Lethal graft-versus-host disease in mouse models of T cell receptor gene therapy. Nat Med

Division of Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Nature medicine (Impact Factor: 27.36). 05/2010; 16(5):565-70, 1p following 570. DOI: 10.1038/nm.2128
Source: PubMed


The transfer of T cell receptor (TCR) genes can be used to induce immune reactivity toward defined antigens to which endogenous T cells are insufficiently reactive. This approach, which is called TCR gene therapy, is being developed to target tumors and pathogens, and its clinical testing has commenced in patients with cancer. In this study we show that lethal cytokine-driven autoimmune pathology can occur in mouse models of TCR gene therapy under conditions that closely mimic the clinical setting. We show that the pairing of introduced and endogenous TCR chains in TCR gene-modified T cells leads to the formation of self-reactive TCRs that are responsible for the observed autoimmunity. Furthermore, we demonstrate that adjustments in the design of gene therapy vectors and target T cell populations can be used to reduce the risk of TCR gene therapy-induced autoimmune pathology.

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Available from: Reno Debets, Oct 14, 2015
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    • "In addition, the exogenous TCR α/β pairs could partner with the endogenous TCR components, reducing the expression of the desired TCR complex. Moreover, these altered TCR pairings could result in the recognition of self-antigen and the development of autoimmune disease [70] . The latter effect could be diminished by silencing the endogenous TCR using short hairpin RNA (shRNA) [71] or by permanently removing the endogenous TCR using artificial nucleases, such as transcription activator-like effector nucleases (TALENs) [72] or clustered regularly interspaced short palindromic repeat (CRISPR)-associated proteins (CRISPR/Cas9) [72] [73] [74] [75] . "
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    ABSTRACT: The adoptive transfer of T cells is a promising approach to treat cancers. Primary human T cells can be modified using viral and non-viral vectors to promote the specific targeting of cancer cells via the introduction of exogenous T-cell receptors (TCRs) or chimeric antigen receptors (CARs). This gene transfer displays the potential to increase the specificity and potency of the anticancer response while decreasing the systemic adverse effects that arise from conventional treatments that target both cancerous and healthy cells. This review highlights the generation of clinical-grade T cells expressing CARs for immunotherapy, the use of these cells to target B-cell malignancies and, particularly, the first clinical trials deploying the Sleeping Beauty gene transfer system, which engineers T cells to target CD19+ leukemia and non-Hodgkin’s lymphoma.
    Chinese journal of cancer 09/2014; Chin J Cancer(Vol.33 Issue 9):421-433. DOI:10.5732/cjc.014.10100 · 2.16 Impact Factor
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    • "Importantly, genetically engineered T lymphocytes expressing very high affinity self/tumor-specific TCRs also target normal tissues expressing the cognate antigen (e.g., melanocytes in the skin, eye, and ear for Melan-A-specific T cells and neurons for MAGE-A3-specific T cells), and can mount harmful cytotoxic immune responses in vivo (Johnson et al., 2009; Morgan et al., 2013). Moreover, TCR mispairing between introduced and endogenous TCR α and β chains has also been shown to lead to off-target toxicity (Bendle et al., 2010; van Loenen et al., 2010). Therefore, TCR optimization through affinity alteration must include the evaluation of optimal T cell responsiveness and lack of cross-reactivity to ensure the safety of TCR-engineered T cells in clinical trials. "
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    ABSTRACT: Cytotoxic CD8 T cells mediate immunity to pathogens and they are able to eliminate malignant cells. Immunity to viruses and bacteria primarily involves CD8 T cells bearing high affinity T cell receptors (TCRs), which are specific to pathogen-derived (non-self) antigens. Given the thorough elimination of high affinity self/tumor-antigen reactive T cells by central and peripheral tolerance mechanisms, anti-cancer immunity mostly depends on TCRs with intermediate-to-low affinity for self-antigens. Because of this, a promising novel therapeutic approach to increase the efficacy of tumor-reactive T cells is to engineer their TCRs, with the aim to enhance their binding kinetics to pMHC complexes, or to directly manipulate the TCR-signaling cascades. Such manipulations require a detailed knowledge on how pMHC-TCR and co-receptors binding kinetics impact the T cell response. In this review, we present the current knowledge in this field. We discuss future challenges in identifying and targeting the molecular mechanisms to enhance the function of natural or TCR-affinity optimized T cells, and we provide perspectives for the development of protective anti-tumor T cell responses.
    Frontiers in Immunology 06/2013; 4:154. DOI:10.3389/fimmu.2013.00154
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    • "Moreover, exogenous TCRs can also join with endogenous TCRs, thus decreasing the surface expression of exogenous TCRαβ chains. In addition to the decrease in introduced TCR expression, mixed TCR dimers with unknown specificities generated by TCR mispairing can also cause autoimmunity, thus adversely affecting the safety of TCR gene therapy.11,12 Another safety issue in TCR gene therapy is the copy number of the integrated vector. "
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    ABSTRACT: Adoptive immunotherapy using TCR gene-modified T-lymphocytes is an attractive strategy for targeting malignancies. However, TCR mispairings between endogenous and introduced TCR chains are a major concern, as they may induce mixed TCRs with unknown specificities and may reduce the expression of therapeutic TCRs. To overcome these problems, we have recently established a novel retroviral siTCR vector encoding small-interfering RNAs (siRNAs) to knockdown endogenous TCR genes for the efficient expression of therapeutic TCRs. In this study, to improve the efficacy of siTCR vectors, we developed 2A peptide-based siTCR vectors that could increase the expression levels of transduced TCRs compared with internal promoter-based siTCR vectors. We also evaluated the efficacy of an siTCR strategy and the addition of a new interchain disulfide bond created by cysteine modification. We found that the effect of the cysteine modification depended on TCR variations, while the siTCR strategy improved the expression of all TCRs tested. Furthermore, the combined effect of the siTCR and cysteine modification strategies was highly significant for certain TCRs. Therefore, our novel siTCR technology, in isolation or in combination with another strategy, may open the door to effective immunotherapy for cancer patients.Molecular Therapy - Nucleic Acids (2012) 1, e63. doi:10.1038/mtna.2012.52; published online 18 December 2012.
    Molecular Therapy - Nucleic Acids 12/2012; 1(12):e63. DOI:10.1038/mtna.2012.52 · 4.51 Impact Factor
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