title: Low-dose temozolomide before dendritic-cell vaccination reduces (specifically) CD4+CD25++Foxp3+ regulatory T-cells in advanced melanoma patients.
abstract: BACKGROUND
  In cancer immunotherapy, dendritic cells (DCs) play a fundamental role in the dialog between innate and adaptive immune response, but several immunosuppressive mechanisms remain to be overcome. For example, a high number of CD4+CD25++Foxp3+ regulatory T-cells (Foxp3+Tregs) have been observed in the peripheral blood and tumor microenvironment of cancer patients. On the basis of this, we conducted a study on DC-based vaccination in advanced melanoma, adding low-dose temozolomide to obtain lymphodepletion.
  
  
  METHODS
  Twenty-one patients were entered onto our vaccination protocol using autologous DCs pulsed with autologous tumor lysate and keyhole limpet hemocyanin. Patients received low-dose temozolomide before vaccination and 5 days of low-dose interleukin-2 (IL-2) after vaccination. Circulating Foxp3+Tregs were evaluated before and after temozolomide, and after IL-2.
  
  
  RESULTS
  Among the 17 evaluable patients we observed 1 partial response (PR), 6 stable disease (SD) and 10 progressive disease (PD). The disease control rate (PR+SD = DCR) was 41% and median overall survival was 10 months. Temozolomide reduced circulating Foxp3+Treg cells in all patients. A statistically significant reduction of 60% was observed in Foxp3+Tregs after the first cycle, whereas the absolute lymphocyte count decreased by only 14%. Conversely, IL-2 increased Foxp3+Treg cell count by 75.4%. Of note the effect of this cytokine, albeit not statistically significant, on the DCR subgroup led to a further 33.8% reduction in Foxp3+Treg cells.
  
  
  CONCLUSIONS
  Our results suggest that the combined immunological therapy, at least as far as the DCR subgroup is concerned, effectively reduced the number of Foxp3+Treg cells, which exerted a blunting effect on the growth-stimulating effect of IL-2. However, this regimen, with its current modality, would not seem to be capable of improving clinical outcome.
authors.affiliation: Immunotherapy Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori-IRST, IRCCS, Meldola, FC, Italy. l.ridolfi@irst.emr.it
authors.forename: Laura
authors.initials: L
authors.lastname: Ridolfi
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Petrini
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Granato
authors.forename: Giusy
authors.initials: G
authors.lastname: Gentilcore
authors.forename: Ester
authors.initials: E
authors.lastname: Simeone
authors.forename: Paolo Antonio
authors.initials: PA
authors.lastname: Ascierto
authors.forename: Elena
authors.initials: E
authors.lastname: Pancisi
authors.forename: Valentina
authors.initials: V
authors.lastname: Ancarani
authors.forename: Laura
authors.initials: L
authors.lastname: Fiammenghi
authors.forename: Massimo
authors.initials: M
authors.lastname: Guidoboni
authors.forename: Francesco
authors.initials: F
authors.lastname: de Rosa
authors.forename: Linda
authors.initials: L
authors.lastname: Valmorri
authors.forename: Emanuela
authors.initials: E
authors.lastname: Scarpi
authors.forename: Stefania Vittoria Luisa
authors.initials: SV
authors.lastname: Nicoletti
authors.forename: Stefano
authors.initials: S
authors.lastname: Baravelli
authors.forename: Angela
authors.initials: A
authors.lastname: Riccobon
authors.forename: Ruggero
authors.initials: R
authors.lastname: Ridolfi
mesh_terms: D000328:Adult; D000368:Aged; D060908:CTLA-4 Antigen / Q000378:metabolism; D019496:Cancer Vaccines / Q000627:therapeutic use*; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D003713:Dendritic Cells / Q000166:cytology*; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006433:Hemocyanins; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D008297:Male; D008545:Melanoma / Q000276:immunology / Q000628:therapy*; D008875:Middle Aged; D050378:T-Lymphocytes, Regulatory / Q000166:cytology*; D000077204:Temozolomide; D016896:Treatment Outcome
chemical_list: D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D019496:Cancer Vaccines; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D003606:Dacarbazine; D006433:Hemocyanins; C032808:keyhole-limpet hemocyanin; D000077204:Temozolomide