title: Induction of immunity to prostate cancer antigens: results of a clinical trial of vaccination with irradiated autologous prostate tumor cells engineered to secrete granulocyte-macrophage colony-stimulating factor using ex vivo gene transfer.
abstract: Vaccination with irradiated granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting gene-transduced cancer vaccines induces tumoricidal immune responses. In a Phase I human gene therapy trial, eight immunocompetent prostate cancer (PCA) patients were treated with autologous, GM-CSF-secreting, irradiated tumor vaccines prepared from ex vivo retroviral transduction of surgically harvested cells. Expansion of primary cultures of autologous vaccine cells was successful to meet trial specifications in 8 of 11 cases (73%); the yields of the primary culture cell limited the number of courses of vaccination. Side effects were pruritus, erythema, and swelling at vaccination sites. Vaccine site biopsies manifested infiltrates of dendritic cells and macrophages among prostate tumor vaccine cells. Vaccination activated new T-cell and B-cell immune responses against PCA antigens. T-cell responses, evaluated by assessing delayed-type hypersensitivity (DTH) reactions against untransduced autologous tumor cells, were evident in two of eight patients before vaccination and in seven of eight patients after treatment. Reactive DTH site biopsies manifested infiltrates of effector cells consisting of CD45RO+ T-cells, and degranulating eosinophils consistent with activation of both Th1 and Th2 T-cell responses. A distinctive eosinophilic vasculitis was evident near autologous tumor cells at vaccine sites, and at DTH sites. B-cell responses were also induced. Sera from three of eight vaccinated men contained new antibodies recognizing polypeptides of 26, 31, and 150 kDa in protein extracts from prostate cells. The 150-kDa polypeptide was expressed by LNCaP and PC-3 PCA cells, as well as by normal prostate epithelial cells, but not by prostate stromal cells. No antibodies against prostate-specific antigen were detected. These data suggest that both T-cell and B-cell immune responses to human PCA can be generated by treatment with irradiated, GM-CSF gene-transduced PCA vaccines.
authors.affiliation: Johns Hopkins Oncology Center, Brady Urological Institute, and Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors.forename: J W
authors.initials: JW
authors.lastname: Simons
authors.forename: B
authors.initials: B
authors.lastname: Mikhak
authors.forename: J F
authors.initials: JF
authors.lastname: Chang
authors.forename: A M
authors.initials: AM
authors.lastname: DeMarzo
authors.forename: M A
authors.initials: MA
authors.lastname: Carducci
authors.forename: M
authors.initials: M
authors.lastname: Lim
authors.forename: C E
authors.initials: CE
authors.lastname: Weber
authors.forename: A A
authors.initials: AA
authors.lastname: Baccala
authors.forename: M A
authors.initials: MA
authors.lastname: Goemann
authors.forename: S M
authors.initials: SM
authors.lastname: Clift
authors.forename: D G
authors.initials: DG
authors.lastname: Ando
authors.forename: H I
authors.initials: HI
authors.lastname: Levitsky
authors.forename: L K
authors.initials: LK
authors.lastname: Cohen
authors.forename: M G
authors.initials: MG
authors.lastname: Sanda
authors.forename: R C
authors.initials: RC
authors.lastname: Mulligan
authors.forename: A W
authors.initials: AW
authors.lastname: Partin
authors.forename: H B
authors.initials: HB
authors.lastname: Carter
authors.forename: S
authors.initials: S
authors.lastname: Piantadosi
authors.forename: F F
authors.initials: FF
authors.lastname: Marshall
authors.forename: W G
authors.initials: WG
authors.lastname: Nelson
mesh_terms: D000951:Antigens, Neoplasm / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology*; D018014:Gene Transfer Techniques; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000209:etiology; D008297:Male; D008875:Middle Aged; D011471:Prostatic Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D013601:T-Lymphocytes / Q000276:immunology; D014611:Vaccination; D014614:Vaccines, Synthetic / Q000276:immunology*
chemical_list: D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D014614:Vaccines, Synthetic; D016178:Granulocyte-Macrophage Colony-Stimulating Factor