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Blood, 15 July 2005, Vol. 106, No. 2, pp. 470-476.
Prepublished online as a Blood First Edition Paper on March 24, 2005; DOI 10.1182/blood-2004-09-3663.
 Previous Article | Next Article 
Submitted September 21, 2004
Accepted March 10, 2005
Generation of human tumor-specific, HLA class I-restricted Th1 and Tc1 cells by cell engineering with tumor peptide-specific T cell receptor genes
Takemasa Tsuji, Masaki Yasukawa, Junko Matsuzaki, Takayuki Ohkuri, Kenji Chamoto, Daiko Wakita, Taichi Azuma, Hironari Niiya, Hiroyuki Miyoshi, Kiyotaka Kuzushima, Yoshihiro Oka, Haruo Sugiyama, Hiroaki Ikeda, and Takashi Nishimura*
Division of Immunoregulation, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan
First Department of Internal Medicine, Ehime University School of Medicine, Ehime, Japan
Subteam for Manipulation of Cell Fate, BioResource Center, RIKEN Tsukuba Institute, Ibaraki, Japan
Division of Immunology, Aichi Cancer Center Research Institute, Aichi Cancer Center Hospital, Nagoya, Japan
Department of Molecular Medicine, Osaka University Graduate School of Medicine, Osaka, Japan
Department of Functional Diagnostic Science, Osaka University Graduate School of Medicine, Osaka, Japan
* Corresponding author; email: tak24{at}igm.hokudai.ac.jp.
Tumor antigen-specific CD4+ and CD8+ T lymphocytes, especially interferon- (IFN-)-producing Th1 and Tc1 cells, play a crucial role in tumor eradication. Adoptive transfer using tumor-specific Th1 and Tc1 cells is a promising therapeutic strategy for tumor immunotherapy. However, its clinical application has been hampered because of difficulties in generating tumor-specific Th1 cells from tumor patients. To overcome this problem, we have developed an efficient method to prepare tumor-specific Th1 and Tc1 cells. T-cell receptor (TCR)  and  genes obtained from an HLA-A24-restricted, WT1 peptide-specific Tc clone were lentivirally transduced to polyclonally-activated Th1 and Tc1 cells. As expected, TCR gene-modified Tc1 cells showed cytotoxicity and IFN- production in response to peptide-loaded lymphoblastoid cell lines, WT1 gene-transduced cells, and freshly isolated leukemia cells expressing both WT1 and HLA-A24. Surprisingly, we further demonstrated that Th1 cells transduced with HLA-class I-restricted TCR genes also showed both cytotoxicity and cytokine production in an HLA-A24-restricted manner. In contrast to gene-modified Tc1 cells, Th1 cells produced high amounts of interleukin-2 (IL-2) in addition to IFN-, which is beneficial for induction of antitumor cellular immunity. Thus, TCR gene-modified HLA-class I-restricted Th1 and Tc1 cells are a powerful strategy for the application to adoptive immunotherapy of human cancer.
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