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Enhanced anti-tumor activity mediated by combination chimeric antigen receptor T cells targeting GD2 and GPC2 in high-risk neuroblastoma.
Wu, Huantong; Zhang, Guangji; Liu, Zhongfeng; Liu, Weihua; Wang, Xuan; Zhao, Yu.
Afiliación
  • Wu H; Cell Therapy Center, Beijing Institute of Geriatrics, Xuanwu Hospital Capital Medical University, National Clinical Research Center for Geriatric Diseases, and Key Laboratory of Neurodegenerative Diseases, Ministry of Education, Beijing, China; Center of Neural Injury and Repair, Beijing Institute f
  • Zhang G; Cell Therapy Center, Beijing Institute of Geriatrics, Xuanwu Hospital Capital Medical University, National Clinical Research Center for Geriatric Diseases, and Key Laboratory of Neurodegenerative Diseases, Ministry of Education, Beijing, China; Center of Neural Injury and Repair, Beijing Institute f
  • Liu Z; Cell Therapy Center, Beijing Institute of Geriatrics, Xuanwu Hospital Capital Medical University, National Clinical Research Center for Geriatric Diseases, and Key Laboratory of Neurodegenerative Diseases, Ministry of Education, Beijing, China; Center of Neural Injury and Repair, Beijing Institute f
  • Liu W; Cell Therapy Center, Beijing Institute of Geriatrics, Xuanwu Hospital Capital Medical University, National Clinical Research Center for Geriatric Diseases, and Key Laboratory of Neurodegenerative Diseases, Ministry of Education, Beijing, China; Center of Neural Injury and Repair, Beijing Institute f
  • Wang X; Department of Oncology, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Shandong Lung Cancer Institute, First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong Province, China.
  • Zhao Y; Cell Therapy Center, Beijing Institute of Geriatrics, Xuanwu Hospital Capital Medical University, National Clinical Research Center for Geriatric Diseases, and Key Laboratory of Neurodegenerative Diseases, Ministry of Education, Beijing, China; Center of Neural Injury and Repair, Beijing Institute f
Cytotherapy ; 26(11): 1308-1319, 2024 Nov.
Article en En | MEDLINE | ID: mdl-38904586
ABSTRACT
BACKGROUND

AIMS:

Chimeric antigen receptor T (CAR-T) cells targeting single antigens show limited activity against solid tumors due to poor T cell persistence, low efficiency infiltration, and exhaustion together with heterogeneous tumor-associated antigen (TAA) expression. This is also true in high-risk neuroblastoma (HRNB), a lethal pediatric extracranial malignancy. To overcome these obstacles, a combinational strategy using GD2-specific and GPC2-specific CAR-T cells was developed to improve immunotherapeutic efficacy.

METHODS:

We individually developed GD2-specific and GPC2-specific CARs containing a selective domain (sCAR) which was a peptide of 10 amino acids derived from human nuclear autoantigen La/SS-B. These constructs allowed us to generate two different HRNB antigen-specific CAR-T cells with enhanced biological activity through stimulating sCAR-engrafted T cells via a selective domain-specific monoclonal antibody (SmAb). Binding affinity and stimulation of GD2- and GPC2-specific sCARs by SmAb were measured, and transient and persistent anti-tumor cytotoxicity of GD2sCAR-T and GPC2sCAR-T cells were quantified in neuroblastoma cell lines expressing different TAA levels. The anti-tumor pharmaceutical effects and cellular mechanisms mediated by single or combinational sCAR-T cells were evaluated in vitro and in vivo.

RESULTS:

GD2- and GPC2-specific sCARs had antigen-specific binding affinity similar to their parental counterparts and were recognized by SmAb. SmAb-mediated stimulation selectively activated sCAR-T proliferation and increased central memory T cells in the final products. SmAb-stimulated sCAR-T cells had enhanced transient cytolytic activity, and combination therapy extended long-term anti-tumor activity in vitro through TNF-α and IL-15 release. Stimulated sCAR-T cells overcame heterogeneous antigen expression in HRNB, and the multi-TAA-targeting strategy was especially efficacious in vivo, inducing apoptosis through the caspase-3/PARP pathway and inhibiting the release of several tumor-promoting cytokines.

CONCLUSIONS:

These data suggest that combined targeting of multiple TAAs is a promising strategy to overcome heterogenous antigen expression in solid tumors and extend CAR-T cell persistence for HRNB immunotherapy.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Inmunoterapia Adoptiva / Glipicanos / Receptores Quiméricos de Antígenos / Gangliósidos / Neuroblastoma Límite: Animals / Humans Idioma: En Revista: Cytotherapy Asunto de la revista: TERAPEUTICA Año: 2024 Tipo del documento: Article Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
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XML
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Inmunoterapia Adoptiva / Glipicanos / Receptores Quiméricos de Antígenos / Gangliósidos / Neuroblastoma Límite: Animals / Humans Idioma: En Revista: Cytotherapy Asunto de la revista: TERAPEUTICA Año: 2024 Tipo del documento: Article Pais de publicación: Reino Unido