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Induction of Antibodies against GM2 Ganglioside by Immunizing Melanoma Patients Using GM2-Keyhole Limpet Hemocyanin + QS21 Vaccine: A Dose-Response Study¹

Department of Medicine, Clinical Immunology Service, [P. B. C., A. N. D., L. W., P. O. L.], and Department of Epidemiology and Biostatistics [K. S. P.], Memorial Sloan-Kettering Cancer Center, New York, New York 10021, and Progenics Pharmaceuticals, Inc., Tarrytown, New York [D. M. M., W. B.H., C. Z., R. J. I.]

In a previous randomized Phase III trial (P. O. Livingston et al., J. Clin. Oncol., 12: 1036–1044, 1994), we demonstrated that immunization with GM2 and bacille Calmette-Guérin reduced the risk of relapse in stage III melanoma patients who were free of disease after surgical resection and who had no preexisting anti-GM2 antibodies. That vaccine formulation induced IgM anti-GM2 antibodies in 74% but induced IgG anti-GM2 antibodies in only 10% of the patients. To optimize the immune response against GM2, a reformulated vaccine was produced conjugating GM2 to keyhole limpet hemocyanin (KLH) and using the adjuvant QS21 (GM2-KLH/QS21). In pilot studies, 70 µg of vaccine induced IgG anti-GM2 antibodies in 76% of the patients. We wished to define the lowest vaccine dose that induced consistent, high-titer IgM and IgG antibodies against GM2. Fifty-two melanoma patients who were free of disease after resection but at high risk for relapse were immunized with GM2-KLH/QS21 vaccine at GM2 doses of 1, 3, 10, 30, or 70 µg on weeks 1, 2, 3, 4, 12, 24, and 36. Serum collected at frequent and defined intervals was tested for anti-GM2 antibodies. Overall, 88% of the patients developed IgM anti-GM2 antibodies; 71% also developed IgG anti-GM2 antibodies. GM2-KLH doses of 3–70 µg seemed to be equivalent in terms of peak titers and induction of anti-GM2 antibodies. At the 30-µg dose level, 50% of the patients developed complement fixing anti-GM2 antibodies detectable at a serum dilution of 1:10. We conclude that the GM2-KLH/QS21 formulation is more immunogenic than our previous formulation and that 3 µg is the lowest dose that induces consistent, high-titer IgM and IgG antibodies against GM2.

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