title: Metastatic melanoma patients treated with dendritic cell vaccination, Interleukin-2 and metronomic cyclophosphamide: results from a phase II trial.
abstract: Dendritic cells (DC) are the most potent antigen presenting cells and have proven effective in stimulation of specific immune responses in vivo. Competing immune inhibition could limit the clinical efficacy of DC vaccination. In this phase II trial, metronomic Cyclophosphamide and a Cox-2 inhibitor have been added to a DC vaccine with the intend to dampen immunosuppressive mechanisms. Twenty-eight patients with progressive metastatic melanoma were treated with autologous DCs pulsed with survivin, hTERT, and p53-derived peptides (HLA-A2(+)) or tumor lysate (HLA-A2(-)). Concomitantly the patients were treated with IL-2, Cyclophosphamide, and Celecoxib. The treatment was safe and tolerable. Sixteen patients (57 %) achieved stable disease (SD) at 1st evaluation and 8 patients had prolonged SD (7-13.7 months). The median OS was 9.4 months. Patients with SD had an OS of 10.5 months while patients with progressive disease (PD) had an OS of 6.0 months (p = 0.048) even though there were no differences in prognostic factors between the two groups. Despite the use of metronomic Cyclophosphamide, regulatory T cells did not decrease during treatment. Indirect IFN-γ ELISPOT assays showed a general increase in immune responses from baseline to the time of 4th vaccination. Induction of antigen-specific immune responses was seen in 9 out of 15 screened HLA-A2(+) patients. In conclusion, the number of patients obtaining SD more than doubled and 6-month survival significantly increased compared to a previous trial without Cyclophosphamide and Celecoxib. A general increase in immune responses against the tested peptides was observed.
authors.affiliation: Department of Haematology, Center for Cancer Immune Therapy, Copenhagen University Hospital, Herlev, Herlev Ringvej 75, 2730 Herlev, Denmark.
authors.forename: Eva
authors.initials: E
authors.lastname: Ellebaek
authors.forename: Lotte
authors.initials: L
authors.lastname: Engell-Noerregaard
authors.forename: Trine Zeeberg
authors.initials: TZ
authors.lastname: Iversen
authors.forename: Thomas Moerch
authors.initials: TM
authors.lastname: Froesig
authors.forename: Shamaila
authors.initials: S
authors.lastname: Munir
authors.forename: Sine Reker
authors.initials: SR
authors.lastname: Hadrup
authors.forename: Mads Hald
authors.initials: MH
authors.lastname: Andersen
authors.forename: Inge Marie
authors.initials: IM
authors.lastname: Svane
mesh_terms: D059250:Administration, Metronomic; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000401:mortality / Q000556:secondary; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use*; D000068579:Celecoxib; D003131:Combined Modality Therapy; D052246:Cyclooxygenase 2 Inhibitors / Q000627:therapeutic use; D003520:Cyclophosphamide / Q000627:therapeutic use*; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D015789:HLA-A2 Antigen / Q000276:immunology; D006801:Humans; D007376:Interleukin-2 / Q000276:immunology / Q000627:therapeutic use*; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality / Q000556:secondary; D008875:Middle Aged; D011720:Pyrazoles / Q000627:therapeutic use; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality / Q000473:pathology; D013449:Sulfonamides / Q000627:therapeutic use; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D019496:Cancer Vaccines; D052246:Cyclooxygenase 2 Inhibitors; D015789:HLA-A2 Antigen; C508594:IL2 protein, human; D007376:Interleukin-2; D011720:Pyrazoles; D013449:Sulfonamides; D003520:Cyclophosphamide; D000068579:Celecoxib