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J Immunother. 2010 Feb-Mar;33(2):211-8. doi: 10.1097/CJI.0b013e3181bb499f.

Low-dose cyclophosphamide treatment impairs regulatory T cells and unmasks AFP-specific CD4+ T-cell responses in patients with advanced HCC.

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Department of Gastroenterology, Hepatology and Endocrinology, Medical School Hannover, 30625 Hannover, Germany.


Immunotherapy represents a potential therapeutic option for patients with hepatocellular carcinoma (HCC). However, CD4CD25Foxp regulatory T cells, which suppress potential antigen-specific T-cell responses, are increased in patients with HCC and might impair the effect of an immune-based therapeutic approach. In this study, we demonstrate that depletion of regulatory T cells in vitro unmasks alpha-fetoprotein-specific T-cell responses in HCC patients. On the basis of these results, we performed a clinical trial, in which 13 patients with advanced HCC ineligible for any other type of treatment were treated with 150, 250, or 350 mg/m cyclophosphamide on day 1 and 29 to suppress regulatory T cells in these patients (NCT00396682). The primary end point of this trial was regulatory T-cell number and function. Low-dose cyclophosphamide treatment (150 and 250 mg/m) induced a decrease in the absolute and relative frequency of CD4CD25Foxp regulatory T cells in peripheral blood on days 8 and 29. Suppressor function of regulatory T cells was impaired after treatment of patients with 250 mg/m on days 8 and 21. Finally, alpha-fetoprotein-specific T-cell responses were unmasked in 6/13 treated patients. In summary, systemic treatment of HCC patients with low-dose cyclophosphamide decreases the frequency and suppressor function of circulating CD4CD25Foxp regulatory T cells in peripheral blood and could be used in combination with immunotherapeutic approaches in HCC.

[Indexed for MEDLINE]

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