Editors' ChoiceCancer Vaccine Development

Triple Whammy

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Science Translational Medicine  04 Jan 2012:
Vol. 4, Issue 115, pp. 115ec1
DOI: 10.1126/scitranslmed.3003625

Normally, heavily glycosylated mucin proteins serve protective functions, such as covering epithelial cells and preventing pathogens from reaching the cell surface—and they might also serve as useful targets for cancer therapeutics. The mucin MUC1 is abnormally glycosylated and strongly overexpressed on many cancer cell types, including those from breast, ovary, colon, rectum, pancreas, and prostate carcinomas. Tumor-associated MUC1 has been identified by the National Cancer Institute as a leading candidate for cancer vaccine development. However, previous attempts to develop MUC1-targeted cancer vaccines have been largely unsuccessful in that the candidates have not elicited effective antibody and cellular immune responses; for example, heavily glycosylated MUC1 sequences are not processed by antigen presenting cells, and therefore T helper cells and cytotoxic T lymphocytes (CTLs) are not activated. Now, Lakshminarayanan et al. report on the design of a new MUC1-targeted vaccine that produces a significant therapeutic response in a mouse model of mammary cancer.

To address the complex issues that have caused other MUC1 vaccine candidates to fail, the researchers devised a vaccine constructed of three covalently linked components: an aberrantly glycosylated MUC1 peptide, a Toll-like receptor agonist (to elicit cytokines and chemokines that promote immune cell interactions), and a T-helper epitope [to promote immunoglobulin G (IgG) antibody production and aid antigen presentation]. This approach enabled generation of both antibody-mediated and CTL responses. Administration of the tripartite vaccine to experimental mice, which were then challenged with MUC1-expressing mammary tumor cells and subsequently given a booster vaccine, caused a significant reduction in tumor burden and weight as compared with control vaccines. The tripartite vaccine elicited a robust IgG antibody response against the MUC1 glycopeptide, which induced antibody-dependent cell-mediated cytotoxicity and significantly enhanced cancer cell lysis as compared with the control vaccines. In the experimental animals, the vaccine also generated a cellular immune response, producing CTLs that recognized MUC1.

Because numerous types of cancers share the MUC1 carbohydrate signature, the results presented by Lakshminarayanan et al. provide an innovative vaccine design strategy that may have therapeutic applicability across a wide range of malignancies. These findings increase optimism for cancer vaccine development, so that one could imagine possible treatments for malignancies refractory to current therapies.

V. Lakshminarayanan et al., Immune recognition of tumor-associated mucin MUC1 is achieved by a fully synthetic aberrantly glycosylated MUC1 tripartite vaccine. Proc. Natl. Acad. Sci. U.S.A. 14 December 2011 (10.1073/pnas.1115166109). [Abstract]

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