The main objective of this award is to enable the candidate to acquire the skills necessary to become an independent clinical investigator in the field of marrow transplantation for acute leukemia. This research award is intended to evaluate radiolabeled monoclonal antibody therapy as a means to improve the outcome of hematopoietic stem cell transplant (HSCT) for patients with acute myeloid (AML) and lymphoid (ALL) leukemia. Studies of 131I-anti-CD45 antibody combined with conventional HSCT regimens have shown that this antibody can deliver significant targeted radiation to hematopoietic tissues while relatively sparing normal organs. Preliminary results of a study of patients with AML in first remission receiving antibody, busulfan and cyclophosphamide followed by related HSCT are encouraging. In contrast, many patients with advanced AML or ALL receiving radiolabeled antibody, cyclophosphamide and total body irradiation followed by related or unrelated HSCT have relapsed. These preliminary results indicate the need to further define the impact on disease free-survival of a regimen using 131I-anti-CD45 antibody in patients with AML in first remission with an extended Phase II study and a subsequent Phase III study, as proposed in Aim 1. The high relapse rates and transplant-related mortality in patients with advanced acute leukemia suggest the need to find methods to improve targeting of hematopoietic tissues without adding excess toxicity, as proposed in Aim 2. Preliminary pre-clinical studies have suggested that alternative radioisotopes of higher energy and shorter half-life than 131I such as yttrium-90 (90Y) may improve the relative radiation delivered to target hematopoietic tissues. The potential benefit of this isotope can be determined by studying the relative organ localization and retention of 90Y-anti-CD45 antibody in non-human primates, an animal model that has been very predictive of the biodistribution of radiolabeled anti-CD45 antibody in humans. If these pre-clinical studies suggest a potential therapeutic advantage for 90Y, they will provide the background necessary to initiate the evaluation of this approach in a Phase I clinical study, To complement the proposed mentored research activities, the candidate will also participate in a structured didactic program in clinical research and nuclear medicine. ? ? ?

National Institute of Health (NIH)
National Cancer Institute (NCI)
Mentored Patient-Oriented Research Career Development Award (K23)
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Subcommittee G - Education (NCI)
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Ojeifo, John O
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Oregon Health and Science University
Schools of Medicine
United States
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Nemecek, Eneida R; Guthrie, Katherine A; Sorror, Mohamed L et al. (2011) Conditioning with treosulfan and fludarabine followed by allogeneic hematopoietic cell transplantation for high-risk hematologic malignancies. Biol Blood Marrow Transplant 17:341-50
Green, Damian J; Pagel, John M; Nemecek, Eneida R et al. (2009) Pretargeting CD45 enhances the selective delivery of radiation to hematolymphoid tissues in nonhuman primates. Blood 114:1226-35
Nemecek, Eneida R; Green, Damian J; Fisher, Darrell R et al. (2008) Extracorporeal adsorption therapy: a method to improve targeted radiation delivered by radiometal-labeled monoclonal antibodies. Cancer Biother Radiopharm 23:181-91
Nemecek, Eneida R; Hamlin, Donald K; Fisher, Darrell R et al. (2005) Biodistribution of yttrium-90-labeled anti-CD45 antibody in a nonhuman primate model. Clin Cancer Res 11:787-94
Nemecek, E R; Gooley, T A; Woolfrey, A E et al. (2004) Outcome of allogeneic bone marrow transplantation for children with advanced acute myeloid leukemia. Bone Marrow Transplant 34:799-806