GANGLIOSIDE GD2 AS TARGET FOR IMMUNOTHERAPY IN MELANOMA

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The overall objective of this proposal is to apply an anti-idiotype(ld) based vaccine approach for the treatment of human melanoma. Disialoganglioside GD2 is expressed at high density on melanoma cells and will be used as a target for immunotherapy. We will initiate a Phase 1b clinical trial with an anti-id antibody, designated 1A7 (lgG1-k), which functionally mimics GD2. Murine monoclonal anti-GD2 antibody 14G2a was used as the immunizing antibody or Ab1, against which anti-ld 1A7 (or Ab2) was generated. 1A7 was used to induce anti-GD2 specific antibodies (Ab1') in mice, rabbits, and monkeys. In this clinical study, we will use anti-ld 1A7 mixed with the QS-21 adjuvant to actively immunize GD2 positive melanoma patients. The objectives of this trial are 1) to determine the effects of 1A7 on the ability of patients to generate Ab3 (Ab1') responses and cytolytic T lymphocytes (CTL) specific for autologous and/or allogeneic tumor cells; 2) to evaluate the toxicity of 1A7; 3) to determine the optimal immunomodulatory dose of the anti-ld 1A7; and 4) to monitor for clinical responses. At the completion of the Phase lb trial, we will begin a Phase II trial using the optimum immunomodulatory dose. Our goal will also be to enhance in animal models the anti-GD2 immune responses by using DNA vaccines based on the structure of 1A7 by recombinant DNA technology. These DNA vaccines will be plasmids and recombinant vaccinia virus capable of expression of 1A7 fragments in mammalian cells. 1A7 fragments will be a single chain polypeptide consisting of the variable domains of the heavy and light chains linked by a 15 amino acid linker. Therapeutic potential of these vaccines will be evaluated by determining the humoral and cellular immune responses in mice and compared with the standard 1A7-QS-21 vaccine as well s the antigen vaccine GD2-KLH plus QS-21. All of these vaccines will be tested for tumor protection and therapy of established tumors in an immunocompetent murine lymphoma model consisting of EL4 cells which express GD2 at high density. This study will be prelude to a clinical trial for melanoma patients with second generation anti-ld based DNA vaccines.