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Table 1 Preclinical (in vitro and in vivo) studies of NK cell based immunotherapy for HCC

From: Combinational immune-cell therapy of natural killer cells and sorafenib for advanced hepatocellular carcinoma: a review

Interventions Design Strategy References
Activation of NK cells by intrahepatic injection of α-galactosylceramide- pulsed dendritic cells Mouse model of liver tumor (in vivo) Chemical therapy and DC cell transfer [64]
Activation of NK cells by Adenoviral IL-12 gene transfer Rats model of orthotopic HCC (in vivo) Cytokine gene therapy [64]
Activation of innate and acquired immunity by injection of IL-12gene-transduced dendritic cells Mouse model of liver tumor (in vivo) Cytokine gene therapy and DC cell transfer [65]
Augmentation of anti-human HCC effect of NK cells by IL-15 gene- modified NKL cell line Xenograft tumor models (in vivo) Cytokine gene modified NK cell lines and NK cell transfer [66]
Enhancement of anti-human HCC function of NK cell line by hIFN-alpha gene modification Cytotoxic assay (in vitro) and Xenograft tumor models (in vivo) Cytokine gene modified NK cell lines and NK cell transfer [67]
Strong role of MICA in HCV-related HCC patients Genome-wide association study (in vitro) Gene therapy [68]
Activation of NK cells via binding of MICA and NKG2D Cytotoxic assay (in vitro) Gene therapy and MAb therapy [69, 70]
Anti-HCC drugs such as sorafenib triggered anti-tumor activity of NK cells by down-regulation of ADAM10 or ADAM9 and increasing membrane bound of MICA on surface of the tumor cells Cytotoxic assay (in vitro) Chemo-immunotherapy [71, 72]
Sorafenib induced antitumor activity of NK cells by modulating the crosstalk between tumor-associated macrophages (TAM) and NK cells Animal experiments (in vivo) and killing assay (in vitro) Chemo-immunotherapy [73]
Antitumor effects of bortezomib via induction of MICA/B expression on HCC cells and increasing cytolytic activity of NK cells Cytotoxicity assay (in vitro) Chemo-immunotherapy [74]
Over-expression of MICA or MICB on hepatoma cells and activation of NK cells via induction of NKG2D ligands by histone deacetylase inhibitor Cytotoxicity assay and epigenetic study (in vitro) Chemo-immunotherapy [75,76,77]
Ex vivo generation, activation
and expansion of NK cells for immunotherapy of advanced cancer
(In vitro and in vivo) NK cell transfer [41, 78,79,80]
Increasing proliferation, survival and anti-tumor activation of human NK cells by interleukin-15 gene modification Cell culture and cytotoxicity assay (in vitro) Cytokine gene modified NK cell lines [81, 82]
Prevention of relapse of HCC relapse after partial hepatectomy by adoptive transfer of TRAIL-expressing NK cells Murine HCC metastasis model (in vivo) Adoptive transfer of activated NK cells [83]
Rapid and sustained regression of HCC by adoptive transfer of allogeneic suicide gene-modified killer cells mainly NK cells Cell culture and animal models (in vitro and in vivo) Adoptive transfer of gene-modified killer cells [84]
Induction of proliferation and activation of NK cells as well as inhibition of tumor growth, neovascularization and lung metastasis via intratumoral or intravascular IL-12gene therapy Murine or rat model of HCC (in vivo) Cytokine gene therapy [64, 85, 86]
Increasing the serum levels of IL-12 and activation of NK cells via transferring CD40L gene into dendritic cells by adenovirus Rat HCC model (in vivo) Gene therapy [87]
Anti-tumor activity of type I and type III interferons and critical role of NK cells in their activity BNL hepatoma model of HCC (in vivo) Cytokine gene therapy [88]
Dual functional therapy involving both gene therapy with the aim of inhibiting tumor growth and immune-stimulatory (particularly NK cells) by inducing type I IFN production for treatment of HBV and HCC (In vitro and in vivo) Cytokine gene therapy [89,90,91,92,93]
Activation of NK cells and clearance of HBV via blocking the inhibitory receptor NKG2A In vivo mAb therapy [94]
Regulatory role of T-cell Ig and ITIM domain (TIGIT) as an inhibitory receptor on NK cells in acute viral hepatitis and liver regeneration (In vitro and in vivo) mAb therapy [95,96,97]
Increasing cytotoxic activity of NK cells against HCC via co-culture with K562-mb15-41BBL cell line, enhancing anti-HCC effects of sorafenib by adding NK cells to the culture of HCC cell lines and inhibiting cytotoxicity of NK cells via blocking NKG2D antibody Cytotoxicity assays (in vitro) and Xenograft mice model (in vivo) Adoptive transfer of activated NK cells and Chemo-immunotherapy [98]
Role of androgen receptor (AR) on NK cell activity by altering IL-12A expression and the effect of sorafenib on enhancing IL-12A expression via suppressing AR signals. Better suppression of HCC via combining sorafenib with NK cells. Cell cytotoxicity test (in vitro) and liver orthotopicxeno graft mice model (in vivo) Chemo-immunotherapy [99]
Increasing HCC tumor growth and lung metastasis in sorafenib-pretreated mice. Reducing the number of NK cells and inhibition of NK cell cytotoxicity against tumor cells and proliferation of NK92-MI cells by sorafenib In vivo and in vitro Chemo-immunotherapy [100]