title: Cancer cells engineered to secrete granulocyte-macrophage colony-stimulating factor using ex vivo gene transfer as vaccines for the treatment of genitourinary malignancies.
abstract: When irradiated and administered intradermally as vaccines, cancer cells engineered to secrete high levels of granulocyte-macrophage colony-stimulating factor (GM-CSF) by gene transfer elicit potent anticancer immune responses in a variety of animal tumor models. Upon vaccination, antigens present in the cancer cells are phagocytosed and processed by skin dendritic cells. These dendritic cells then prime anticancer immune responses by presenting antigenic peptides to T cells. The immune responses generated are capable of eradicating small but lethal cancer cell inocula with minimal toxicity in preclinical animal tumor studies. To develop this vaccination strategy for the treatment of human genitourinary cancers, we have conducted phase I clinical trials using human genitourinary cancer cells as sources of cancer cell antigens. In the first human clinical trial of genetically engineered cancer cell vaccines, a phase I clinical trial of kidney cancer cell vaccines (n = 18), kidney cancer cells were removed at surgery, propagated briefly in vitro, and then genetically modified to secrete high levels of GM-CSF via ex vivo transduction with the retrovirus MFG-GM-CSF. After irradiation, the kidney cancer cells were administered as vaccines to 18 patients with advanced kidney cancers. Vaccine treatment, which caused few side effects, nonetheless appeared to trigger anticancer immune responses manifest as conversion of delayed-type hypersensitivity (DTH) skin responses against irradiated autologous cancer cells after vaccination. Biopsies of vaccine sites yielded findings reminiscent of biopsies from preclinical animal model studies, with evidence of vaccine cell recruitment of dendritic cells, T cells, and eosinophils. One patient with measurable kidney cancer metastases treated at the highest vaccine dose level experienced a partial treatment response. The bioactivity of GM-CSF-secreting autologous cancer cell vaccines was confirmed in a phase I clinical trial for prostate cancer (n = 8). Vaccine cells were prepared from surgically harvested prostate tumors by ex vivo transduction with MFG-GM-CSF in a manner similar to that used for the kidney cancer trial. Vaccine treatment was well tolerated and associated with induction of anticancer immunity as assessed using DTH skin testing. In addition, new antiprostate cancer cell antibodies were detected in serum samples from treated men as a consequence of vaccination. These first clinical trials of GM-CSF-secreting cancer cell vaccines for the treatment of genitourinary cancers have demonstrated both safety and bioactivity, in that very few side effects have been seen and anticancer immune responses have been detected. Future clinical studies will be required to assess vaccine treatment efficacy, refine vaccination dose and schedule, define the appropriate clinical context for the use of such vaccines, and ascertain optimal combinations involving vaccines and other local or systemic anticancer treatments.
authors.affiliation: Johns Hopkins Oncology Center, Baltimore, MD 21231, USA. bnelson@jhmi.edu
authors.forename: W G
authors.initials: WG
authors.lastname: Nelson
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: Kim
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: Goeman
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
mesh_terms: D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm / Q000097:blood / Q000276:immunology; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use; D002292:Carcinoma, Renal Cell / Q000276:immunology* / Q000628:therapy; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D018014:Gene Transfer Techniques; D005818:Genetic Engineering; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000276:immunology; D007680:Kidney Neoplasms / Q000276:immunology* / Q000628:therapy; D008297:Male; D008875:Middle Aged; D011471:Prostatic Neoplasms / Q000276:immunology* / Q000628:therapy; D012190:Retroviridae / Q000235:genetics
chemical_list: D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D016178:Granulocyte-Macrophage Colony-Stimulating Factor