We initiated a clinical trial for patients with advanced
malignant melanoma treated with an anti-idiotype antibody that mimics the disialoganglioside GD2. We report the clinical and immune responses of the first 12 patients entered into this trial. Patients received 1-, 2-, 4-, or 8-mg doses of the anti-idiotype antibody mixed with 100 microg of
QS-21 adjuvant every other week, four times, and then monthly. Twelve patients have been on trial for 2-23 months, and all of them have generated immune responses. Patients were removed from the study if they demonstrated
disease progression. Hyperimmune sera from all 12 patients revealed an anti-anti-idiotypic Ab3 response, as demonstrated by the inhibition of Ab2 binding to Ab1 by patients'
immune sera. To further test the anti-anti-idiotypic response, patients' Ab3
antibodies were affinity purified on
Sepharose 4B columns containing adsorbed immunizing anti-
idiotype immunoglobulin. Purified Ab3 of all patients studied inhibited binding of Ab1 to a GD2-positive cell line. Purified Ab3 also inhibited binding of Ab1 to purified GD2, in a manner comparable to equal quantities of purified Ab1. The patient Ab3 was truly an Ab1' because it specifically bound to purified disialoganglioside GD2. The isotypic specificity of the Ab3 antibody was predominantly
IgG, with only minimal
IgM. The predominant
IgG subclass was
IgG1, with approximately equal quantities of
IgG2,
IgG3, and
IgG4. These Ab3
antibodies reacted specifically with
tumor cells expressing GD2 by immune flow cytometry and immunoperoxidase assays. Five patients' Ab3
antibodies studied for antibody-dependent cellular cytotoxicity were positive. One patient had a complete clinical response, with resolution of soft tissue disease, and six patients had stable disease, ranging from 9 to 23 months, and are being continued on vaccine therapy. Toxicity consisted of local reaction at the site of the injection, including induration and
pain that generally resolved within a few days. Mild
fever and
chills were observed in 75% of the patients but rarely required
acetaminophen. There was no additional toxicity, including
abdominal pain that was previously seen with infusion of murine monoclonal anti-GD2 antibody. Current trials include patients with stage III
melanoma and
small cell lung cancer. Future trials will attempt to enhance the antitumor response by the addition of
interleukin 2,
granulocyte macrophage colony-stimulating factor, and other
cytokines, together with the 1A7
vaccine.