THE IMMUNOGENICITY OF MUC1 PEPTIDES AND FUSION PROTEIN

Mucinl (MUCl) is highly expressed in breast cancer, has an ubiquitous distribution and, due to altered glycosylation, peptides within the VNTR are exposed. These peptides are the target for anti-MUCl antibodies, which give a differential reaction on cancer compared with normal tissue. The amino acids, APDTR or adjacent amino acids, are highly immunogenic in mice for antibody production (after immunisation with either breast cancer cells, human milk fat globule (HMFG) or the VNTR peptide). In addition, human studies show that this region of the MUCl VNTR functions as target epitopes for cytotoxic T cells. We have performed preclinical and clinical studies to examine the immune responses to MUCl in mice and humans: (a) MUCl(+) 3T3 or P815(+) 3T3 cells in syngeneic mice are rejected, with the generation of both cytotoxic T lymphocyte (CTL) and DTH responses and a weak antibody response; this type of immunity gives rise to total resistance to re-challenge with high doses of these tumors; (b) immunisation with peptides (VNTR x 2), a fusion protein (VNTR x 5), or HMFG leads to no CTLs, DTH, good antibody production and weak tumour protection (to 10(6) cells, but not 5 x 10(6) cells) (possibly a TH2 type response); (c) immunisation with mannan-fusion protein (MFP) gives rise to good protection (resistance to 50 x 10(6) cells), CTL and DTH responses and weak antibody responses (possibly a TH1 type response, similar in magnitude to that obtained after tumor rejection); (d) established tumors can be rapidly rejected by delayed treatment of MFP; (e) the CTL responses are MHC restricted (in contrast to the human studies); (f) APDTR appears not to be the T cell reactive epitope in mice. On the basis of these findings, two clinical trials are in progress: (a) VNTR x 2 (diphtheria toroid) which gives rise to some T cell proliferation, DTH and antibody responses in some patients and (b) an MFP trial. The ability to alter the immune response towards cellular immunity with mannan or to humoral immunity with peptides, allows the immune response to be selectively manipulated.