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Blood, 15 November 2007, Vol. 110, No. 10, pp. 3564-3572.
Prepublished online as a Blood First Edition Paper on July 27, 2007; DOI 10.1182/blood-2007-02-075010.
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Submitted February 21, 2007
Accepted July 23, 2007
Selecting highly affine and well expressed TCRs for gene therapy of melanoma
Annelies Jorritsma, Raquel Gomez-Eerland, Maarten Dokter, Willeke van de Kasteele, Yvonne M Zoet, Ilias IN Doxiadis, Nathalie Rufer, Pedro Romero, Richard A Morgan, Ton N.M. Schumacher, and John BAG Haanen*
Department of Immunology, the Netherlands Cancer Institute, Amsterdam, Netherlands
Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, Netherlands
Division of Clinical Onco-Immunology, Ludwig Institute for Cancer Research, Lausanne, Switzerland
Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
* Corresponding author; email: j.haanen{at}nki.nl.
A recent phase I trial has demonstrated that the generation of tumor-reactive T lymphocytes by transfer of specific T cell receptor (TCR) genes into autologous lymphocytes is feasible. However, compared to results obtained by infusion of tumor-infiltrating lymphocytes, the response rate observed in this first TCR gene therapy trial is low. One strategy that is likely to enhance the success rate of TCR gene therapy is the use of tumor-reactive TCRs with a higher capacity for tumor cell recognition. We therefore sought to develop standardized procedures for the selection of well-expressed, high affinity and safe human TCRs. Here we show that TCR surface expression can be improved by modification of TCR alpha and beta sequences and that such improvement has a marked effect on the in vivo function of TCR gene-modified T cells. From a panel of human, melanoma-reactive TCRs we subsequently selected the TCR with the highest affinity. Furthermore, a generally applicable assay was utilized to assess the lack of alloreactivity of this TCR against a large series of common HLA alleles. The procedures described in this study should be of general value for the selection of well and stably expressed, high affinity, safe human TCRs for subsequent clinical testing.
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