Published online 13 August 2009
Haematologica, Vol 95, Issue 1, 126-134 doi:10.3324/haematol.2009.006486
Copyright © 2010 by Ferrata Storti Foundation

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Cell Therapy and Immunotherapy

Development of a Wilms’ tumor antigen-specific T-cell receptor for clinical trials: engineered patient’s T cells can eliminate autologous leukemia blasts in NOD/SCID mice

Shao-An Xue¹, Liquan Gao¹, Sharyn Thomas¹, Daniel P. Hart¹, John Zhao Xue¹, Roopinder Gillmore¹, Ralf-Holger Voss², Emma Morris¹, Hans J. Stauss¹

¹ Department of Immunology, Division of Infection & Immunity, University College London, Royal Free Hospital, Rowland Hill Street, London, UK
² Department of Hematology and Oncology, Johannes Gutenberg University, Mainz, Germany

Correspondence: Shao-An Xue/Hans Stauss, Department of Immunology, UCL Medical School, Royal Free Hospital, Rowland Hill Street, London NW3 2PF, UK. E-mail: s.xue{at}medsch.ucl.ac.uk/h.stauss{at}medsch.ucl.ac.uk

Background: The Wilms’ tumor antigen (WT1) is an attractive target for immunotherapy of leukemia. In the past, we isolated and characterized the specificity and function of a WT1-specific T-cell receptor. The goal of this translational study was to develop a safe and efficient WT1-T-cell receptor retroviral vector for an adoptive immunotherapy trial with engineered T cells.

Design and Methods: We generated a panel of retroviral constructs containing unmodified or codon-optimized WT1-T-cell receptor and β genes, linked via internal ribosome entry sites or 2A sequences, with or without an additional inter-chain disulfide bond in the T-cell receptor constant domains. These constructs were functionally analyzed in vitro, and the best one was tested in an autologous primary leukemia model in vivo.

Results: We identified a WT1-T-cell receptor construct that showed optimal tetramer staining, antigen-specific cytokine production and killing activity when introduced into primary human T cells. Fresh CD34⁺ cells purified from a patient with leukemia were engrafted into NOD/SCID mice, followed by adoptive immunotherapy with patient’s autologous T cells transduced with the WT1-T-cell receptor. This therapeutic treatment evidently decreased leukemia engraftment in mice and resulted in a substantial improvement of leukemia-free survival.

Conclusions: This is the first report that patient’s T cells, engineered to express the WT1-T-cell receptor, can eliminate autologous leukemia progenitor cells in an in vivo model. This study provides a firm basis for the planned WT1-T-cell receptor gene therapy trial in leukemia patients.

Key words: WT1, TCR, gene therapy, immunotherapy, leukemia.

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