Low-dose cyclophosphamide treatment impairs regulatory T cells and unmasks AFP-specific CD4+ T-cell responses in patients with advanced HCC.
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.
Greten
Tim F
TF
Department of Gastroenterology, Hepatology and Endocrinology, Medical School Hannover, 30625 Hannover, Germany. Greten.Tim@mh-hannover.de
Ormandy
Lars A
LA
Fikuart
Annika
A
Höchst
Bastian
B
Henschen
Sylvana
S
Hörning
Monique
M
Manns
Michael P
MP
Korangy
Firouzeh
F
D000368:Aged; D000369:Aged, 80 and over; D000951:Antigens, Neoplasm / Q000276:immunology; D015704:CD4 Antigens / Q000096:biosynthesis; D006528:Carcinoma, Hepatocellular / Q000097:blood / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000494:pharmacology; D054796:Drug Dosage Calculations; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D006801:Humans; D007167:Immunotherapy; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis; D008113:Liver Neoplasms / Q000097:blood / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D008213:Lymphocyte Activation / Q000187:drug effects; D008212:Lymphocyte Depletion; D008875:Middle Aged; D009367:Neoplasm Staging; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D000509:alpha-Fetoproteins / Q000276:immunology
D000951:Antigens, Neoplasm; D015704:CD4 Antigens; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D053645:Interleukin-2 Receptor alpha Subunit; D000509:alpha-Fetoproteins; D003520:Cyclophosphamide