Generation of tumor-specific, HLA class I-restricted human Th1 and Tc1 cells by cell engineering with tumor peptide-specific T-cell receptor genes

Tsuji, Takemasa; Yasukawa, Masaki; Matsuzaki, Junko; Ohkuri, Takayuki; Chamoto, Kenji; Wakita, Daiko; Azuma, Taichi; Niiya, Hironari; Miyoshi, Hiroyuki; Kuzushima, Kiyotaka; Oka, Y.; Sugiyama, Haruo; Ikeda, Hiroaki; Nishimura, Takashi

doi:10.1182/blood-2004-09-3663

Cited by 93 publications

(77 citation statements)

References 46 publications

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“…It has recently been shown that CD4 + T cells are also successfully transduced with the TCR and these cells recognize antigen productively. 9,14 In contrast to these reports, CD4 + T cells were not stained with MAGE-A4 143-151 / HLA-A*2402 tetramers without co-expression with CD8, suggesting that ab TCR used in our study was dependent on CD8 (Supplementary Figure 3). The decreased TCR transduction efficiency from 99% in SupT1 cells to 12.7-32.6% in PBMCs may reflect the mispairing with endogenous TCR or more likely the differences of transduction efficacy to cell line or mixed population such as PBMCs.…”

Section: Construction Of Ab Tcr-expressing Retroviral Vector and Efficontrasting

confidence: 53%

Long-term phenotypic, functional and genetic stability of cancer-specific T-cell receptor (TCR) αβ genes transduced to CD8+ T cells

et al. 2008

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In adoptive T-cell transfer as an intervention for malignant diseases, retroviral transfer of T-cell receptor (TCR) genes derived from CD8 + cytotoxic T-lymphocyte (CTL) clones provides an opportunity to generate a large number of T cells with the same antigen specificity. We cloned the TCR-ab genes from a human leukocyte antigen (HLA)-A*2402-restricted CTL clone specific for MAGE-A4 143-151 . The TCR-ab genes were transduced to 99.2% of non-TCR expressing SupT1, a human T-cell line, and to 12.7-32.6% of polyclonally activated CD8 + T cells by retroviral transduction. As expected, TCR-ab gene-modified CD8 + T cells showed cytotoxic activity and interferon-g production in response to peptide-loaded T2-A*2402 and tumor cell lines expressing both MAGE-A4 and HLA-A*2402. A total of 24 clones were established from TCR-ab gene-transduced peripheral blood mononuclear cells and all clones were functional on a transduced TCRdependent manner. Four clones were kept in culture over 6 months for analyses in detail. The transduced TCR-ab genes were stably maintained phenotypically, functionally and genetically. Our results indicate that TCR-transduced ab T cells by retroviral transduction represent an efficient and promising strategy for adoptive T-cell transfer for long term.

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Section: Construction Of Ab Tcr-expressing Retroviral Vector and Efficontrasting

confidence: 53%

Long-term phenotypic, functional and genetic stability of cancer-specific T-cell receptor (TCR) αβ genes transduced to CD8+ T cells

et al. 2008

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“…CD4 ϩ T cells have previously been reported to kill in an MHC class IIrestricted and Ag-specific manner using primarily the Fas/Fas ligand and apoptosis-inducing pathways as well as, albeit it in general to a lesser extent, the exocytotic pathway (31). Interestingly, recent reports suggest that antitumor responses of TCR-transduced CD4 ϩ T cells may require MHC class II expression on target cells (32,33). Cointroduction of WT1-specific TCR and CD8␣ genes appeared to rescue cytotoxicity, but not cytokine production by human Th1 cell toward naturally processed tumor Ag on MHC class II-negative leukemia cells (T. Nishimura, unpublished observations).…”

Section: Discussionmentioning

confidence: 99%

CD8α Coreceptor to Improve TCR Gene Transfer to Treat Melanoma: Down-Regulation of Tumor-Specific Production of IL-4, IL-5, and IL-10

Willemsen

Sebestyén

Ronteltap

et al. 2006

The Journal of Immunology

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Therapeutic success of TCR gene transfer to treat tumors depends on the ability of redirected T cells to become activated upon tumor recognition in vivo. Help provided by tumor-specific Th1 cells is reported to relieve T cells from an anergized state and to induce tumor regression. We recently demonstrated the ability to generate melanoma-specific Th1 cells by genetic introduction of both a CD8-dependent TCR and the CD8α coreceptor into CD4+ T cells. In this study, we analyzed a TCR that binds Ag independently of CD8, a property generally preferred to induce tumor-specific T cell responses, and addressed the contribution of CD8α following introduction into TCR-transduced CD4+ T cells. To this end, primary human CD4+ T cells were gene transferred with a high-avidity TCR, and were shown not only to bind peptide/MHC class I, but also to effectively kill Ag-positive tumor cells in the absence of CD8α. The introduction of CD8α up-regulates the tumor-specific production of TNF-α and IL-2 to some extent, but significantly down-regulates production of IL-4, IL-5, and IL-10 in CD4+ T cells. The introduction of a mutated cysteine motif in CD8α, which prevents its binding to LCK and linker for activation of T cells, did not adversely affect expression and T cell cytotoxicity, but counteracted the CD8α-mediated down-regulation of IL-4 and IL-5, but not IL-10. In conclusion, CD8α down-regulates the production of major Th2-type cytokines, in part mediated by LCK and/or linker for activation of T cells, and may induce differentiation of tumor-specific Th1 cells, which makes this coreceptor an interesting candidate to improve the clinical potential of TCR gene transfer to treat cancer.

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“…The technology of TCR gene-engineering is possibly one efficient tool with which to expand necessary specific effector T cells. Recently, retroviral vector-mediated TCR gene transduction has been utilized in basic research and some clinical trials (Roszkowski et al, 2005;Hughes et al, 2005;Morgan et al, 2006;Tsuji et al, 2005). Recently, the use of a lentiviral vector system was shown to be the optimal way to transduce specific TCR genes into naïve T cells (Van Tendeloo et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Novel Approach to the Characterization of Melanoma Associated-Peptide-Specific CTL Lines from Melanoma Patients

Akiyama¹,

Komiyama²,

Iizuka³

et al. 2011

Breakthroughs in Melanoma Research

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Generation of tumor-specific, HLA class I-restricted human Th1 and Tc1 cells by cell engineering with tumor peptide-specific T-cell receptor genes

Cited by 93 publications

References 46 publications

Long-term phenotypic, functional and genetic stability of cancer-specific T-cell receptor (TCR) αβ genes transduced to CD8+ T cells

Long-term phenotypic, functional and genetic stability of cancer-specific T-cell receptor (TCR) αβ genes transduced to CD8+ T cells

CD8α Coreceptor to Improve TCR Gene Transfer to Treat Melanoma: Down-Regulation of Tumor-Specific Production of IL-4, IL-5, and IL-10

Novel Approach to the Characterization of Melanoma Associated-Peptide-Specific CTL Lines from Melanoma Patients

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