This project investigates the clinical and preclinical antitumor activity of the hu14.18-IL2 immunocytokine (1C) (EMD 273063). Hu14.18-IL2 consists of the humanized 14.18 monoclonal antibody (which recognizes the GD2 disialoganglioside expressed on human neuroblastoma and melanoma) linked genetically to human recombinant interleukin-2 (IL2). The chimeric form of the 14.18 antibody (the ch14.18 antibody) has been tested in Phase I neuroblastoma (NBL) and melanoma (MEL) clinical trials, alone and combined with other treatments, including IL2, and has shown some antitumor effects. The chimeric ch14.18-IL2 fusion protein (ch14.18-IL2) has a greater antitumor effect than either IL2 or ch14.18 or a combined regimen that includes both IL2 and ch14.18 molecules, when tested in tumor-bearing mice. Preclinical data show hu14.18-IL2 functions similarly to ch14.18-IL2 in vitro and in tumor-bearing mice, but is less likely to induce, neutralizing anti-immunocytokine antibodies in patients receiving it. We have recently completed two Phase I studies that each delivered hu14.18-IL2 intravenously over 4 hours daily for 3 days, at monthly intervals. In 33 adults with MEL, the maximum tolerated dose (MTD) was found to be 7.5 mg/m2/d. In 28 children with NBL, the MTD was 12 mg/m2/d. Immune activation was seen in both trials. The dose limiting toxicities at MTD for both studies were hypotension and hypoxia, both known toxicities of IL2. We now propose integrated clinical and lab studies to test and improve the antitumor efficacy of hu14.18-IL2 in MEL and NBL. Phase II and pilot clinical studies will use clinical grade material made for these studies by the NCI. Patients with measurable MEL, patients with advanced MEL that have had all evaluable disease surgically resected, and 3 cohorts of patients with NBL, will receive the same hu14.18-IL2 treatment schedule in order to determine whether it mediates antitumor activity in patients with measurable or minimal residual disease. Lab analyses will measure immune activation in treated patients, and the immune response against hu14.18-IL2, to determine which of these parameters correlate with toxicity or with antitumor effects. Finally, we will test strategies to enhance the antitumor efficacy of hu14.18-IL2 in tumor-bearing mice by increasing the number and type of effector cells able to be further activated and targeted to tumor by hu14.18-IL2. ? ? ?
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