Therapeutic aspects of polymorphic epithelial mucin in adenocarcinoma

Abstract

The gene MUC1 encodes a large membrane-associated glycoprotein, previously termed polymorphic epithelial mucin and now known as MUC1. The majority of the extracellular domain is made up of tandem repeats of 20 amino acids. In some epithelial malignancies, MUC1 is up-regulated, and as a result of changes in glycosyl and sialytransferases, the complex carbohydrate side chains are truncated, leading to exposure of novel peptide and carbohydrate epitopes. Cellular and humoral immune responses to MUC1 have been documented in malignant disease, and T-cell responses to MUC1 may not depend on presentation by the major histocompatibility complex. Several immunogens based on MUC1 are being investigated. These include cell lines expressing MUC1 given alone or fused with professional antigen-presenting cells and peptide epitopes, given either with conventional immunological adjuvants or coupled to mannan, which may target uptake into antigen-presenting cells. Cellular and humoral immune responses to these agents have been recorded in patients with advanced malignancy. Targeting of peptide epitopes may also be achieved using antibodies to MUC1 through induction of idiotypes and retrospective analyses in ovarian cancer have suggested a survival benefit for patients. The use of cDNA in coding MUC1 may allow endogenous processing of antigen. Phase I studies using vaccinia as a vector have been completed. Studies using carbohydrate antigens suggest that the ability to generate specific immune responses may influence survival of patients with metastatic epithelial malignancies. While examining the potential role of immunogens based on MUC1, it is also necessary to understand the nature of immunosuppression in patients with advanced malignancy in order to develop strategies to enhance the immunogenicity of potential cancer vaccines.