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20082492jem. 20082492 [pii] 94. Simpson TR, Li F, Montalvo-Ortiz W, Sepulveda MA, Bergerhoff K, Arce F, Roddie C, Henry JY,Yagita H, Wolchok JD, Peggs KS, Ravetch JV,Allison JP, Quezada SA (2013) Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma. J Exp Med. 20130579 95. Collison LW, Workman CJ, Kuo TT, Boyd K, WangY, Vignali KM, Cross R, Sehy D, Blumberg RS, Vignali DA (2007) The inhibitory cytokine IL-35 contributes to regulatory T-cell function.

J Natl Cancer Inst 23:1347–1359 120. Fernbach DJ, Sutow WW, Thurman WG, Vietti TJ (1960) Preliminary report: clinical trials with cyclophosphamide in children with acute leukemia. Cancer Chemother Rep 8:102–105 121. Glaser M (1979) Regulation of specific cell-mediated cytotoxic response against SV40induced tumor associated antigens by depletion of suppressor T cells with cyclophosphamide in mice. J Exp Med 149(3):774–779 122. Awwad M, North RJ (1989) Cyclophosphamide-induced immunologically mediated regression of a cyclophosphamide-resistant murine tumor: a consequence of eliminating precursor L3T4+ suppressor T-cells.

In end-stage cancer patients, metronomic (low dose, daily) dosing of cyclophosphamide was shown to decrease Treg numbers and suppressive function [127]. Similar effects of metronomic cyclophosphamide have been observed in the blood of patients with hepatocellular carcinoma, wherein alpha fetoprotein (AFP)-specific CD4 T-cell responses also increased [128]. In patients with solid tumors, cyclophosphamide decreased Treg populations and did not impair CD8 T-cell responses to an oncolytic adenovirus [129].

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