CELLULAR MUCINS - TARGETS FOR IMMUNOTHERAPY

Mucins are attracting great interest as potential targets for immunoth erapy in the development of vaccines for cancers expressing Mucin1 (MU C1) (e.g., breast, pancreas, ovary, and others) as there is (1) a 10-f old increase in the amount in adenocarcinomas; (2) an alteration in ex pression where they become ubiquitous, acid (3) due to altered glycosy lation, new epitopes appear on the cell surface that are absent in nor mal tissues. These new epitopes can be carbohydrate; others are peptid e in nature. The cloning of the cDNAs from mucins, particularly MUC1, has led to rapid advances being made, and it is clear that a highly im munogenic peptide exists within the variable number of tandem repeats (VNTR) found in all mucins. This peptide is immunogenic in mice, givin g rise to strong antibody production, and most monoclonal antibodies m ade to breast cancer, which react with the protein core, react with th e peptide APDTR. It is now also clear that humans with breast cancer h ave, in their draining lymph nodes, precursors of cytotoxic T cells th at can be stimulated in vitro to react against breast cancer and indee d against the APDTR or a closely related peptide - shown from antibody -blocking studies. These CTLs are unique in that they are non-MHC rest ricted. The identification of suitable targets, coupled with the known immunogenicity of both the peptide and neo-carbohydrate epitopes, has led to the development of several different programs to immunize huma ns against breast cancer using either synthetic carbohydrates or pepti des conjugated with adjuvants, and clinical trials are now in progress to evaluate their immunogenicity and anti-cancer effects.