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Engineering T cells for immunotherapy of primary human hepatocellular carcinoma.

ABSTRACT: Liver cancers, majority of which are primary hepatocellular carcinoma (HCC), continue to be on the rise in the world. Furthermore, due to the lack of effective treatments, liver cancer ranks the 4^th most common cause of male cancer deaths. Novel therapies are urgently needed. Over the last few years, immunotherapies, especially the checkpoint blockades and adoptive cell therapies of engineered T cells, have demonstrated a great potential for treating malignant tumors including HCC. In this review, we summarize the current ongoing research of antigen-specific immunotherapies including cancer vaccines and adoptive cell therapies for HCC. We briefly discuss the HCC cancer vaccine and then focus on the antigen-specific T cells genetically engineered with the T cell receptor genes (TCRTs) and the chimeric antigen receptor genes (CARTs). We first review the current options of TCRTs and CARTs immunotherapies for HCC, and then analyze the factors and parameters that may help to improve the design of TCRTs and CARTs to enhance their antitumor efficacy and safety. Our goals are to render readers a panoramic view of the current stand of HCC immunotherapies and provide some strategies to design better TCRTs and CARTs to achieve more effective and durable antitumor effects.

SUBMITTER: Caraballo Galva LD

PROVIDER: S-EPMC7093251 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Engineering T cells for immunotherapy of primary human hepatocellular carcinoma.

Caraballo Galva Leidy D LD Cai Lun L Shao Yanxia Y He Yukai Y

Journal of genetics and genomics = Yi chuan xue bao 20200128 1

Liver cancers, majority of which are primary hepatocellular carcinoma (HCC), continue to be on the rise in the world. Furthermore, due to the lack of effective treatments, liver cancer ranks the 4<sup>th</sup> most common cause of male cancer deaths. Novel therapies are urgently needed. Over the last few years, immunotherapies, especially the checkpoint blockades and adoptive cell therapies of engineered T cells, have demonstrated a great potential for treating malignant tumors including HCC. In ...[more]

PMID: 32089500

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Project description:Dendritic cells (DC) as professional antigen presenting cells are able to prime T-cells against the tumor-associated antigen α-fetoprotein (AFP) for immunotherapy of hepatocellular carcinoma (HCC). However, a strong immunosuppressive tumor environment limits their efficacy in patients. The co-stimulation with CD40Ligand (CD40L) is critical in the maturation of DC and T-cell priming. In this study, the impact of intratumoral (i.t.) CD40L-expressing DC to improve vaccination with murine (m)AFP-transduced DC (Ad-mAFP-DC) was analyzed in subcutaneous (s.c.) and orthotopic murine HCC. Murine DC were adenovirally transduced with Ad-mAFP or Ad-CD40L. Hepa129-mAFP-cells were injected into the right flank or the liver of C3H-mice to induce subcutaneous (s.c.) and orthotopic HCC. For treatments, 106 Ad-mAFP-transduced DC were inoculated s.c. followed by 106 CD40L-expressing DC injected intratumorally (i.t.). S.c. inoculation with Ad-mAFP-transduced DC, as vaccine, induced a delay of tumor-growth of AFP-positive HCC compared to controls. When s.c.-inoculation of Ad-mAFP-DC was combined with i.t.-application of Ad-CD40L-DC synergistic antitumoral effects were observed and complete remissions and long-term survival in 62% of tumor-bearing animals were achieved. Analysis of the tumor environment at different time points revealed that s.c.-vaccination with Ad-mAFP-DC seems to stimulate tumor-specific effector cells, allowing an earlier recruitment of effector T-cells and a Th1 shift within the tumors. After i.t. co-stimulation with Ad-CD40L-DC, production of Th1-cytokines was strongly increased and accompanied by a robust tumor infiltration of mature DC, activated CD4+-, CD8+-T-cells as well as reduction of regulatory T-cells. Moreover, Ad-CD40L-DC induced tumor cell apoptosis. Intratumoral co-stimulation with CD40L-expressing DC significantly improves vaccination with Ad-mAFP-DC in pre-established HCC in vivo. Combined therapy caused an early and strong Th1-shift in the tumor environment as well as higher tumor apoptosis, leading to synergistic tumor regression of HCC. Thus, CD40L co-stimulation represents a promising tool for improving DC-based immunotherapy of HCC.

Dataset Information

Engineering T cells for immunotherapy of primary human hepatocellular carcinoma.

Publications

Engineering T cells for immunotherapy of primary human hepatocellular carcinoma.

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