Recombinant Vaccinia Virus Encoding Human MUC1 and IL2 as Immunotherapy in Patients With Breast Cancer

Abstract

Polymorphic epithelial mucin, encoded by the MUC1 gene, is present at the apical surface of glandular epithelial cells. It is over-expressed and aberrantly glycosylated in most breast tumors, resulting in an antigenically distinct molecule and a potential target for immunotherapy. This transmembrane protein, when produced by tumor cells, is often cleaved into the circulation, where it is detectable as a tumor marker (CA 15.3) by various antibodies, allowing for early detection of recurrences and evaluation of treatment efficacy. The objective of the current study was to examine the clinical and environmental safety and immunogenicity of a live recombinant vaccinia virus expressing the human MUC1 and IL2 genes (VV TG5058), referred to here as 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 patients were vaccinated intramuscularly with a single dose of TG1031; three patients were treated at each of three progressive dose levels ranging from 5x10(5) to 5x10(7) plaque-forming units. A boost injection at their original dose level was administered in patients responding immunologically, clinically, or both. Vaccination resulted in no significant clinical adverse effects, and there was no environmental contamination by live TG1031. All patients had been vaccinated as children, and patients treated at the highest 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 increase in vaccinia virus antibody titers. Peripheral blood mononuclear cells of one patient at the intermediate dose level showed a proliferative response to in vitro culture with vaccinia virus, with a stimulation index of 6. A second patient treated at the intermediate dose level had a stimulation index of 7 to MUC1 peptide and of 14 after a boost injection. This patient had a concomitant decrease in carcinoembryonic antigen serum levels and remained clinically stable for 10 weeks. Evidence of MUC1-specific cytotoxic T lymphocytes was detected in two patients. Immunohistochemical analysis revealed an increase in T memory cells (CD45RO) in tumor biopsies after vaccination. The absence of serious adverse events, together with the documentation of immune stimulations in vivo, warrant the further use of TG1031 in immunotherapy trials of breast cancer.

Heat shock fusion protein induces both specific and nonspecific anti‐tumor immunity

“…A synthetic MUC1 peptide vaccine in a liposomal formulation was shown to prolong survival of the patients with non-small cell lung cancer [6]. Vaccinia viruses that express both MUC1 VNTR and IL-2 were shown to induce MUC1-specific antibodies and CTL in some of the patients with advanced inoperable breast cancer [7]. MUC1 coupled with keyhole limpet hemocyanin (KLH) + QS-21 (a potent adjuvant) was demonstrated to induce MUC-1-specific antibody but only a minimal T cell response in clinical trials [8][9][10].…”

A Unique Mucin Immunoenhancing Peptide with Antitumor Properties

“…T-Cell immunity is thought to be a major driving force in the rejection of tumor cells (25). Indeed, many tumor vaccination models, including those aimed at using the MUC1 antigen, attempt to specifically invoke Th1 immunity in the hopes of generating tumor-specific T cells (12,30,31). It is clear that DA-3/sec cells elicit T-cell immunity; however, what role the MUC1/ sec-derived peptide plays in the generation of Th1 immunity is still unclear.…”

Protection against MUC1 expressing mouse tumours by intra‐muscular injection of MUC1 cDNA requires functional CD8+ and CD4+ T cells but does not require the MUC1 tandem repeat domain

“…Moreover, only MUC1 expressed endogenously, as would be the case for DNA-based immunogens, will be processed to produce a peptide from the signal sequence. Including a DNA-based formulation such as recombinant vaccinia expressing MUC1 that has been tested recently, 36 or naked cDNA (clinical study initiated), may therefore be important. The requirement for a prime boost type protocol for induction of MUC1 specific CTL detectable in vitro also suggests that combinations of different formulations of MUC1 should be evaluated.…”