title: Monoclonal antibody blockade of IL-2 receptor α during lymphopenia selectively depletes regulatory T cells in mice and humans.
abstract: Lymphodepletion augments adoptive cell transfer during antitumor immunotherapy, producing dramatic clinical responses in patients with malignant melanoma. We report that the lymphopenia induced by the chemotherapeutic agent temozolomide (TMZ) enhances vaccine-driven immune responses and significantly reduces malignant growth in an established model of murine tumorigenesis. Unexpectedly, despite the improved antitumor efficacy engendered by TMZ-induced lymphopenia, there was a treatment related increase in the frequency of immunosuppressive regulatory T cells (T(Regs); P = .0006). Monoclonal antibody (mAb)-mediated inhibition of the high-affinity IL-2 receptor α (IL-2Rα/CD25) during immunotherapy in normal mice depleted T(Regs) (73% reduction; P = .0154) but also abolished vaccine-induced immune responses. However, during lymphodepletion, IL-2Rα blockade decreased T(Regs) (93% reduction; P = .0001) without impairing effector T-cell responses, to augment therapeutic antitumor efficacy (66% reduction in tumor growth; P = .0024). Of clinical relevance, we also demonstrate that anti-IL-2Rα mAb administration during recovery from lymphodepletive TMZ in patients with glioblastoma reduced T(Reg) frequency (48% reduction; P = .0061) while permitting vaccine-stimulated antitumor effector cell expansion. To our knowledge, this is the first report of systemic antibody-mediated T(Reg) depletion during lymphopenia and the consequent synergistic enhancement of vaccine-driven cellular responses, as well as the first demonstration that anti-IL-2Rα mAbs function differentially in nonlymphopenic versus lymphopenic contexts.
authors.affiliation: The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, USA.
authors.forename: Duane A
authors.initials: DA
authors.lastname: Mitchell
authors.forename: Xiuyu
authors.initials: X
authors.lastname: Cui
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Schmittling
authors.forename: Luis
authors.initials: L
authors.lastname: Sanchez-Perez
authors.forename: David J
authors.initials: DJ
authors.lastname: Snyder
authors.forename: Kendra L
authors.initials: KL
authors.lastname: Congdon
authors.forename: Gary E
authors.initials: GE
authors.lastname: Archer
authors.forename: Annick
authors.initials: A
authors.lastname: Desjardins
authors.forename: Allan H
authors.initials: AH
authors.lastname: Friedman
authors.forename: Henry S
authors.initials: HS
authors.lastname: Friedman
authors.forename: James E
authors.initials: JE
authors.lastname: Herndon
authors.forename: Roger E
authors.initials: RE
authors.lastname: McLendon
authors.forename: David A
authors.initials: DA
authors.lastname: Reardon
authors.forename: James J
authors.initials: JJ
authors.lastname: Vredenburgh
authors.forename: Darell D
authors.initials: DD
authors.lastname: Bigner
authors.forename: John H
authors.initials: JH
authors.lastname: Sampson
mesh_terms: D000328:Adult; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology / Q000627:therapeutic use; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000276:immunology / Q000628:therapy; D019496:Cancer Vaccines / Q000627:therapeutic use; D002478:Cells, Cultured; D003131:Combined Modality Therapy; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000627:therapeutic use; D000077561:Daclizumab; D004353:Drug Evaluation, Preclinical; D005909:Glioblastoma / Q000276:immunology / Q000628:therapy; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology / Q000627:therapeutic use; D007167:Immunotherapy / Q000379:methods; D053645:Interleukin-2 Receptor alpha Subunit / Q000037:antagonists & inhibitors* / Q000276:immunology; D008212:Lymphocyte Depletion / Q000379:methods*; D008231:Lymphopenia / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D013379:Substrate Specificity / Q000187:drug effects / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D000077204:Temozolomide; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018906:Antineoplastic Agents, Alkylating; D019496:Cancer Vaccines; D007074:Immunoglobulin G; D053645:Interleukin-2 Receptor alpha Subunit; D003606:Dacarbazine; D000077561:Daclizumab; D000077204:Temozolomide