Immunotherapy of hepatocellular carcinoma

Korangy, Firouzeh; Höchst, Bastian; Manns, Michael P.; Greten, Tim F.

doi:10.1586/egh.10.18

Cited by 17 publications

(13 citation statements)

References 102 publications

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“…Immunotherapy with NK- or T-cell augmenting therapies to date has yielded some early promising results [24-27] but the low affinity of endogenous tumor-specific T-cell receptors and the immunosuppressive milieu of the tumor microenvironment represent barriers to effectively harnessing the power of the endogenous immune system to control cancer. Yeast-derived scFv offer many advantageous properties for the development of anti-tumor biologics.…”

Section: Discussionmentioning

confidence: 99%

Validation of glypican-3-specific scFv isolated from paired display/secretory yeast display library

Siegel

Scholler

et al. 2012

BMC Biotechnol

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BackgroundGlypican-3 (GPC3) is a heparan-sulfate proteoglycan frequently expressed on the cell membrane of malignant hepatocytes in hepatocellular carcinoma. The capacity for screening potential antibodies in vitro using human hepatocellular lines is critical to ensure binding to this highly post-translationally modified glycophosphatidylinositiol-linked protein. We hypothesized that we could utilize a recently described paired display/secretory yeast library to isolate human-derived scFv against glypican-3 for potential diagnostic and/or therapeutic application.ResultsUsing two different biotinylated antigen targets, a synthesized 29mer fragment GPC3550-558 and a truncated GPC3368-548 fused with glutathione S-transferase (GST) we enriched the yeast display library to greater than 30% target-specific yeast with both positive selection and depletion of streptavidin- and GST-specific clones. After cloning of scFv cDNA from the enriched sub-library, scFv specificity was validated by ELISA for binding to recombinant protein from prokaryotic and eukaryotic sources and ultimately naturally presented human protein on the cell membrane of human hepatocellular cell lines. Specificity was confirmed using non-expressing cell lines and shRNA knockdown. Ultimately, five unique scFv with affinity EC50 ranging from 5.0-110.9nM were identified.ConclusionsUsing a paired display/secretory yeast library, five novel and unique scFvs for potential humoral or chimeric therapeutic development in human hepatocellular carcinoma were isolated and characterized.

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Section: Discussionmentioning

confidence: 99%

Validation of glypican-3-specific scFv isolated from paired display/secretory yeast display library

Siegel

Scholler

et al. 2012

BMC Biotechnol

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“…Immunotherapies with cytokines, vaccines, and T-cell adoptive therapy have been tested in early clinical trials for hepatocellular carcinoma with minor impact on the course of the disease (1)(2)(3)(4), with the exception of a pilot study using adoptive T-cell therapy (5). Immunostimulatory monoclonal antibodies (ISmAb) have recently emerged as a new therapeutic tool in oncology (6,7).…”

Section: Introductionmentioning

confidence: 99%

Combined Immunostimulatory Monoclonal Antibodies Extend Survival in an Aggressive Transgenic Hepatocellular Carcinoma Mouse Model

Morales-Kastresana

Sanmamed

Rodríguez

et al. 2013

Clinical Cancer Research

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Purpose: Immunostimulatory monoclonal antibodies (ISmAb) that unleash antitumor immune responses are showing efficacy in cancer clinical trials. Anti-B7-H1 (PD-L1) monoclonal antibodies (mAb) block a critical inhibitory pathway in T cells, whereas anti-CD137 and OX40 mAbs provide T-cell costimulation. A combination of these ISmAbs (anti-CD137 þ anti-OX40 þ anti-B7-H1) was tested using a transgenic mouse model of multifocal and rapidly progressing hepatocellular carcinoma, in which c-myc drives transformation and cytosolic ovalbumin (OVA) is expressed in tumor cells as a model antigen.Experimental Design: Flow-cytometry and immunohistochemistry were used to quantify tumorinfiltrating lymphocytes (TIL) elicited by treatment and assess their activation status and cytolytic potential. Tolerance induction and its prevention/reversal by treatment with the combination of ISmAbs were revealed by in vivo killing assays.Results: The triple combination of ISmAbs extended survival of mice bearing hepatocellular carcinomas in a CD8-dependent fashion and synergized with adoptive T-cell therapy using activated OVA-specific TCRtransgenic OT-1 and OT-2 lymphocytes. Mice undergoing therapy showed clear increases in tumor infiltration by activated and blastic CD8 þ and CD4 þ T lymphocytes containing perforin/granzyme B and expressing the ISmAb-targeted receptors on their surface. The triple combination of ISmAbs did not result in enhanced OVA-specific cytotoxic T lymphocyte (CTL) activity but other antigens expressed by cell lines derived from such hepatocellular carcinomas were recognized by endogenous TILs. Adoptively transferred OVA-specific OT-1 lymphocytes into tumor-bearing mice were rendered tolerant, unless given the triple mAb therapy. Conclusion: Extension of survival and dense T-cell infiltrates emphasize the translational potential of combinational immunotherapy strategies for hepatocellular carcinoma.

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“…Alternative approaches are therefore needed to overcome these barriers to successful therapy and immunotherapy represents one possible option (18). A number of different immune suppressor mechanisms and cells have been identified in HCC including CD4 + Tregs, myeloid derived suppressor cells and indoleamine 2,3-dioxygenase and PD-1 expression (19). …”

Section: Introductionmentioning

confidence: 99%

Human CCR4+CCR6+Th17 Cells Suppress Autologous CD8+ T Cell Responses

Zhao

Hoechst

Gamrekelashvili

et al. 2012

The Journal of Immunology

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The role of Th17 cells in cancer patients remains unclear and controversial. In this study, we have analyzed the phenotype of in vitro primed Th17 cells and further characterized their function on the basis of CCR4 and CCR6 expression. We show a novel function for a subset of IL-17 secreting CD4+ T cells, namely CCR4+CCR6+Th17 cells. When cultured together, CCR4+CCR6+Th17 cells suppressed the lytic function, proliferation and cytokine secretion of both antigen specific and CD3/CD28/CD2 stimulated autologous CD8+ T cells. In contrast, CCR4negCCR6+ CD4+ T cells, which also secrete IL-17, did not affect the CD8+ T cells. Suppression of CD8+ T cells by CCR4+CCR6+Th17 cells was partially dependent on TGF-β, since neutralization of TGF-β in cocultures reversed their suppressor function. In addition, we also found an increase in the frequency of CCR4+CCR6+, but not CCR4negCCR6+ Th17 cells in peripheral blood of HCC patients. Our study not only underlies the importance of analysis of subsets within Th17 cells to understand their function, but also suggests Th17 cells as yet another immune evasion mechanism in HCC. This has important implications when studying the mechanisms of carcinogenesis as well as designing effective immunotherapy protocols for patients with cancer.

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Immunotherapy of hepatocellular carcinoma

Cited by 17 publications

References 102 publications

Validation of glypican-3-specific scFv isolated from paired display/secretory yeast display library

Validation of glypican-3-specific scFv isolated from paired display/secretory yeast display library

Combined Immunostimulatory Monoclonal Antibodies Extend Survival in an Aggressive Transgenic Hepatocellular Carcinoma Mouse Model

Human CCR4+CCR6+Th17 Cells Suppress Autologous CD8+ T Cell Responses

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