstract

Keywords

ASJC Scopus subject areas

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