The overall goal of this program project grant is to develop effective strategies for treating patients with hematologic malignancies using radiolabeled monoclonal antibodies (Ab) in conjunction with stem cell transplantation (SCT). Our prior studies have established the feasibility and anti-tumor activity of this approach. We now propose to improve, refine and extend this approach for both B cell lymphomas and acute leukemias by optimizing therapy directed at the CD20 and CD45 antigens, respectively. In Dr. Press' Project, we will investigate the potential of pretargeted radioimmunotherapy (RIT) with tetravalent anti-CD20 and anti- CD45 (scFv)4-streptavidin (SA) fusion proteins and radiobiotin and of extracorporeal antibody adsorption therapy to improve the delivery of radiation to target tissues compared to non-target sites in macaque models. We will also produce, purify and characterize sufficient quantities of the anti-CD20 1F5(scFv)4SA and anti-CD45 BC8(scFv)4SA fusion proteins under """"""""good manufacturing practice"""""""" conditions to conduct human Phase I clinical trials. In Dr. Gopal's Project, we will extend and optimize myeloablative RIT for B cell lymphomas by 1) conducting a Phase II trial of (131)I-anti-CD20 antibody with etoposide, cyclophosphamide and autologous SCT, 2) by exploring the ability of a synergistic chemotherapeutic agent (fludarabine) to enhance the efficacy of (131)I-anti-CD20 Ab for older patients, 3) by conducting a Phase I trial of pretargeted anti-CD20 RIT in NHL and 4) by continuing long-term follow-up of 158 patients treated with myeloablative (131)I-anti-CD20 + ASCT. In Project 3, we will extend and optimize RIT for acute leukemia by 1) conducting a multi-center Phase II trial of (131)I-anti-CD45 Ab combined with busulfan and cyclophosphamide in patients <60 yr old with first remission AML, 2) by establishing the maximally tolerated dose of (131)I-anti-CD45 Ab which can be safely combined with a non-myeloablative SCT conditioning regimen for AML patients >60 yr old and 3) by conducting a Phase I trial of pretargeted anti-CD45 RIT in relapsed AML, ALL, or high risk MDS. We anticipate that these investigations will allow us to maximize the therapeutic efficacy and minimize the toxicity of myeloablative RIT for hematologic malignancies.
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