The goal of Project 1 is to develop """"""""combined modality radioimmunotherapy"""""""" (CMRIT) as an integral part of a multimodality treatment plan, with curative intent for patients with non-Hodgkin's lymphoma (NHL). Lym-1 preferentially targets an HLA-DRIO epitope present on most malignant B-cells, providing a remarkable opportunity to enhance the therapeutic index by specifically targeting a radionuclide to NHL. The majority of 72 NHL patients treated with one of 3 new drugs developed at UC Davis: 131l-Lym-1, 67Cu-2lT-BAT-Lym-1, and 90Y- 2IT-BAD-Lym-1, responded. A time dependent proportional hazards model conclusively showed that response to 1311-Lym-1 therapy was associated with improved survival in a multivariate analysis that adjusted for risk factors. Several patients are alive more than 5 years after RIT. CMRIT with the advanced radiopharamceuticals 90Y-DOTA-peptide- Lym-1 and Taxol will be evaluated as a therapeutic strategy for NHL. In a Raji-tumored nude mouse model, CMRIT with 90Y-DOTA-peptide-Lym-1 and Taxol, in doses clinically achievable in humans, provided therapeutic synergy without increased toxicity, when administered at the optimal time and sequence. Other advances designed for the new Phase clinical protocols in Project 1 are: patient-specific dosing, peripheral blood stem cell support to ameliorate myelotoxicity and allow higher doses of 90Y, a biodegradable Unker, """"""""DOTA-peptide"""""""" to decrease normal organ doses and increase the therapeutic index, and low doses of Cyclosporin A to prevent development of human anti-mouse antibody. Preclinical studies will examine the potential for therapeutic synergy of RIT and agents that promote apoptosis and/or inhibit DNA repair, specifically, anti-CD22 monoclonal antibodies and nucleoside analogues. Preclinical and Phase l clinical studies proposed in Project 1 will continue the progress achieved over the past several years. Cohesive interaction of our interdisciplinary group will allow successful completion of these plans. The Phase l CMRIT trials designed for this Proposal will facilitate subsequent Phase 11 and 111 trials at other institutions. New strategies developed in preclinical studies will continue to allow translation of novel advances from the laboratory to the clinic, for the ultimate benefits of patients with NHL.
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