This is a competitive renewal for the Program grant: Synergistic Multimodality Antibody Therapy. Translational research will continue in order to develop combined modality radioimmunotherapy (CMRIT) with curative intent for patients with non-Hodgkin's lymphoma, breast and prostate cancer. Trials of single agent radiolabeled Lym-1 and ml7O provided evidence for therapeutic response in the majority of patients. Lym-1 and ml70 are antibodies of particular interest because of new evidence for preferential reactivity of Lym-1 with malignant lymphocytes and evidence for intense reactivity of ml70 with almost all breast and prostate Cancers. Based on past work, proposed trials use: 1)90Y-DOTA- peptide-Lym-1 in NHL and 90Y-DOTA-peptide-m170 in breast and prostate cancer because therapeutic indices are about ten times that of the corresponding 1311 labeled antibodies; 2) a high dose, fractionated strategy with peripheral blood stem cell support to deliver greater and more uniform tumor radiation; and, 3) paclitaxel (Taxol) as a synergistic radiosensitizer to overcome p53 and BCL2 therapy resistance common in these malignancies. Patient-specific dosimetry will be used to direct dosing with a goal of developing an individualized patient therapy plan to be used in later phase ll/lll multicenter trials. A peptide library will be used in Project 3 to generate new radiopharamceuticals to further improve the therapeutic index. The program already has clinical and/or preclinical evidence that supports the utility of each of the modalities proposed for the novel CMRIT. Projects 1 and 2 will examine the potential synergy of other agents: 1) novel anti CD22 antibodies and fludarabine to reinforce radiation apoptosis; and, 2) integrin-binding peptides to increase tumor uptake and retention of the radiolabeled antibodies by inducing apoptotic neovascular leak and later collapse. A cohesive interdisciplinary team with established state-of-the-art resources, scientific, administrative and fiscal controls, data management, radiochemistry and radiopharmaceutical methods, pharamacokinetic and dosimetric methods, is established. The information from this Program is relevant to the use of other conjugated and unconjugated antibodies, and to combined modality approaches to cancer therapy.
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