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IL-21- and CXCL9-engineered GPC3-specific CAR-T cells combined with PD-1 blockade enhance cytotoxic activities against hepatocellular carcinoma.
Chen, Shanshan; Gong, Fusheng; Liu, Shijia; Xie, Yunqing; Ye, Xingming; Lin, Xiaowei; Wang, Xiangru; Zheng, Qiuhong; Liu, Qinying; Sun, Yang.
Afiliación
  • Chen S; Fujian Provincial Key Laboratory of Tumor Biotherapy, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, 350014, China.
  • Gong F; Fujian Provincial Key Laboratory of Tumor Biotherapy, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, 350014, China.
  • Liu S; Fujian Provincial Key Laboratory of Tumor Biotherapy, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, 350014, China.
  • Xie Y; Fujian Provincial Key Laboratory of Tumor Biotherapy, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, 350014, China.
  • Ye X; Fujian Provincial Key Laboratory of Tumor Biotherapy, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, 350014, China.
  • Lin X; Fujian Provincial Key Laboratory of Tumor Biotherapy, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, 350014, China.
  • Wang X; Fujian Provincial Key Laboratory of Tumor Biotherapy, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, 350014, China.
  • Zheng Q; Fujian Provincial Key Laboratory of Tumor Biotherapy, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, 350014, China.
  • Liu Q; Xiamen Humanity Hospital, Xiamen, 361003, China.
  • Sun Y; Fujian Provincial Key Laboratory of Tumor Biotherapy, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, 350014, China.
Clin Exp Med ; 24(1): 204, 2024 Aug 28.
Article en En | MEDLINE | ID: mdl-39196390
ABSTRACT
The application of CAR-T cells in solid tumors poses several challenges, including poor T cell homing ability, limited infiltration of T cells and an immunosuppressive tumor environment. In this study, we developed a novel approach to address these obstacles by designing GPC3-specific CAR-T cell that co-express IL-21 and CXCL9 (21 × 9 GPC3 CAR-T cells) and blocking the PD-1 expression on it. The proliferation, cell phenotype, cytokine secretion and cell migration of indicated CAR-T cells were evaluated in vitro. The cytotoxic activities of genetically engineered CAR-T cells were accessed in vitro and in vivo. Compared to conventional GPC3 CAR-T cells, the 21 × 9 GPC3 CAR-T cells demonstrated superior proliferation, cytokine secretion and chemotaxis capabilities in vitro. Furthermore, when combined with PD-1 blockade, the 21 × 9 GPC3 CAR-T cells exhibited enhanced proliferation, cytokine secretion and enrichment of effector T cells such as CTL, NKT and TEM cells. In xenograft tumor models, the PD-1 blocked 21 × 9 GPC3 CAR-T cells effectively suppressed HCC xenograft growth and increased T cell infiltration. Overall, our study successfully generated GPC3 CAR-T cells expressing both IL-21 and CXCL9, demonstrated that combining PD-1 blockade can further enhance CAR-T cell function by promoting proliferation, cytokine secretion, chemotaxis and antitumor activity. These findings present a hopeful and potentially effective strategy for GPC3-positive HCC patients.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Inmunoterapia Adoptiva / Interleucinas / Carcinoma Hepatocelular / Glipicanos / Quimiocina CXCL9 / Receptor de Muerte Celular Programada 1 / Receptores Quiméricos de Antígenos / Neoplasias Hepáticas Límite: Animals / Humans Idioma: En Revista: Clin Exp Med Asunto de la revista: MEDICINA Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Italia
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Inmunoterapia Adoptiva / Interleucinas / Carcinoma Hepatocelular / Glipicanos / Quimiocina CXCL9 / Receptor de Muerte Celular Programada 1 / Receptores Quiméricos de Antígenos / Neoplasias Hepáticas Límite: Animals / Humans Idioma: En Revista: Clin Exp Med Asunto de la revista: MEDICINA Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Italia