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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Intramural Research (Z01)
Project #
1Z01CB004002-26
Application #
5200913
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
26
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Division of Cancer Biology and Diagnosis
Department
Type
DUNS #
City
State
Country
United States
Zip Code