title: CD25 blockade depletes and selectively reprograms regulatory T cells in concert with immunotherapy in cancer patients.
abstract: Regulatory T cells (T(regs)) are key mediators of immune tolerance and feature prominently in cancer. Depletion of CD25(+) FoxP3(+) T(regs) in vivo may promote T cell cancer immunosurveillance, but no strategy to do so in humans while preserving immunity and preventing autoimmunity has been validated. We evaluated the Food and Drug Administration-approved CD25-blocking monoclonal antibody daclizumab with regard to human T(reg) survival and function. In vitro, daclizumab did not mediate antibody-dependent or complement-mediated cytotoxicity but rather resulted in the down-regulation of FoxP3 selectively among CD25(high) CD45RA(neg) T(regs). Moreover, daclizumab-treated CD45RA(neg) T(regs) lost suppressive function and regained the ability to produce interferon-γ, consistent with reprogramming. To understand the impact of daclizumab on T(regs) in vivo, we performed a clinical trial of daclizumab in combination with an experimental cancer vaccine in patients with metastatic breast cancer. Daclizumab administration led to a marked and prolonged decrease in T(regs) in patients. Robust CD8 and CD4 T cell priming and boosting to all vaccine antigens were observed in the absence of autoimmunity. We conclude that CD25 blockade depletes and selectively reprograms T(regs) in concert with active immune therapy in cancer patients. These results suggest a mechanism to target cancer-associated T(regs) while avoiding autoimmunity.
authors.affiliation: Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Rech
authors.forename: Rosemarie
authors.initials: R
authors.lastname: Mick
authors.forename: Sunil
authors.initials: S
authors.lastname: Martin
authors.forename: Adri
authors.initials: A
authors.lastname: Recio
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Aqui
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Powell
authors.forename: Theresa A
authors.initials: TA
authors.lastname: Colligon
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Trosko
authors.forename: Leah I
authors.initials: LI
authors.lastname: Leinbach
authors.forename: Charles H
authors.initials: CH
authors.lastname: Pletcher
authors.forename: Carol K
authors.initials: CK
authors.lastname: Tweed
authors.forename: Angela
authors.initials: A
authors.lastname: DeMichele
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Fox
authors.forename: Susan M
authors.initials: SM
authors.lastname: Domchek
authors.forename: James L
authors.initials: JL
authors.lastname: Riley
authors.forename: Robert H
authors.initials: RH
authors.lastname: Vonderheide
mesh_terms: D019138:Antibodies, Blocking / Q000276:immunology / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized / Q000276:immunology / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000276:immunology / Q000628:therapy*; D019496:Cancer Vaccines / Q000276:immunology; D065150:Cellular Reprogramming / Q000276:immunology*; D003131:Combined Modality Therapy; D000077561:Daclizumab; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology / Q000627:therapeutic use; D007167:Immunotherapy / Q000379:methods*; D053645:Interleukin-2 Receptor alpha Subunit / Q000037:antagonists & inhibitors* / Q000276:immunology; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008212:Lymphocyte Depletion; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014611:Vaccination
chemical_list: D019138:Antibodies, Blocking; D061067:Antibodies, Monoclonal, Humanized; D019496:Cancer Vaccines; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D007074:Immunoglobulin G; D053645:Interleukin-2 Receptor alpha Subunit; D000077561:Daclizumab; D017493:Leukocyte Common Antigens