title: Durable complete clinical responses in a phase I/II trial using an autologous melanoma cell/dendritic cell vaccine.
abstract: Advanced metastatic melanoma is incurable by standard treatments, but occasionally responds to immunotherapy. Recent trials using dendritic cells (DC) as a cellular adjuvant have concentrated on defined peptides as the source of antigens, and rely on foreign proteins as a source of help to generate a cell-mediated immune response. This approach limits patient accrual, because currently defined, non-mutated epitopes are restricted by a small number of human leucocyte antigens. It also fails to take advantage of mutated epitopes peculiar to the patient's own tumour, and of CD4+ T lymphocytes as potential effectors of anti-tumour immunity. We therefore sought to determine whether a fully autologous DC vaccine is feasible, and of therapeutic benefit. Patients with American Joint Cancer Committee stage IV melanoma were treated with a fully autologous immunotherapy consisting of monocyte-derived DC, matured after culture with irradiated tumour cells. Of 19 patients enrolled into the trial, sufficient tumour was available to make treatments for 17. Of these, 12 received a complete priming phase of six cycles of either 0.9x10(6) or 5x10(6) DC/intradermal injection, at 2-weekly intervals. Where possible, treatment continued with the lower dose at 6-weekly intervals. The remaining five patients could not complete priming, due to progressive disease. Three of the 12 patients who completed priming have durable complete responses (average duration 35 months+), three had partial responses, and the remaining six had progressive disease (WHO criteria). Disease regression was not correlated with dose or with the development of delayed type hypersensitivity responses to intradermal challenge with irradiated, autologous tumour. However, plasma S-100B levels prior to the commencement of treatment correlated with objective clinical response ( P=0.05) and survival (log rank P<0.001). The treatment had minimal side-effects and was well tolerated by all patients. Mature, monocyte-derived DC preparations exposed to appropriate tumour antigen sources can be reliably produced for patients with advanced metastatic melanoma, and in a subset of those patients with lower volume disease their repeated administration results in durable complete responses.
authors.affiliation: Melanoma Therapy Group, Mater Misericordiae Adult Hospital, Raymond Terrace, 4101, South Brisbane, Australia.
authors.forename: Michael G E
authors.initials: MG
authors.lastname: O'Rourke
authors.forename: Maree
authors.initials: M
authors.lastname: Johnson
authors.forename: Catherine
authors.initials: C
authors.lastname: Lanagan
authors.forename: Janet
authors.initials: J
authors.lastname: See
authors.forename: Jie
authors.initials: J
authors.lastname: Yang
authors.forename: John R
authors.initials: JR
authors.lastname: Bell
authors.forename: Greg J
authors.initials: GJ
authors.lastname: Slater
authors.forename: Beverley M
authors.initials: BM
authors.lastname: Kerr
authors.forename: Beth
authors.initials: B
authors.lastname: Crowe
authors.forename: David M
authors.initials: DM
authors.lastname: Purdie
authors.forename: Suzanne L
authors.initials: SL
authors.lastname: Elliott
authors.forename: Kay A O
authors.initials: KA
authors.lastname: Ellem
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Schmidt
mesh_terms: D000328:Adult; D000368:Aged; D019496:Cancer Vaccines; D002455:Cell Division; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D007167:Immunotherapy / Q000379:methods; D008297:Male; D008545:Melanoma / Q000276:immunology* / Q000401:mortality / Q000628:therapy*; D008875:Middle Aged; D009000:Monocytes / Q000166:cytology; D009362:Neoplasm Metastasis; D009414:Nerve Growth Factors; D011379:Prognosis; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins / Q000097:blood; D012878:Skin Neoplasms / Q000276:immunology* / Q000628:therapy; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D019496:Cancer Vaccines; D009414:Nerve Growth Factors; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins