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

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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Figure 1: Lethal autoimmune pathology induced by OT-I TCR–modified T cells.
Figure 2: TI-GVHD is explained by mixed-TCR dimer formation.
Figure 3: IFN-γ−mediated pathogenesis of TI-GVHD.
Figure 4: TI-GVHD is observed with multiple TCRs.
Figure 5: TI-GVHD is observed with different strategies that promote in vivo T cell function.
Figure 6: Prevention of TI-GVHD by TCR engineering or by the use of oligoclonal T cell populations.

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Acknowledgements

We thank the Experimental Animal Department for animal husbandry, H. van Tinteren for advice on statistical analysis and R. Gomez for experimental assistance. We are grateful to A. Pfauth and F. van Diepen for assistance with flow cytometry. G.M.B. is supported by a Leukaemia and Lymphoma Research Travel Fellowship (06037). C.L. is a fellow in the PhD Fellowship Program of Boehringer Ingelheim Fonds-Foundation for Basic Research in Biomedicine. T.N.M.S. and J.B.A.G.H. are supported by grants from The Netherlands Organization for Scientific Research (431-00-005), the Dutch Cancer Society (NKI 2009-4282 and 2003-2860), The Landsteiner Foundation for Blood Transfusion Research (04-08) and FP6 Integrated Project Adoptive T cell Targeting to Activate Cancer Killing (ATTACK). Cytotoxic T lymphocyte clone LP9 was kindly provided by G. Adema (Radboud University).

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Contributions

G.M.B. designed experiments, performed experiments, analyzed and interpreted data and wrote the paper. C.L. designed experiments, performed experiments, analyzed and interpreted data and wrote the paper. A.I.H. designed experiments, performed experiments, analyzed and interpreted data. L.B. performed experiments and analyzed data. M.A.d.W. and A.J. made the initial observation of cachexia and rapid death of mice in mouse models of TCR gene therapy. A.D.M.K. performed experiments and interpreted data. N.P. and R.D. generated and provided the TRP2 TCR sequences. E.K. and W.U. provided the Tag-specific mAb and advice on in vivo depletion. J.-Y.S. performed experiments and analyzed data. J.B.A.G.H. interpreted data. T.N.M.S. designed experiments, interpreted data and wrote the paper.

Corresponding authors

Correspondence to Gavin M Bendle or Ton N M Schumacher.

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The authors declare no competing financial interests.

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Supplementary Figures 1–7, Supplementary Table 1 and Supplementary Methods (PDF 2142 kb)

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Bendle, G., Linnemann, C., Hooijkaas, A. et al. Lethal graft-versus-host disease in mouse models of T cell receptor gene therapy. Nat Med 16, 565–570 (2010). https://doi.org/10.1038/nm.2128

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