title: Transient T cell depletion causes regression of melanoma metastases.
abstract: BACKGROUND
  Cognate immunity against neoplastic cells depends on a balance between effector T cells and regulatory T (Treg) cells. Treg cells prevent immune attack against normal and neoplastic cells by directly suppressing the activation of effector CD4+ and CD8+ T cells. We postulated that a recombinant interleukin 2/diphtheria toxin conjugate (DAB/IL2; Denileukin Diftitox; Ontak) may serve as a useful strategy to deplete Treg cells and break tolerance against neoplastic tumors in humans.
  
  
  METHODS
  We administered DAB/IL2 (12 microg/kg; four daily doses; 21 day cycles) to 16 patients with metastatic melanoma and measured the effects on the peripheral blood concentration of several T cell subsets and on tumor burden.
  
  
  RESULTS
  We found that DAB/IL2 caused a transient depletion of Treg cells as well as total CD4+ and CD8+ T cells (< 21 days). T cell repopulation coincided with the de novo appearance of melanoma antigen-specific CD8+ T cells in several patients as determined by flow cytometry using tetrameric MART-1, tyrosinase and gp100 peptide/MHC conjugates. Sixteen patients received at least one cycle of DAB/IL2 and five of these patients experienced regressions of melanoma metastases as measured by CT and/or PET imaging. One patient experienced a near complete response with the regression of several hepatic and pulmonary metastases coupled to the de novo appearance of MART-1-specific CD8+ T cells. A single metastatic tumor remained in this patient and, after surgical resection, immunohistochemical analysis revealed MART1+ melanoma cells surrounded by CD8+ T cells.
  
  
  CONCLUSIONS
  Taken together, these data indicate that transient depletion of T cells in cancer patients may disrupt the homeostatic control of cognate immunity and allow for the expansion of effector T cells with specificity against neoplastic cells. Several T cell depleting agents are clinically available and this study provides strong rationale for an examination of their efficacy in cancer patients.
  
  
  BACKGROUND
  NCT00299689 (ClinicalTrials.gov Identifier).
authors.affiliation: Molecular Targets Program, James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, USA. m0rask01@gwise.louisville.edu
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Rasku
authors.forename: Amy L
authors.initials: AL
authors.lastname: Clem
authors.forename: Sucheta
authors.initials: S
authors.lastname: Telang
authors.forename: Beverly
authors.initials: B
authors.lastname: Taft
authors.forename: Kelly
authors.initials: K
authors.lastname: Gettings
authors.forename: Hana
authors.initials: H
authors.lastname: Gragg
authors.forename: Daniel
authors.initials: D
authors.lastname: Cramer
authors.forename: Sheron C
authors.initials: SC
authors.lastname: Lear
authors.forename: Kelly M
authors.initials: KM
authors.lastname: McMasters
authors.forename: Donald M
authors.initials: DM
authors.lastname: Miller
authors.forename: Jason
authors.initials: J
authors.lastname: Chesney
mesh_terms: D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004167:Diphtheria Toxin / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism; D007376:Interleukin-2 / Q000494:pharmacology* / Q000627:therapeutic use; D007958:Leukocyte Count; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D008875:Middle Aged; D009362:Neoplasm Metastasis / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D011993:Recombinant Fusion Proteins / Q000494:pharmacology / Q000627:therapeutic use; D012074:Remission Induction; D012878:Skin Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology; D013997:Time Factors; D016896:Treatment Outcome; D047368:Tumor Burden
chemical_list: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D004167:Diphtheria Toxin; D007074:Immunoglobulin G; D007376:Interleukin-2; D011993:Recombinant Fusion Proteins; C078456:denileukin diftitox