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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 × 105, 5 × 106, and 5 × 107 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 &agr;β) receptors, (2) increase in the CD4/CD8 ratio (2.5-fold) (3) augmentation of T-helper type 1 cell (TH1) (interferon-γ and tumor necrosis factor-&agr; ) 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-ζ and p56lck. These results suggest that VV/MUC-1/IL-2 gene therapy with a maximum tolerated dose of 5 × 107 pfu is safe and well tolerated.