DAB(389)IL2 (denileukin diftitox) suppresses growth of melanoma metastases

Abstract

18010 Background: CD4+CD25high regulatory T (Treg) cells have been found to suppress the activation of anti-tumor effector T cells. Depletion of Treg cells using anti-CD25 antibodies can induce a CD8+ T cell dependent rejection of melanoma in mice. Furthermore, Treg cells are increased in human lymph nodes containing melanoma metastases relative to adjacent benign lymph nodes. Taken together, these observations provide rationale for an examination of the effect of Treg cell depletion on the progression of metastatic melanoma in humans. Recombinant interleukin 2/diphtheria toxin conjugate (DAB[389]IL2; also termed ONTAK or denileukin diftitox) binds to CD25 and, following internalization, causes cell death. DAB(389)IL2 was recently reported to selectively deplete peripheral blood Treg cells in patients with renal cell carcinoma. Methods: The effect of DAB(389)IL2 on tumor growth was examined in 4 patients with Stage IV melanoma who had either progressed after biochemotherapy and/or high dose IL-2 or were ineligible for these treatments. DAB(389)IL2 (9 or 12 μg/kg) was administered daily x 4 days every three weeks for two cycles. FDG-PET/CT imaging was obtained just prior to DAB(389)IL2 administration and within 2 weeks of completion of the second cycle. In the setting of stable disease or tumor regression, DAB(389)IL2 was continued for two more cycles and a subsequent FDG-PET/CT imaging study was obtained. Results: Two patients received 9 μg/kg DAB(389)IL2 and, after two cycles, experienced overt progression consisting of a combination of tumor growth and newly detectable tumors. Two patients received 12 μg/kg DAB(389)IL2 and, after two cycles, experienced a combination of stable disease and marked regression of several metastatic tumors. In one patient, tumor volume of right and left axillary metastases shrunk by 33% and 43%, respectively, after two cycles of DAB(389)IL2. The second responding patient experienced resolution of several dermal metastases, reduction in the tumor volume of a left adrenal mass, and the complete regression of two hepatic metastases. Conclusions: We conclude that DAB(389)IL2 may provide a safe and effective treatment for stage IV melanoma. A phase II clinical trial is now underway to examine the efficacy of DAB(389)IL2 in this patient population. No significant financial relationships to disclose.