title: Immunization by particle-mediated transfer of the granulocyte-macrophage colony-stimulating factor gene into autologous tumor cells in melanoma or sarcoma patients: report of a phase I/IB study.
abstract: The primary objective of this phase I study was to determine the safety of an autologous tumor vaccine given by intradermal injection of lethally irradiated granulocyte-macrophage colony-stimulating factor (GM-CSF) gene-transfected autologous melanoma and sarcoma cells. Secondary objectives included validation of the gene delivery technology (particle-mediated gene transfer), determining the host immune response to the tumor after vaccination, and monitoring patients for evidence of antitumor response. Sixteen patients were treated with either of two different doses of GM-CSF-treated tumor cells. One patient received treatment with both doses of tumor cells. No treatment-related local or systemic toxicity was noted in any patient. Patients administered 100% treated cells (i.e., with a preparation of tumor cells that had all been exposed to GM-CSF DNA transfection) had a more extensive lymphocytic infiltrate at the vaccine site than did patients given 10% treated cells (a preparation of tumor cells in which 10% had been exposed to GM-CSF transfection) or nontreated tumor. The generation of a systemic immune response to autologous tumor by a delayed-type hypersensitivity response to the intradermal placement of nontransfected tumor cells was noted in one patient. One patient had a transient partial response of metastatic tumor sites. The entire procedure, from tumor removal to vaccine placement, was accomplished in less than 6 hr in all patients. Four of 17 patient tumor preparations produced greater than 3.0 ng of GM-CSF per 10(6) cells per 24 hr in vitro. The one patient with greater than 30 ng of GM-CSF per 10(6) cells per 24 hr in vitro had positive DTH, a significant histologic inflammatory response, and clinically stable disease. This technique of gene transfer was safe and feasible, but resulted in clinically relevant levels of gene expression in only a minority of patients.
authors.affiliation: Department of Surgery, University of Wisconsin School of Medicine, Madison, WI 53792, USA. mahvi@surgery.wisc.edu
authors.forename: D M
authors.initials: DM
authors.lastname: Mahvi
authors.forename: F-S
authors.initials: FS
authors.lastname: Shi
authors.forename: N-S
authors.initials: NS
authors.lastname: Yang
authors.forename: S
authors.initials: S
authors.lastname: Weber
authors.forename: J
authors.initials: J
authors.lastname: Hank
authors.forename: M
authors.initials: M
authors.lastname: Albertini
authors.forename: J
authors.initials: J
authors.lastname: Schiller
authors.forename: H
authors.initials: H
authors.lastname: Schalch
authors.forename: M
authors.initials: M
authors.lastname: Larson
authors.forename: L
authors.initials: L
authors.lastname: Pharo
authors.forename: J
authors.initials: J
authors.lastname: Gan
authors.forename: D
authors.initials: D
authors.lastname: Heisey
authors.forename: T
authors.initials: T
authors.lastname: Warner
authors.forename: P M
authors.initials: PM
authors.lastname: Sondel
mesh_terms: D019470:Biolistics; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000627:therapeutic use*; D018076:DNA, Complementary / Q000235:genetics; D004306:Dose-Response Relationship, Immunologic; D005240:Feasibility Studies; D006046:Gold; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics*; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000276:immunology; D007155:Immunologic Factors / Q000235:genetics*; D007271:Injections, Intradermal; D007890:Leiomyosarcoma / Q000473:pathology / Q000628:therapy; D008080:Liposarcoma / Q000473:pathology / Q000628:therapy; D008545:Melanoma / Q000473:pathology / Q000556:secondary / Q000628:therapy*; D012449:Safety; D012509:Sarcoma / Q000473:pathology / Q000628:therapy*; D012983:Soft Tissue Neoplasms / Q000473:pathology / Q000628:therapy*; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured / Q000637:transplantation; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000627:therapeutic use*
chemical_list: D019496:Cancer Vaccines; D018076:DNA, Complementary; D007155:Immunologic Factors; D019444:Vaccines, DNA; D006046:Gold; D016178:Granulocyte-Macrophage Colony-Stimulating Factor