Abstract
To determine the clinical toxicities and antibody response against sTn and tumor cells expressing sTn following immunization of high-risk breast cancer patients with clustered sTn-KLH [sTn(c)-KLH] conjugate plus QS-21. Twenty-seven patients with no evidence of disease and with a history of either stage IV no evidence of disease, rising tumor markers, stage II (>or=4 positive axillary nodes), or stage III disease received a total of five injections each during weeks 1, 2, 3, 7, and 19. Immunizations consisted of sTn(c)-KLH conjugate containing 30, 10, 3, or 1 microg sTn(c) plus 100 microg QS-21. Induction of IgM and IgG antibodies against synthetic sTn(c) and natural sTn on ovine submaxillary mucin were measured before and after therapy. Fluorescence-activated cell sorting analyses assessed reactivity of antibodies to LSC and MCF-7 tumor cells. The most common toxicities were transient local skin reactions at the injection site and mild flu-like symptoms. All patients developed significant IgM and IgG antibody titers against sTn(c). Antibody titers against ovine submaxillary mucin were usually of lower titers. IgM reactivity with LSC tumor cells was observed in 21 patients and with MCF-7 cells in 13 patients. There was minimal IgG reactivity with LSC cells. Immunization with sTn(c)-KLH conjugate plus QS-21 is well tolerated and immunogenic in high-risk breast cancer patients. Future trials will incorporate sTn(c) as a component of a multiple antigen vaccine.
Highlights
To determine the clinical toxicities and antibody response against sialyl Tn (sTn) and tumor cells expressing sTn following immunization of high-risk breast cancer patients with clustered sTn-keyhole limpet hemocyanin (KLH) [sTn(c)-KLH] conjugate plus QS-21
Immunization of mice with either synthetic single sTn-KLH or clustered sTn-KLH [sTn(c)-KLH] conjugates plus QS-21 induced IgM and IgG antibodies reactive with ovine submaxillary mucin (OSM) and the respective synthetic antigens as well as IgG antibodies reactive with sTn-positive tumor cells in both groups of mice [30]
The similar reactivity of both sets of sera with OSM and sTn-positive tumor cells implies that the sera were reactive with either the clustered or the unclustered configuration
Summary
To determine the clinical toxicities and antibody response against sTn and tumor cells expressing sTn following immunization of high-risk breast cancer patients with clustered sTn-KLH [sTn(c)-KLH] conjugate plus QS-21. The conformation of sTn found on naturally occurring mucins may be different from that of synthetic sTn. For example, the monoclonal antibody B72.3, preferentially reactive with tumor cells over normal cells and OSM, has been shown to react primarily with clusters of sTn [5, 30, 31]. The similar reactivity of both sets of sera with OSM and sTn-positive tumor cells implies that the sera were reactive with either the clustered or the unclustered configuration Monoclonal antibodies, such as B72.3, that have the greatest specificity for tumor cells over normal cells react primarily with sTn clusters, suggesting that this is the most relevant target for vaccine construction
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