The development of anticancer
vaccines requires the identification of unique
epitope markers, preferably expressed exclusively on the surface of
cancer cells. This Account describes the path of development of a
carbohydrate-based
vaccine for metastatic
breast cancer, including the selection and synthesis of
Globo-H as the target, the development of the
vaccine conjugate and adjuvant design, the study of the immune response and consideration of class switch, and the analysis of
Globo-H distribution on the surface of various
cancer cells, cancer stem cells, and normal cells. The first synthesis of
Globo-H was accomplished through the use of glycal chemistry; this approach delivered sufficient material for evaluation in phase I human trials. The development of a programmable one-pot synthesis method rendered the synthesis more practical and enabled the midstage proof-of-concept phase II trial and late-stage phase III trial. Finally, enzymatic synthesis of
Globo-H coupled with cofactor regeneration was used for the late-stage multicenter trials and manufacture of the product. Along this path of development, it was discovered that the
vaccine induced
antibodies to target not only
Globo-H, but also SSEA3 and SSEA4. Moreover, these three
glycolipids were found to be uniquely expressed not only on the cell surface of
breast cancer but on 15 additional
cancer types, suggesting the broad application of this
vaccine in
cancer treatment and perhaps
cancer prevention. In addition, a new
glycolipid adjuvant was designed to target the CD1d receptor on dendritic cells and B cells for presentation to and activation of T cells to modulate the immune response and induce a class switch from
IgM to
IgG, thereby overcoming the common problem of
carbohydrate-based
vaccines that often induce mainly
IgM antibodies. As demonstrated in this
vaccine development, the chemical approach to the synthesis and conjugation of
carbohydrate-based immunogens provides the flexibility for access to various structures and linkers to identify optimal compositions for development. The enzymatic method was then introduced to enable the practical synthesis of the
vaccine candidate for clinical development and commercialization. Overall, this Account illustrates the path of development of a
cancer vaccine, from selection of a unique
glycan marker on
breast cancer cells and the cancer stem cells as target to the use of chemistry in combination with immunology and
cancer biology to enable the design and development of the
Globo-H vaccine to target three specific
glycan markers exclusively expressed on the cell surface of a number of different types of
cancer.