Rolling in the MUC1
Writing in the journal Vaccines last year, Behjatolah Monzavi-Karbassi, Ph.D., and colleagues reviewed some of the challenges associated with development of glycoprotein-based vaccines. Citing the favorite target of glycan-based vaccine developers, MUC1, cancer vaccines targeting this antigen had been based on carrier-conjugated unglycosylated MUC1 tandem repeat peptides or carrier-conjugated glycosylated epitopes. These efforts proved largely unsuccessful. MUC1 is a high-molecular-weight glycoprotein having few isoforms encoding both a transmembrane and cleavage-truncated secreted (soluble) product. Both forms are expressed by more than 90% of solid epithelial tumor cancers as well as most common nonsolid tumors including multiple myeloma.
Obstacles, the authors said, partially relate to the conformational differences between nonglycosylated vaccine sequences and tumor-expressed, aberrantly glycosylated MUC1. Moreover, densely glycosylated MUC1 glycopeptide might be inefficiently processed by antigen-presenting cells, which ultimately means T helper cells and CTLS aren’t highly activated.
In 2012, Vani Lakshminarayanan, Ph.D., and colleagues working in the laboratory of Sandra Gendler, Ph.D., at the department of biochemistry and molecular biology, Mayo Clinic, AZ, and the Complex Carbohydrate Research Center University of Georgia in Athens, GA, thought that better immunogenicity of MUC1 would be obtained using glycopeptides more representative of the novel forms of MUC1. The rationale was that individuals would be less tolerant to these novel cancer-associated glycopeptide forms and that direct linking of the vaccine components would result in superior cytotoxic CD8+ T cells, eliciting robust titers of IgG antibodies that lyse relevant tumor cells by antibody-dependent cell-mediated cytotoxicity (ADCC).
They note that MUC1 is aberrantly glycosylated by epithelial cancer cells, as shown by truncated O-linked saccharides. The resultant glycopeptide epitopes can bind cell surface major histocompatibility complex (MHC) molecules and can be recognized by cytotoxic T lymphocytes (CTLs), whereas aberrantly glycosylated MUC1 protein on the tumor cell surface can be bound by antibodies to mediate ADCC.
The vaccine is composed of the immunoadjuvant Pam(3)CysSK(4), a peptide T(helper) epitope and an aberrantly glycosylated MUC1 peptide. Covalent linkage of the three vaccine components, they said, was essential for maximum efficacy. The vaccine produced CTLs, which recognized both glycosylated and nonglycosylated peptides, whereas a similar nonglycosylated vaccine gave CTLs, which recognized only nonglycosylated peptides. Antibodies elicited by the glycosylated tripartite vaccine were significantly more lytic compared with the unglycosylated control.
Results of vaccine testing in a humanized mouse model of mammary cancer demonstrated that the tripartite vaccine could elicit IgG antibodies that can lyse MUC1-expressing cancer cells, stimulate cytotoxicity of T lymphocytes, and activate innate immune responses, thereby reversing tolerance and generating a therapeutic response.
The authors say that besides its own aptness as a clinical target, these studies of MUC1 are likely predictive of a covalent linking strategy applicable to many additional tumor-associated antigens.
“This vaccine elicits a very strong immune response,” said study co-senior author Geert-Jan Boons, Ph.D., Franklin Professor of Chemistry and a researcher in the UGA Cancer Center and its Complex Carbohydrate Research Center. “It activates all three components of the immune response.”
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