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.

描述（由申请人提供）：尽管造血细胞移植（HCT）具有治愈作用，但许多 AML 患者会复发，而其他患者可能没有完全匹配的供体，这是少数族裔群体中尤其严重的问题，我们的目标是利用造血细胞移植来克服这些限制。一种用于单倍体相合 HCT 的新型放射免疫治疗 (RIT) 策略，使用我们的临床前小鼠同系 AML 模型仅需要一个匹配的 HLA 单倍型。 90Y 和 131I 放射性标记的抗 CD45 抗体将辐射靶向白血病部位，以放大对目标组织的辐射，同时最大限度地减少非特异性毒性。然而，迄今为止使用的放射性核素存在局限性，为此我们建议通过以下方式改进当前的 AML 治疗方案。在靶向抗 CD45 RIT 中使用高能放射性核素砹 211 (211At) 代替半相合期间的全身照射该提案将：目标 1：比较半相合 HCT 中使用 211At-抗 CD45 RIT 观察到的植入动力学、毒性和存活率与在小鼠白血病模型中使用 90Y-抗 CD45 RIT 或标准 TBI 观察到的植入动力学、毒性和存活率。目标 2：使用 α 和 β 发射体评估白血病小鼠脾脏和骨髓中的微观生物分布新颖的数字放射自显影成像技术，并估计促进 211At-和 90Y-抗 CD45 RIT 提供的半相合 HCT 植入的辐射需求。目标 3：表征 α- 和 α- 和 90Y-抗 CD45 RIT 诱导的细胞损伤的程度和机制。当在播散性小鼠 AML 模型中通过抗 CD45 RIT 靶向白血病细胞时，我们预计会出现 β 发射体 211At 和 90Y。临床前研究旨在定义一种新型单倍体 HCT 预处理方案，使用 211At-抗 CD45 RIT，无需 TBI，该方案的毒性低于当前方法，但有利于单倍体供体的造血移植。这些目标不仅定义了目标组织的最小吸收辐射剂量。使用新型数字放射自显影成像技术进行单倍体移植所需的数据，阐明细胞损伤的机制，同时还确定其他潜在的治疗干预措施，以改善白血病的治疗选择这项 NCI 指导研究科学家 K01 奖提案以 Orozco 博士之前在优化抗 CD45 RIT 放射性核素方面的成果为基础，并得到了深思熟虑的职业发展计划的支持，并增加了翻译和临床培训，以及该委员会由全国知名的研究人员组成，例如：Orozco 博士的导师 Oliver W. Press 博士，他是一位医师科学家，也是该领域无可争议的领导者。血液系统恶性肿瘤的放射免疫疗法；Jose Lopez 博士是一位著名的拉丁裔医师科学家，现任西北血液中心（前身为普吉特湾血液中心）的首席科学官；Janine McCune 博士是威斯康星大学药学系教授，因她对抗癌药物的药代动力学和药效学的研究；以及威斯康星大学免疫学系教授 Ed Clark 博士，他以 B 淋巴细胞和树突状细胞调节研究而闻名。弗雷德·哈钦森癌症研究中心、华盛顿大学和西雅图癌症护理联盟拥有丰富的资源、临床和基础科学研究人员，使西雅图成为开始职业生涯并成为一名成功的独立研究者的理想地点。实验室优化基于抗体的血液恶性肿瘤治疗方案，以及改善半相合 HCT 结局的机会。