Dr. Waldmann's studies have focused on the role played by the IL-2/IL- 2R system in normal and abnormal T-cell function and the use of these insights to develop IL-2R directed therapy for leukemia/lymphoma. Recently, Dr. Waldmann co-discovered a 15 kDa lymphokine, IL-15/IL-T, that stimulates T-cell proliferation. He demonstrated that IL-15 requires IL-2Rbeta and IL-2Rgamma expression for its action. On analysis of the 5' untranslated region of normal IL-15 he demonstrated that the presence of 10 upstream AUGs acts to interfere with IL-15 mRNA translation. When compared to activated monocytes IL-15 mRNA expression was 10-fold greater in the HTLV-I-associated adult T-cell leukemia (ATL) line HuT-102, and was translated into large quantities of IL-15. The predominant IL-15 message produced by HuT-102 is a chimeric mRNA joining a segment of the R region of the LTR of HTLV-I and the ORF of IL-15. In addition, the presence of the R segment eliminated over 200 bps of the IL-15 5' UTR including 8 of 10 upstream AUGs. Thus, IL-15 synthesis by the ATL cell line HuT-102 appears to involve a marked increase in IL-15 mRNA transcription and translation secondary to a putative proximal integration of HTLV-I provirus with the consequent production of a fusion message involving the HTLV-I R segment and the ORF of IL-15. One of Dr. Waldmann's most crucial contributions was his recognition that the IL-2R represents an extraordinarily useful therapeutic target. For example, Dr. Waldmann demonstrated that resting cells do not express IL-2Ralpha whereas a large number of IL-2Ralpha are expressed by malignant cells in ATL, Dr. Waldmann has completed a clinical trial with 90Y-anti-Tac for patients with HTLV-I-associated ATL. Nine (9) of the 16 patients in this trial manifested a partial or complete remission following 90Y- anti-Tac therapy. Recently Dr. Waldmann has extended these studies by initiating new clinical trials using 90Y linked to humanized rather than murine anti-Tac to provide a relatively non-immunogenic agent for the treatment of an extended array of human leukemias and lymphomas. Furthermore, using a tumor model in nude mice Dr. Waldmann demonstrated the efficacy of the alpha-particle-emitting radiolabeled murine anti-Her-2/neu monoclonal antibody (212Pb-AE1) in the prevention of development of human ovarian SK-OV-3 tumors that express Her-2/neu receptors. Thus the 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.
