Mucin based breast cancer vaccines.
Of the 8 human epithelial mucins identified so far, MUC1 has been the focus of attention for immunotherapeutic applications. The gene MUC1 encodes a large membrane associated glycoprotein where the majority of the extracellular domain is made up of tandem repeats of 20 amino acids. In breast cancer MUC1 is up-regulated and as a result of changes in glycosyl transferases, the complex carbohydrate side-chains are shortened leading to the exposure of novel peptide and carbohydrate epitopes. Cellular and humoral immune responses to MUC1 have been documented in benign and malignant breast disease and in some circumstances, T-cell responses to MUC1 may not depend on presentation by the major histocompatibility complex. Several immunogens based on MUC1 are being investigated for the immunotherapy of breast cancer in model systems and in the clinic. These include cell lines that express MUC1, either given alone or fused with professional antigen presenting cells. Approaches that may prove more feasible in the clinic include the use of peptide epitopes, usually from the tandem repeat of the extracellular domain, given either with conventional immunological adjuvants or coupled to mannan (a polysaccharide also known as polymannose), which may target uptake of peptide into antigen presenting cells. Cellular and humoral immune responses to these immunogens have been noted in patients with advanced malignancy. Targeting of peptide epitopes may also be achieved using antibodies to MUC1 through the idiotype network. Use of antibodies to MUC1 has been associated with a survival benefit for patients with ovarian cancer, but prospective studies are awaited. The use of cDNA encoding MUC1 may allow endogenous processing of antigen and thus augment immunogenicity. Phase I studies using the vaccinia virus as a vector have been completed and Phase II studies have begun. Studies examining the potential role of carbohydrate antigens have suggested that the ability to generate a specific immune response may influence survival of patients with metastatic epithelial malignancies. Again, these findings will be tested in the Phase III setting. 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.
ICRF Breast Biology Group, 3rd Floor Thomas Guy House, Guy's Hospital, London, SE1 9RT, UK. miles@icrf.icnet.uk
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Miles
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Taylor-Papadimitriou