title: A case report: immune responses and clinical course of the first human use of granulocyte/macrophage-colony-stimulating-factor-transduced autologous melanoma cells for immunotherapy.
abstract: The first use of granulocyte/macrophage-colony-stimulating-factor-transduced, lethally irradiated, autologous melanoma cells as a therapeutic vaccine in a patient, with rapidly progressive, widely disseminated malignant melanoma resulted in the generation of a novel antitumour immune response associated with partial, albeit temporary, clinical benefit. An initially negative reaction to non-transduced, autologous melanoma cells was converted to a delayed-type hypersensitivity (DTH) reaction of increasing magnitude following successive vaccinations. While intradermal vaccine sites showed prominent dendritic cell accrual, DTH sites revealed a striking influx of eosinophils in addition to activated/memory T lymphocytes and macrophages, recalling the histology of challenge tumour cell rejection in immune mice. Cytotoxic T lymphocytes (CTL) reactive with autologous melanoma cells were detectable at high frequency after vaccination, not only in limiting-dilution analysis, but also in bulk culture without added cytokines. Clonal analysis of CTL showed a conversion from a purely CD8+ response to a high proportion of CD4+ clones following vaccination. A prominent acute-phase response manifested by a five- to tenfold increase in C-reactive protein was observed, as was a systemic eosinophila. Vaccination resulted in the regression of axillary lymphatic metastases, stabilisation of pulmonary metastases, and a dramatic, reversible increase in cerebral oedema associated with multiple central nervous system metastases: however, lesions in the adrenal glands, pancreas and spleen proved refractory. The antitumour effects and immune response were not detectable 2 months following the last vaccination. Irradiation of the extensive cerebral metastases resulted in rapid deterioration and death of the patient.
authors.affiliation: Queensland Cancer Fund Research Unit, Queensland Institute of Medical Research, Bancroft Centre, Brisbane, Australia.
authors.forename: K A
authors.initials: KA
authors.lastname: Ellem
authors.forename: M G
authors.initials: MG
authors.lastname: O'Rourke
authors.forename: G R
authors.initials: GR
authors.lastname: Johnson
authors.forename: G
authors.initials: G
authors.lastname: Parry
authors.forename: I S
authors.initials: IS
authors.lastname: Misko
authors.forename: C W
authors.initials: CW
authors.lastname: Schmidt
authors.forename: P G
authors.initials: PG
authors.lastname: Parsons
authors.forename: S R
authors.initials: SR
authors.lastname: Burrows
authors.forename: S
authors.initials: S
authors.lastname: Cross
authors.forename: A
authors.initials: A
authors.lastname: Fell
authors.forename: C L
authors.initials: CL
authors.lastname: Li
authors.forename: J R
authors.initials: JR
authors.lastname: Bell
authors.forename: P J
authors.initials: PJ
authors.lastname: Dubois
authors.forename: D J
authors.initials: DJ
authors.lastname: Moss
authors.forename: M F
authors.initials: MF
authors.lastname: Good
authors.forename: A
authors.initials: A
authors.lastname: Kelso
authors.forename: L K
authors.initials: LK
authors.lastname: Cohen
authors.forename: G
authors.initials: G
authors.lastname: Dranoff
authors.forename: R C
authors.initials: RC
authors.lastname: Mulligan
mesh_terms: D001344:Autopsy; D015415:Biomarkers; D001932:Brain Neoplasms / Q000556:secondary; D002097:C-Reactive Protein / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D004802:Eosinophilia / Q000209:etiology; D018014:Gene Transfer Techniques; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics* / Q000627:therapeutic use; D006801:Humans; D006968:Hypersensitivity, Delayed; D008207:Lymphatic Metastasis; D008297:Male; D008545:Melanoma / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D008875:Middle Aged; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014161:Transduction, Genetic; D014182:Transplantation, Autologous; D014611:Vaccination
chemical_list: D015415:Biomarkers; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D002097:C-Reactive Protein