Eradication of Hepatocellular Carcinoma by NKG2D-Based CAR-T Cells

Sun, Bin; Yang, Dong; Dai, Hongjiu; Liu, Xiuyun; Jia, Ru; Cui, Xiaoyue; Li, Wenxuan; Cai, Chen; Xu, Jianming; Zhao, Xudong

doi:10.1158/2326-6066.cir-19-0026

Cited by 88 publications

(76 citation statements)

References 55 publications

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“…Another recent study of NKG2D-based CAR-T cells from Sun et al [106] showed that the NK group 2 member D ligands (NKG2DLs), such as MICA or ULBP2 were overexpressed in hepatoma cell lines SMMC-7721 and MHCC97H. The CAR-T cells with extracellular domains containing human NKG2D, 4-1BB, and CD3 ζ signal domain (BBZ) had effective kill effects on hepatoma cell lines SMMC-7721 and MHCC97H cell lines with high expression of NKG2DL in vitro and in vivo, but had ineffective cytotoxic effects on SMMC-7721 or Hep3B cell lines with negative NKG2DL.…”

Section: Targeted Stimulation Of Nkg2d Improves the Therapeutic Effecmentioning

confidence: 99%

Recent Advances in Molecular Mechanisms of the NKG2D Pathway in Hepatocellular Carcinoma

Wang¹,

Li²,

Sun³

2020

Biomolecules

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Hepatocellular carcinoma is a common malignant tumor with high mortality. Its malignant proliferation, invasion, and metastasis are closely related to the cellular immune function of the patients. NKG2D is a key activated and type II membrane protein molecule expressed on the surface of almost all NK cells. The human NKG2D gene is 270 kb long, located at 12p12.3–p13.1, and contains 10 exons and 9 introns. The three-dimensional structure of the NKG2D monomeric protein contains two alpha-helices, two beta-lamellae, and four disulfide bonds, and its’ signal of activation is transmitted mainly by the adaptor protein (DAP). NKG2D ligands, including MICA, MICB, and ULBPs, can be widely expressed in hepatoma cells. After a combination of NKG2D and DAP10 in the form of homologous two polymers, the YxxM motif in the cytoplasm is phosphorylated and then signaling pathways are also gradually activated, such as PI3K, PLCγ2, JNK-cJunN, and others. Activated NK cells can enhance the sensitivity to hepatoma cells and specifically dissolve by releasing a variety of cytokines (TNF-α and IFN-γ), perforin, and high expression of FasL, CD16, and TRAIL. NK cells may specifically bind to the over-expressed MICA, MICB, and ULBPs of hepatocellular carcinoma cells through the surface activating receptor NKG2D, which can help to accurately identify hepatoma, play a critical role in anti-hepatoma via the pathway of cytotoxic effects, and obviously delay the poor progress of hepatocellular carcinoma.

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Section: Targeted Stimulation Of Nkg2d Improves the Therapeutic Effecmentioning

confidence: 99%

Recent Advances in Molecular Mechanisms of the NKG2D Pathway in Hepatocellular Carcinoma

Wang¹,

Li²,

Sun³

2020

Biomolecules

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“…Chimeric antigen receptor (CAR) modified T cells have revolutionized the field of immunotherapy for cancer ( 1 ). CD19.CAR-T cells induced clinical responses in more than 60% of patients with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (ALL) ( 2 ).…”

Section: Introductionmentioning

confidence: 99%

Pre-sensitization of Malignant B Cells Through Venetoclax Significantly Improves the Cytotoxic Efficacy of CD19.CAR-T Cells

Yang

Wang

et al. 2020

Front. Immunol.

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Chimeric antigen receptor (CAR) T cell therapy has shown promising responses in patients with refractory or relapsed aggressive B-cell malignancies that are resistant to conventional chemotherapy or stem cell transplantation. A potentially combinatorial therapeutic strategy may be the inhibition of anti-apoptotic Bcl-2 family proteins, overexpressed in most cancer cells. In this study we investigated the combination of 3rd-generation CD19.CAR-T cells and the BH3 mimetics venetoclax, a Bcl-2 inhibitor, or S63845, a Mcl-1 inhibitor, under three different treatment conditions: pre-sensitization of cancer cells with BH3 mimetics followed by CAR-T cell treatment, simultaneous combination therapy, and the administration of BH3 mimetics after CAR-T cell treatment. Our results showed that administration of CAR-T cells and BH3 mimetics had a significant effect on the quantity and quality of CD19.CAR-T cells. The administration of BH3 mimetics prior to CAR-T cell therapy exerted an enhanced cytotoxic efficacy by upregulating the CD19 expression and pro-apoptotic proteins in highly sensitive tumor cells, and thereby improving both CD19.CAR-T cell cytotoxicity and persistence. In simultaneous and post-treatment approaches, however, the quantity of CAR-T cells was adversely affected. Our findings indicate pre-sensitization of highly sensitive tumor cells with BH3 mimetics could enhance the cytotoxic efficacy of CAR-T cell treatment.

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“…CAR-T cells targeting glypican-3 can inhibit the growth of HCC [93,94] . Besides, there are HCC recognition antigens such as NKG2D [95] and CD147 [96] for CAR-T cell transformation. In addition, the CAR of CAR-T cells can be inserted into the expression of a variety of cytokine genes to overcome the immunosuppressive effects of the HCC microenvironment [97,98] .…”

Section: Chimeric Antigen Receptor T Cell Therapymentioning

confidence: 99%

The immune microenvironment and progression of immunotherapy and combination therapeutic strategies for hepatocellular carcinoma

Feng¹,

Xu²,

Liu³

et al. 2021

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Eradication of Hepatocellular Carcinoma by NKG2D-Based CAR-T Cells

Cited by 88 publications

References 55 publications

Recent Advances in Molecular Mechanisms of the NKG2D Pathway in Hepatocellular Carcinoma

Recent Advances in Molecular Mechanisms of the NKG2D Pathway in Hepatocellular Carcinoma

Pre-sensitization of Malignant B Cells Through Venetoclax Significantly Improves the Cytotoxic Efficacy of CD19.CAR-T Cells

The immune microenvironment and progression of immunotherapy and combination therapeutic strategies for hepatocellular carcinoma

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