Dr. Waldmann's studies have focused on the role played by the IL-2-IL-15R system in normal and abnormal T-cell function and the use of these insights to develop IL-2R directed therapy for leukemia. Dr. Waldmann, during an analysis of the adult T-cell leukemia (ATL) cell line HuT-102, co-discovered a 15 kDa lymphokine, IL-15, that stimulates T-cell proliferation. There is wide-spread expression of IL-15 mRNA in a variety of tissues and cells including skeletal muscle, fibroblasts, epithelial cells and activated monocytes. Nevertheless, it is difficult to demonstrate meaningful quantities of IL-15 in the supernatants of many of these cells suggesting that there are critical post-transcriptional regulatory events affecting IL-15 expression. He showed that IL-15 message includes a number of elements that are impediments to its translation. In particular the 5' UTR of normal human IL-15 message is burdened with 10 upstream AUGs that interfere with efficient IL-15 translation. Furthermore, the unusually long 48 aa leader sequence interferes with this process. The effective IL-15 synthesis by the cell line HuT-102 is a consequence of the production of a fusion message involving the HTLV-IR segment and the open reading frame of IL-15. In this chimeric mRNA the introduction of the R segment eliminated 8 of 10 upstream AUGs of the 5' UTR that normally impede translation. One of Dr. Waldmann's crucial contributions was his recognition that the IL-2R represents an extraordinarily useful therapeutic target. In particular he demonstrated that normal resting cells do not express IL-2Ralpha whereas a large number of IL-2Ralpha are expressed by many forms of leukemic cells including HTLV-I-associated ATL. He completed a clinical trial with 90Y- anti-Tac for patients with HTLV-I-associated ATL. Nine of the 16 patients in this trial manifested a partial or complete remission following therapy. Recently he extended these studies by initiating new clinical trials using 90Y-linked to humanized rather than murine anti-Tac to provide a relatively nonimmunogenic agent for the treatment of an extended array of human leukemias and lymphomas. Furthermore, in tumor models in nude mice he demonstrated the efficacy of alpha-particle-emitting radiolabeled mAbs in the therapy of HER-2/neu expressing ovarian or Tac- positive T-cell tumors. Thus new insights concerning receptors on malignant cells taken in conjunction with the ability to produce humanized antibodies armed with radionuclides is providing a novel perspective for the treatment of certain neoplastic diseases.
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