Table 1 Preclinical (in vitro and in vivo) studies of NK cell based immunotherapy for HCC
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 | |
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 | |
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 | |
Ex vivo generation, activation and expansion of NK cells for immunotherapy of advanced cancer | (In vitro and in vivo) | NK cell transfer | |
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 | |
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 | |
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 | |
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 | |
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] |