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Split chimeric antigen receptor-modified T cells targeting glypican-3 suppress hepatocellular carcinoma growth with reduced cytokine release.
Liu, Xuan; Wen, Jianyun; Yi, Honglei; Hou, Xiaorui; Yin, Yue; Ye, Guofu; Wu, Xuedong; Jiang, Xiaotao.
Afiliación
  • Liu X; Department of Pediatrics, Nanfang Hospital, Southern Medical University, Guangzhou, China.
  • Wen J; Department of Pediatrics, Nanfang Hospital, Southern Medical University, Guangzhou, China.
  • Yi H; Department of Orthopedics, General Hospital of Southern Theater Command, Guangzhou, China.
  • Hou X; Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
  • Yin Y; Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
  • Ye G; State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China.
  • Wu X; Department of Pediatrics, Nanfang Hospital, Southern Medical University, Tonghe Road, Guangzhou, 510515, China.
  • Jiang X; Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Shatai Road, Guangzhou, 510515, China.
Ther Adv Med Oncol ; 12: 1758835920910347, 2020.
Article en En | MEDLINE | ID: mdl-32215059
BACKGROUND: Human glypican-3 (hGPC3) is a protein highly expressed in hepatocellular carcinoma (HCC) but limited in normal tissues, making it an ideal target for immunotherapy. The adoptive transfer of hGPC3-specific chimeric antigen receptor T (CAR-T) cells for HCC treatment has been conducted in clinical trials. Due to the rigid construction, conventional CAR-T cells have some intrinsic limitations, like uncontrollable overactivation and inducing severe cytokine release syndrome. METHODS: We redesigned the hGPC3-specific CAR by splitting the traditional CAR into two parts. By using coculturing assays and a xenograft mouse model, the in vitro and in vivo cytotoxicity and cytokine release of the split anti-hGPC3 CAR-T cells were evaluated against various HCC cell lines and compared with conventional CAR-T cells. RESULTS: In vitro data demonstrated that split anti-hGPC3 CAR-T cells could recognize and lyse hGPC3+ HepG2 and Huh7 cells in a dose-dependent manner. Impressively, split anti-hGPC3 CAR-T cells produced and released a significantly lower amount of proinflammatory cytokines, including IFN-γ, TNF-α, IL-6, and GM-CSF, than conventional CAR-T cells. When injected into immunodeficient mice inoculated subcutaneously with HepG2 cells, our split anti-hGPC3 CAR-T cells could suppress HCC tumor growth, but released significantly lower levels of cytokines than conventional CAR-T cells. CONCLUSIONS: We describe here for the first time the use of split anti-hGPC3 CAR-T cells to treat HCC; split anti-hGPC3 CAR-T cells could suppress tumor growth and reduce cytokine release, and represent a more versatile and safer alternative to conventional CAR-T cells treatment.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Ther Adv Med Oncol Año: 2020 Tipo del documento: Article País de afiliación: China Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
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XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Ther Adv Med Oncol Año: 2020 Tipo del documento: Article País de afiliación: China Pais de publicación: Reino Unido