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Dec 14, 2011

Humoral, Cellular Activity of MUC1 Vaccine Shrinks Tumors In Vivo

  • Scientists report on the design of an anticancer vaccine targeting MUC1, which triggers strong humoral and cellular immune responses in vivo, and leads to a significant reduction in tumor burden in animals carrying MUC1-expressing tumors. The vaccine, generated by a team at the Mayo Clinic Comprehensive Cancer Center and the University of Georgia, is constructed of three components, centered on an MUC1 glycopeptide antigen, which in combination, address the issues that have led to failure of previous attempts to generate MUC1 vaccine candidates that can generate both CTL and antibody-mediated responses.

    Geert-Jan Boons, M.D., and colleagues, describe the development in PNAS, in a paper titled "Immune recognition of tumor-associated MUC1 is achieved by a fully synthetic aberrantly glycosylated MUC1 tripartite vaccine.”

    Tumor-associated MUC1 is an abnormally glycosylated form of the glycoprotein that represents a strong potential target for anticancer therapies. The tumor-associated glycopeptide epitopes can bind MHC molecules and are susceptible to cytotoxic T lymphocyte (CTL) recognition, and the aberrantly glycosylated MUC1 protein on the tumor cell surface can be targeted by antibodies for an antibody-dependent cell-mediated cytotoxicity approach.

    In reality, attempts to develop MUC1-targeting cancer vaccines based on carrier-conjugated unglycosylated MUC1 tandem repeat peptides or carrier-conjugated carbohydrate epitopes, have been largely unsuccessful. Problems here partly relate to the conformational differences between nonglycosylated vaccine sequences and tumor-expressed, aberrantly glycosylated MUC1. Moreover, densely glycosylated MUC1 glycopeptide can't be processed by antigen-presenting cells (APCs), which ultimately means T-helper cells and CTLS aren’t activated.

    More promising results in tumor models have been reported using an two-component vaccine approach based on an MHC I glycopeptide and a T-helper epitope. The drawback here, however, is that such vaccines don’t induce antibody responses.

    The ultimate goal would be to develop an MUC1 vaccine candidate that can elicit both humoral and cellular responses. The Mayo Clinic and University of Georgia researchers have previously described their development of a multicomponent vaccine comprising a glycosylated MUC1-derived glycopeptides covalently linked to a T-helper epitope and Toll-like receptor (TLR) immunoadjuvant, which in wild-type mice elicited extremely high titres of IgG antibodies. In their latest work using a humanized mouse model of mammary cancer, the team reports that the vaccine elicits potent humoral and cellular immune responses, effectively reverses tolerance, and demonstrates potent anticancer effects.

    The vaccine candidate comprises the thiobenzyl ester of Pam3CysSK4 as a TLR2 ligand adjuvant, together with the composite T-helper epitope and aberrantly glycosylated MUC1 peptide, CKLFAVWKITYKDTGTSAPDT(αGalNAc)RPAP, formulated into phospholipid-based small unilamellar vesicles. To test its effects in vivo, the tripart vaccine was administered to experimental mice, and the animals challenged with MUC1-expressing mammary tumor cells after 35 days. A week after the cancer challenge, the mice were given another vaccine boost. Control mice were administered with vaccine constructs comprising either the unglycosylated vaccine or subunits of the overall vaccine structure, i.e., just the glycopeptide or the adjuvant.

    Examination of resulting tumors showed that immunization with the multicomponent vaccine led to significant reductions in tumor burden and weight when compared with treatment using either empty liposomes, or immunization with a control vaccine that didn’t contain the MUC1 glycopeptide epitope, or an unglycosylated multicomponent candidate.

    Immunization with the primary tripartite candidate also elicited robust IgG antibody responses against the MUC1 glycopeptide, including a mixed Th1/Th2 response. Encouragingly, only very low titers of antibodies were generated against the T-helper epitope, “indicating that the candidate vaccine does not suffer from immune suppression,” the team notes.

    Antibody-dependent cell-mediated cytotoxity (ADCC) was investigated by labeling two MUC1- expressing cancer cell types with 51Cr, followed by the addition of antisera and cytotoxic effector cells (NK cells) and measuring released 51Cr. The results showed that antisera obtained following immunization with the glycosylated composite vaccine significantly boosted cancer cell lysis compared with the control compounds, highlighting the importance of glycosylation for antigenic responses.

    The ability of the vaccine candidates to activate CTLs was confirmed by isolating CD8+ T cells from lymph nodes of immunized mice, and incubating them with irradiated dendritic cells (DCs) pulsed with the immunizing peptides. Interestingly, the results indicated that vaccination using a mixture of the glycopeptides and the adjuvant was enough to induce the activation of a small number of CD8+cells, which indicates that covalent attachment of MUC1 and T-helper epitope to the adjuvant is important for optimal activation of CTLs, the authors write. “Our previous studies have shown that covalent attachment of the TLR2 agonist Pam3CysSK4 facilitates selective internalization by TLR2-expressing immune cells such B cells and antigen presenting cells.”

    The overall results indicate that the tripartite vaccine works to reduce tumor burden by triggering specific immunity against MUC1, and by generating nonspecific adjuvant effects mediated by the TLR2 agonist, they suggest. “We hypothesize that a tumor-specific anti-MUC1 response is attainable, but only when the MUC1 component of the vaccine contains the conformational elements of aberrant glycosylation ... 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.”

     


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