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Targeted Alpha Radioimmunotherapy with Haploidentical Bone Marrow Transplantation for AML

靶向α放射免疫疗法与单倍相合骨髓移植治疗AML

基本信息

批准号：
9752482
负责人：
Johnnie Jose Orozco
金额：
$ 16.9万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-23 至 2021-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9752482
关键词：
90Y Acute Acute Myelocytic Leukemia Address Advisory Committees Allogenic Antibodies Antibody Therapy Antineoplastic Agents Apoptosis Astatine B-Lymphocytes Basic Science Biodistribution Blood Bone Marrow Bone Marrow Transplantation Cell Cycle Arrest Chimerism Clinical Clinical Sciences DNA Damage DNA Double Strand Break DNA Repair Dendritic Cells Deposition Development Plans Disease Dose Engraftment Fred Hutchinson Cancer Research Center Future HLA Antigens Haplotypes Hematologic Neoplasms Hematology Hematopoietic Hematopoietic Neoplasms I131 isotope Imaging Techniques Imaging technology Immunofluorescence Immunologic Immunology Immunosuppression Intervention Kinetics Latino Length Leukemic Cell Location Marrow Mediator of activation protein Mentored Research Scientist Development Award Mentors Microscopic Minority Groups Modality Modeling Monoclonal Antibodies Mus Organ PTPRC gene Patient-Focused Outcomes Patients Pharmacy facility Physicians Preparation Prior Chemotherapy Procedures Radiation Radiation Dose Unit Radioimmunotherapy Radioisotopes Radiolabeled Regimen Regulation Relapse Research Research Personnel Resources Scientist Site Spleen Stem cells Techniques Therapeutic Intervention Tissues Toxic effect Training Translations Transplant Recipients Transplantation Transplantation Conditioning Universities Vocational Guidance Washington Western Blotting Whole-Body Irradiation cancer care career career development chemotherapy conditioning digital disorder control ethnic minority population hematopoietic cell transplantation hematopoietic engraftment high risk improved improved outcome interest leukemia leukemia treatment leukemia/lymphoma mouse model novel particle pharmacokinetics and pharmacodynamics post-transplant pre-clinical preclinical study professor public health relevance radiation absorbed dose relapse patients sound

项目摘要

DESCRIPTION (provided by applicant): Despite the curative promise of hematopoietic cell transplant (HCT), many AML patients will relapse while others may not have a fully matched donor, an especially acute problem in ethnic minority groups. We aim to overcome these limitations using a novel radioimmunotherapy (RIT) strategy for haploidentical HCT, requiring only one matched HLA haplotype using our preclinical murine syngeneic AML model. We have shown that RIT using 90Y- and 131I-radiolabeled anti-CD45 antibody targets radiation to sites of leukemia to amplify the radiation to targeted tissues while minimizing non-specific toxicities. However, radionuclides used thus far have limitations, for which we propose to improve current AML treatment options by using the higher energy radionuclide astatine-211 (211At) in targeted anti-CD45 RIT in lieu of total body irradiation during haploidentical HCT. This proposal will: Aim 1: To compare the engraftment kinetics, toxicities, and survival observed with 211At-anti-CD45 RIT for haploidentical HCT with that observed using either 90Y-anti-CD45 RIT or standard TBI in a murine leukemia model. Aim 2: To evaluate the microscopic biodistribution of alpha- and beta-emitters in spleen and bone marrow of leukemic mice using novel digital autoradiographic imaging technologies, and estimate the radiation requirements that facilitate disease control and engraftment from haploidentical HCT delivered by 211At- and 90Y-anti-CD45 RIT. Aim 3: To characterize the magnitude and mechanism of cellular damage induced by the alpha- and beta-emitters, 211At and 90Y, when targeted to leukemic cells by anti-CD45 RIT in a disseminated murine AML model. We anticipate these preclinical studies to define a novel haploidentical HCT conditioning regimen using 211At- anti-CD45 RIT without TBI that will be less toxic than current approaches, yet facilitate hematopoietic engraftment from haploidentical donors. These aims will not only define the minimum absorbed radiation dose of target tissues required for haploidentical engraftment using novel digital autoradiographic imaging techniques, elucidate the mechanism of cellular damage, but also identify other potential therapeutic interventions to improve leukemia treatment options in future research. This NCI Mentored Research Scientist K01 Award proposal builds on prior results by Dr. Orozco in optimizing radionuclides for anti-CD45 RIT, and is bolstered with a well thought out career development plan, with added translation and clinical training, with the guidance from his career advisory committee. The Committee is comprised of nationally prominent investigators such as: Dr. Orozco's mentor, Dr. Oliver W. Press, a physician scientist and undisputed leader in the field of radioimmunotherapy for hematologic malignancies; Dr. Jose Lopez, an established Latino physician scientist who is Chief Scientific Officer at the Bloodworks Northwest, formerly Puget Sound Blood Center; Dr. Janine McCune, Professor in the Department of Pharmacy at the UW, who is known for her research on pharmacokinetics and pharmacodynamics of anticancer agents; and Dr. Ed Clark, Professor in the Department of Immunology at the UW, who is known for his research on B lymphocyte and dendritic cell regulation. The Fred Hutchinson Cancer Research Center, the University of Washington, and the Seattle Cancer Care Alliance have a wealth of resources, clinical and basic science investigators, making Seattle an ideal location from which to embark on a career to become a successful independent investigator at the bench optimizing antibody based therapy options for hematologic malignancies, and opportunities to improve outcomes in haploidentical HCT.