ANTIBODY-RESPONSES IN MELANOMA PATIENTS IMMUNIZED WITH AN ANTIIDIOTYPE ANTIBODY MIMICKING DISIALOGANGLIOSIDE GD2

We initiated a clinical trial for patients with advanced malignant mel anoma treated with an anti-idiotype antibody that mimics the disialoga nglioside GD2., We report the clinical and immune responses of the fir st 12 patients entered into this trial. Patients received 1-, 2-, 4-, or 8-mg doses of the anti-idiotype antibody mixed with 100 mu g of QS- 21 adjuvant every other week, four times, and then monthly. Twelve pat ients have been on trial for 2-23 months, and all of them have generat ed immune responses. Patients were removed from the study if they demo nstrated disease progression. Hyperimmune sera from all 12 patients re vealed an anti-anti-idiotypic Ab3 response, as demonstrated by the inh ibition of Ab2 binding to Abl by patients' immune sera, To further tes t the anti-anti-idiotypic response, patients' Ab3 antibodies were affi nity purified on Sepharose 4B columns containing adsorbed immunizing a nti-idiotype immunoglobulin. Purified Ab3 of all patients studied inhi bited binding of Abl to a GD2-positive cell line. Purified Ab3 also in hibited binding of Abl to purified GD2, in a manner comparable to equa l quantities of purified Abl, The patient Ab3 was truly an Ab1' becaus e it specifically bound to purified disialoganglioside GD2, The isotyp ic specificity of the Ab3 antibody was predominantly IgG, with only mi nimal IgM., The predominant IgG subclass was IgG1, with approximately equal quantities of IgG2, IgG3, and IgG4., These Ab3 antibodies reacte d specifically with tumor cells expressing GD2 by immune flow cytometr y and immunoperoxidase assays. Five patients' Ab3 antibodies studied f or antibody-dependent cellular cytotoxicity were positive, One patient had a complete clinical response, with resolution of soft tissue dise ase, and six patients had stable disease, ranging from 9 to 23 months, and are being continued on vaccine therapy. Toxicity consisted of loc al reaction at the site of the injection, including induration and pai n that generally resolved within a few days. Mild fever and chills wer e observed in 75% of the patients but rarely required acetaminophen, T here was no additional toxicity, including abdominal pain that was pre viously seen with infusion of murine monoclonal anti-GD2 antibody. Cur rent trials include patients with stage III melanoma and small cell lu ng cancer. Future trials will attempt to enhance the antitumor respons e by the addition of interleukin 2, granulocyte macrophage colony-stim ulating factor, and other cytokines, together with the 1A7 vaccine.