Recombinant vaccinia virus encoding human MUC1 and IL2 as immunotherapy inpatients with breast cancer

Polymorphic epithelial mucin, encoded by the MUC1 gene, is present at the a pical surface of glandular epithelial cells. It is over-expressed and aberr antly glycosylated in most breast tumors, resulting in an antigenically dis tinct molecule and a potential target for immunotherapy. This transmembrane protein, when produced by tumor cells, is often cleaved into the circulati on, where it is detectable as a tumor marker (CA 15.3) by various antibodie s, allowing for early detection of recurrences and evaluation of treatment efficacy. The objective of the current study was to examine the clinical an d environmental safety and immunogenicity of a live recombinant vaccinia vi rus expressing the human MUC1 and IL2 genes (VV TG5058), referred to here a s TG1031. The study was an open-label phase 1 and 2 trial in nine patients with advanced inoperable breast cancer recurrences to the chest wall. The p atients were vaccinated intramuscularly with a single dose of TG1031; three patients were treated at each of three progressive dose levels ranging fro m 5 x 10(5) to 5 x 10(7) plaque-forming units. A boost injection at their o riginal dose level was administered in patients responding immunologically, clinically, or both. Vaccination resulted in no significant clinical adver se effects, and there was no environmental contamination by live TG1031. Al l patients had been vaccinated as children, and patients treated at the hig hest dose level mounted a significant anti-vaccinia antibody response. None of the nine patients had a significant increase in MUC1-specific antibody titers after one single injection, whereas five patients had a detectable i ncrease in vaccinia virus antibody titers. Peripheral blood mononuclear cel ls of one patient at the intermediate dose level showed a proliferative res ponse to in vitro culture with vaccinia virus, with a stimulation index of 6. A second patient treated at the intermediate dose level had a stimulatio n index of 7 to MUC1 peptide and of 14 after a boost injection. This patien t had a concomitant decrease in carcinoembryonic antigen serum levels and r emained clinically stable for 10 weeks. Evidence of MUC1-specific cytotoxic T lymphocytes was detected in two patients. Immunohistochemical analysis r evealed an increase in T memory cells (CD45RO) in tumor biopsies after vacc ination. The absence of serious adverse events, together with the documenta tion of immune stimulations in vivo, warrant the further use of TG1031 in i mmunotherapy trials of breast cancer.