title: Phase I trial of antigen-specific gene therapy using a recombinant vaccinia virus encoding MUC-1 and IL-2 in MUC-1-positive patients with advanced prostate cancer.
abstract: MUC-1 is overexpressed on many tumor cells. In addition, aberrant glycosylation of MUC-1 on human tumors leads to exposure of cryptic peptide epitopes that play a role in tumor immunity. As such, it has been identified as a potential target for immunotherapy. The purpose of this phase 1 clinical trial was to determine the maximum tolerated dose, safety of a multiple-dose regimen, and the immunologic effect of vaccinia virus expressing MUC-1 and IL-2 genes (VV/MUC-1/IL-2) in patients with advanced prostate cancer. Five x 10(5), 5 x 10(6), and 5 x 10(7) plaque-forming units (pfu) of vaccinia viruses were used in the dose-escalating study. Viruses were given via intramuscular injection, and clinical response and immune function modulation were analyzed. No grade 3 or 4 toxicity was observed. Objective clinical response was observed after the fourth injection (0.3 ng/mL) in only one patient who received an intermediate dose of virus. Systemic immune modulation in this patient included (1) up-regulation of IL-2 (CD25) and T cell (TcR alphabeta) receptors, (2) increase in the CD4/CD8 ratio (2.5-fold) (3) augmentation of T-helper type 1 cell (TH1) (interferon-gamma and tumor necrosis factor-alpha) but not TH2 (IL-4) cytokine mRNA expression, (4) induction of natural killer cell activity and MHC independent MUC-1 specific cytotoxic T-cell activity, and (5) normalization of mRNA expression of T-cell-associated signal transduction molecules TcR-zeta and p56lck. These results suggest that VV/MUC-1/IL-2 gene therapy with a maximum tolerated dose of 5 x 10(7) pfu is safe and well tolerated.
authors.affiliation: Department of Urology, David Geffen School of Medicine at University of California, Los Angeles 90095, USA.
authors.forename: Allan J
authors.initials: AJ
authors.lastname: Pantuck
authors.forename: Arndt
authors.initials: A
authors.lastname: van Ophoven
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Gitlitz
authors.forename: Cho-Lea
authors.initials: CL
authors.lastname: Tso
authors.forename: Bruce
authors.initials: B
authors.lastname: Acres
authors.forename: Patrick
authors.initials: P
authors.lastname: Squiban
authors.forename: Michael E
authors.initials: ME
authors.lastname: Ross
authors.forename: Arie S
authors.initials: AS
authors.lastname: Belldegrun
authors.forename: Robert A
authors.initials: RA
authors.lastname: Figlin
mesh_terms: D000368:Aged; D015704:CD4 Antigens / Q000096:biosynthesis; D016827:CD8 Antigens / Q000096:biosynthesis; D019496:Cancer Vaccines / Q000627:therapeutic use*; D002469:Cell Separation; D002986:Clinical Trials as Topic; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D007167:Immunotherapy; D007376:Interleukin-2 / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D018396:Mucin-1 / Q000235:genetics*; D010641:Phenotype; D011471:Prostatic Neoplasms / Q000628:therapy*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018417:Th1 Cells; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation; D014616:Vaccinia virus / Q000235:genetics*
chemical_list: D015704:CD4 Antigens; D016827:CD8 Antigens; D019496:Cancer Vaccines; D007376:Interleukin-2; D018396:Mucin-1; D014409:Tumor Necrosis Factor-alpha