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: 28.05). 05/2010; 16(5):565-70, 1p following 570. DOI: 10.1038/nm.2128
Source: PubMed

ABSTRACT 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, Aug 22, 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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    • "As quoted above, no replication competent viruses occurrence was observed in hundreds of patients treated with retrovirally engineered T-cells (Bear et al., 2012). Nevertheless, one has to bear in mind the possible risks associated with this kind of gene therapy such as reactivity to normal tissues expressing the targeted antigen (Johnson et al., 2009; Parkhurst et al., 2011a), possible newly generated specificities associated with TCR mispairing (Bendle et al., 2010; van Loenen et al., 2010), and insertional mutagenesis. Several approaches have been developed to readily eliminate engineered T-cells in case such adverse events take place. "
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    • "This could produce self-reactive T cells by overriding peripheral tolerance mechanisms since these cells expressing these cross-paired TCR chains are not subjected to normal thymic negative selection processes. There is evidence to suggest that this mechanism may contribute to graft-versus-host disease (GVHD) in a mouse model that involved the modification of mouse peripheral T cells with a cloned TCR, where mixed TCRs were produced and resulted in autoreactive cells (Bendle et al., 2010). In addition, a study that introduced human TCRs into human peripheral T cells demonstrated the formation of alloreactive cells expressing mixed TCRs in vitro (van Loenen et al., 2010). "
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