Abstract
Although antigen-specific immune responses including cytotoxic T cells (CTLs) against antigen peptide could be enhanced after tumor antigen peptide vaccinations, the immune responses do not necessarily result in a decrease or eradication of tumor cells in the vaccination trials. We focused on whether antigen-specific CTLs could be damaged by the repeated stimulation of antigenic peptide and whether regulatory T (Treg) cells would be increased by the administration of WT1 peptide. We administered WT1 peptide 22 times over 18 months in a CML patient who was being treated with imatinib. Although WT1 peptide administration every 2 weeks did not show any beneficial effects on the minimal residual disease (copies of bcr-abl transcripts), the transcripts remarkably decreased to the level of major molecular response after changing the administration interval of WT1 peptide from 2 to 4 weeks. An ex vivo study demonstrated that re-stimulation with WT1 peptide made WT1-specific T cells less reactive to WT1 tetramers and the impaired reactivity of CTLs lasted at least for 1 week. In addition, the cytotoxicity of the T cells was hampered by re-stimulation. Treg cells increased up to more than fivefold at the end of the WT1 administration period. The present findings suggested that the administration of the peptide every 4 weeks is superior to every 2 weeks. In addition, the findings that Treg cells increased gradually in accordance with the duration of WT1 peptide administration revealed the significance of manipulating Treg cells for establishing an efficient tumor antigen peptide vaccination.
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Acknowledgments
We appreciate Drs. Manabu Kawakami, Yoshihiro Oka and Haruo Sugiyama (Department of Functional Diagnostic Science, Osaka University Graduate School of Medicine, Osaka, Japan) for designing the protocol of the WT1 peptide vaccinations and giving us valuable advices for the study, and Drs. Shoko Takenouchi, Toshiki Kitajima and Tohri Ida (Division of Hematology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan) for treating the CML patients with WT1 peptide vaccination. We appreciate Dr. Susumu Suzuki (T cell Technology, Ina, Japan) for his generous advice in this study. We thank Dr. Kiyotaka Kuzushima (Aichi Cancer Center Research Institute, Nagoya, Japan) for kindly donating modified-type WT1 tetramers and HIV env tetramers and Dr. Shingo Toji (MBL, Ina, Nagano, Japan) for kindly donating FITC-labeled modified-type WT1 tetramers.
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Saitoh, A., Narita, M., Watanabe, N. et al. WT1 peptide vaccination in a CML patient: induction of effective cytotoxic T lymphocytes and significance of peptide administration interval. Med Oncol 28, 219–230 (2011). https://doi.org/10.1007/s12032-010-9425-3
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DOI: https://doi.org/10.1007/s12032-010-9425-3