The syntheses of two tumor-associated carbohydrate antigens, Tn and TF, have been achieved using
glycal assembly and cassette methodologies. These synthetic antigens were subsequently clustered (c) and
immunoconjugated to a carrier protein (KLH or BSA) or a synthetic lipopeptide (pam) for immunological
study. Three Tn conjugates were used to vaccinate groups of mice, and all preparations proved to be
immunogenic. The Tn(c) covalently linked to KLH (27−KLH) plus the adjuvant QS-21 was the optimal
vaccine, inducing high median IgM and IgG titers against Tn(c) by ELISA. These antibodies were strongly
reactive with the Tn(c) positive human colon cancer cell line LS-C but not the Tn(c) negative colon cancer
cell line LS-B by FACS. The antibodies' reactivities with natural antigens were inhibited with synthetic Tn(c)
but not with structurally unrelated compounds. On the basis of these results, vaccines containing 27−KLH
and 30−pam plus QS-21 are being tested in patients with prostate cancer.
The complex carbohydrate molecule globo H hexasaccharide has been synthesized, conjugated to keyhole limpet hemocyanin, and administered with the immunologic adjuvant QS-21 as a vaccine for patients with prostate cancer who have relapsed after primary therapies such as radiation or surgery. Globo H is one of several candidate antigens present on prostate cancer cells that can serve as targets for immune recognition and treatment strategies. The vaccine, given as five subcutaneous vaccinations over 26 weeks, has been shown to be safe and capable of inducing specific high-titer IgM antibodies against globo H. Its immunogenicity was confirmed in prostate cancer patients with a broad range of stages and tumor burdens. Observations of several patients who had evidence of disease relapse restricted to a rising biochemical marker, prostate-specific antigen (PSA), indicated that a treatment effect could occur within 3 months after completion of the vaccine therapy. This effect was manifested as a decline of the slope of the log of PSA concentration vs. time plot after treatment compared with values before treatment. Five patients continue to have stable PSA slope profiles in the absence of any radiographic evidence of disease for more than 2 years. The concept of using PSA slope profiles in assessing early treatment effects in biological therapies such as vaccines awaits further validation in phase II and III trials. The use of a variety of lesser known candidate glycoprotein and carbohydrate antigens in prostate cancer serves as a focus for the development of a multivalent vaccine of the treatment of relapsed prostate cancer in patients with minimal tumor burden.
The carbohydrate antigen globo H commonly found on breast cancer
cells is a potential target for vaccine therapy. The objectives of this
trial were to determine the toxicity and immunogenicity of three
synthetic globo H-keyhole limpet hemocyanin conjugates plus the
immunologic adjuvant QS-21. Twenty-seven metastatic breast cancer
patients received five vaccinations each. The vaccine was well
tolerated, and no definite differences were observed among the three
formulations. Serologic analyses demonstrated the generation of IgM
antibody titers in most patients, with minimal IgG antibody
stimulation. There was significant binding of IgM antibodies to MCF-7
tumor cells in 16 patients, whereas IgG antibody reactivity was
observed in a few patients. There was evidence of complement-dependent
cytotoxicity in several patients. Affinity column purification
supported the specificity of IgM antibodies for globo H. On the basis
of these data, globo H will constitute one component of a polyvalent
vaccine for evaluation in high-risk breast cancer patients.
A safe synthetic conjugate vaccine in a trimer formation was developed that can break immunologic tolerance by inducing specific humoral responses. It seemed to affect the biochemical progression of the disease as determined by a change in PSA log slope.
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