期刊
MOLECULAR THERAPY
卷 22, 期 3, 页码 634-644出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/mt.2013.277
关键词
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资金
- Inserm
- Fondation pour la Recherche Medicale (Comite Alsace)
- Ligue Nationale Contre le Cancer (Conference de Coordination Inter-Regionale Grand-Est) [1FI10005LBKD]
- ARC [SFI20111203529]
- Agence Nationale pour la Recherche (ANR, LabEx program)
- EU Interreg-IV Program Hepato-Regio-Net
- Agence Nationale pour la Recherche sur le SIDA et les Hepatites Virales (ANRS) [2008 059 ULP]
- Fondation Transplantatio
- Association pour la Recherche sur le Cancer (ARC) [DOC20110603384]
- Alsace Region
Cell therapy based on alloreactivity has completed clinical proof of concept against hematological malignancies. However, the efficacy of alloreactivity as a therapeutic approach to treat solid tumors is unknown. Using cell culture and animal models, we aimed to investigate the efficacy and safety of allogeneic suicide gene-modified killer cells as a cell-based therapy for hepatocellular carcinoma (HCC), for which treatment options are limited. Allogeneic killer cells from healthy donors were isolated, expanded, and phenotypically characterized. Antitumor cytotoxic activity and safety were studied using a panel of human or murine HCC cell lines engrafted in immunodeficient or immunocompetent mouse models. Human allogeneic suicide gene-modified killer cells (aSGMKCs) exhibit a high, rapid, interleukin-2-dependent, and non-major histocompatibility complex class I-restricted in vitro cytotoxicity toward human hepatoma cells, mainly mediated by natural killer (NK) and NK-like T cells. In vivo evaluation of this cell therapy product demonstrates a marked, rapid, and sustained regression of HCC. Preferential liver homing of effector cells contributed to its marked efficacy. Calcineurin inhibitors allowed preventing rejection of allogeneic lymphocytes by the host immune system without impairing their antitumor activity. Our results demonstrate proof of concept for aSGMKCs as immunotherapy for HCC and open perspectives for the clinical development of this approach.
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