Single-agent IL-2 treatment can yield substantial antitumor effects in murine models when IL-2 is used prior to detection of large measurable tumors. Significant dose-dependent, immune-mediated toxicity is also induced by IL-2. Clinical trials have documented both antitumor responses and immune toxicity in patients receiving IL-2. The mechanism of the antitumor effects and the toxicity remains unclear but likely involves IL-2-induced cytokine release, altered metabolic activity and induction of cell-mediated cytolysis, designated the lymphokine-activated killer (LAK) phenomenon. Improved treatment results may require more specific targeting of these immune effector mechanisms toward the neoplastic cells themselves. Monoclonal antibodies (MoAb) have identified molecules preferentially expressed on certain tumor cells. The anti-GD-2 monoclonal antibody, 14.G2a, shows specific binding of neuroblastoma and osteogenic sarcoma, as well as melanoma. In vitro studies document the ability of this antibody to facilitate antibody-dependent, cell-mediated cytotoxicity (ADCC). However, many cancer patients are deficient in cells that mediate ADCC. We have documented that IL-2 administration to adults boosts their in vitro detected ADCC. We are now initiating clinical trials with this combination of IL-2 plus anti-GD-2 MoAb in children with neuroblastoma and osteogenic sarcoma as a groupwide effort of the Children's Cancer Study Group (CCSG). Our hypothesis is that the utility of biologic therapy will be best documented when integrated into the comprehensive care of patients with cancer. The purpose of this proposal is to perform in vitro preclinical analyses and in vitro monitoring of clinical trials which are needed to facilitate a stepwise integrated testing of IL-2 plus MoAb into the treatment of neuroblastoma and osteogenic sarcoma. Patients with metastatic spread of these diseases, unfortunately, show rapid relapses, even after surgical or chemotherapy-induced remission. Thus the efficacy of IL-2 plus MoAb treatment in this setting should be apparent relatively quickly. Because the treatment of these diseases is well coordinated through the multi-institutional organization of the CCSG, these protocols will provide useful data applicable to multimodality treatment of more common adult tumors for which tumor-selective MoAb are also available (i.e., colon, breast and lung adenocarcinomas).
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