T-cell receptor gene transfer for the treatment of leukemia and other tumors

Heemskerk, Mirjam H.M.

doi:10.3324/haematol.2009.016022

Cited by 15 publications

(11 citation statements)

References 25 publications

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“…Such events were not predicted by preclinical studies and were due to cross‐recognition of an unrelated protein expressed by cardiomyocytes . These observations foster the need for improved methods to define and validate the specificity and safety of engineered TCRs . Despite the majority of TCR gene transfer trials are in the autologous setting, such a promising approach is on the way to be applied also in the context of allo‐HSCT.…”

Section: Tcr Gene Transfer and Tcr Gene Editingmentioning

confidence: 99%

Adoptive immunotherapy with genetically modified lymphocytes in allogeneic stem cell transplantation

Cieri

Mastaglio

Oliveira

et al. 2013

Immunological Reviews

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Hematopoietic stem cell transplantation from a healthy donor (allo-HSCT) represents the most potent form of cellular adoptive immunotherapy to treat malignancies. In allo-HSCT, donor T cells are double edge-swords: highly potent against residual tumor cells, but potentially highly toxic, and responsible for graft versus host disease (GVHD), a major clinical complication of transplantation. Gene transfer technologies coupled with current knowledge on cancer immunology have generated a wide range of approaches aimed at fostering the immunological response to cancer cells, while avoiding or controlling GVHD. In this review, we discuss cell and gene therapy approaches currently tested in preclinical models and in clinical trials.

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Section: Tcr Gene Transfer and Tcr Gene Editingmentioning

confidence: 99%

Adoptive immunotherapy with genetically modified lymphocytes in allogeneic stem cell transplantation

Cieri

Mastaglio

Oliveira

et al. 2013

Immunological Reviews

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“…The successful transfer of genes encoding TCRab chains, which recognize a variety of virus-specific and tumor-associated antigens, into primary T cells has been demonstrated (Xue et al, 2005;Engels and Uckert, 2007;Heemskerk, 2010;Yin et al, 2011;Stroncek et al, 2012). In comparison with the transfer of both the TCRa and TCRb genes, which leads to the expression of the TCRab heterodimer in T-cells, the transfer of the TCRz gene into primary T cells appeared to be easier.…”

mentioning

confidence: 99%

Upregulated TCRζ Enhances Interleukin-2 Production in T-Cells from Patients with CML

Zha

Chen

Yang

et al. 2012

DNA and Cell Biology

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T-cell immunodeficiency is a common feature in patients with chronic myeloid leukemia (CML), and deficiency in CD3 levels was detected in T cells from these patients, which may represent a characteristic that is related to a lower T cell activation. In this study, we explored the possibility that forced TCRζ gene expression may upreg-u-late T cell receptor (TCR) signaling activation and reverse interleukin-2 (IL-2) production in T cells from patients with CML. A recombinant eukaryotic vector expressing TCRζ was transfected into T cells by nucleofection. Phosphorylated TCRζ, phosphorylated NF-κB, and the IL-2 level in TCRζ-transfected CD3+T cells that were activated with anti-CD3 and anti-CD28 antibodies were measured by Western blot and enzyme-linked immunosorbent assay (ELISA). Significantly increased TCRζ levels were found in TCRζ-transfected CD3+T cells. After CD3 and CD28 antibody stimulation, a significantly higher phosphorylated TCRζ chain level was demonstrated, and an increased IL-2 production in TCRζ-upregulated T cells was associated with the increased expression of the phosphorylated NF-κB. In conclusion, TCRζ gene transfection could restore TCRζ chain deficiency and enhance IL-2 production in T cells from patients with CML. It is possible that TCRζ chain reconstitution in leukemia-specific, clonally expanded T cells will effectively increase their activation of antileukemia cytotoxicity.

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“…The successful transfer of genes encoding TCRαβ chains, which recognize a variety of virus-specific and tumor-associated antigens, into primary T cells was demonstrated previously [11,12,24,25]. For clinical applications of TCR-redirected T cells, the efficient functional expression of the transgenic TCR is a prerequisite.…”

Section: Discussionmentioning

confidence: 99%

Generation of diffuse large B cell lymphoma-associated antigen-specific Vα6/Vβ13+T cells by TCR gene transfer

et al. 2011

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BackgroundOur previous study had amplified antigen-specific full-length TCR α and β genes of clonally expanded T cells in the peripheral blood (PB) of patients with diffuse large B-cell lymphoma (DLBCL). The transfer of T cell receptor (TCR) genes endows T cells with new antigen specificity. Therefore, the aim of this study is to generate diffuse large B cell lymphoma (DLBCL)-specific T cells by T cell receptor (TCR) gene transfer.Materials and methodsTwo different eukaryotic expression plasmids harboring TCR Vα6 and TCR Vβ13 genes specific for DLBCL-associated antigens were constructed and subsequently transferred into human T cells using Nucleofector™ technique. The expression of targeted genes in TCR gene-modified cells was detected by real-time PCR, and western blot using TCR Vβ antibody. The specific cytotoxicity of TCR gene-transferred T cells in vitro was estimated using a lactate dehydrogenase (LDH) release assay.ResultsTwo different eukaryotic expression plasmids harboring TCR Vα6 and TCR Vβ13 genes specific for DLBCL-associated antigens were constructed and subsequently transferred into T cells from healthy donors. Specific anti-DLBCL cytotoxic T lymphocytes (CTL) could be induced by transduction of specific TCR gene to modify healthy T cells. The transgene cassette of TCR Vβ13-IRES-TCR Vα6 was superior to the other in the function of TCR-redirected T cells.ConclusionsSpecific anti-DLBCL cytotoxic T lymphocyte (CTL) could be inducted by transduction of specific TCR gene to modify healthy T cells.

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T-cell receptor gene transfer for the treatment of leukemia and other tumors

Cited by 15 publications

References 25 publications

Adoptive immunotherapy with genetically modified lymphocytes in allogeneic stem cell transplantation

Adoptive immunotherapy with genetically modified lymphocytes in allogeneic stem cell transplantation

Upregulated TCRζ Enhances Interleukin-2 Production in T-Cells from Patients with CML

Generation of diffuse large B cell lymphoma-associated antigen-specific Vα6/Vβ13+T cells by TCR gene transfer

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