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

• 批准号: 9034393
• 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
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-23 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9034393
• 关键词: 90Y; Acute; Acute Myelocytic Leukemia; Address; Advisory Committees; Allogenic; Antibodies; Antineoplastic Agents; Apoptosis; Astatine; B-Lymphocytes; Basic Science; Biodistribution; Blood; Bone Marrow; Bone Marrow Transplantation; Cell Cycle Arrest; Cell Transplants; Chimerism; Clinical; Clinical Sciences; DNA Damage; DNA Double Strand Break; DNA Repair; Dendritic Cells; Deposition; Development Plans; Disease; Dose; Drug Kinetics; Engraftment; Fred Hutchinson Cancer Research Center; Future; HLA Antigens; Haplotypes; Health; Hematologic Neoplasms; 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; Outcome; PTPRC gene; Patients; Pharmacodynamics; Pharmacy facility; Physicians; Prior Chemotherapy; Procedures; Radiation; Radioimmunotherapy; Radioisotopes; Radiolabeled; Regimen; Regulation; Relapse; Research; Research Personnel; Resources; Scientist; Site; Spleen; Stem cells; Survival Rate; Techniques; Therapeutic Intervention; Tissues; Toxic effect; Training; Translations; Transplant Recipients; Transplantation; Universities; Washington; Western Blotting; Whole-Body Irradiation; base; cancer care; career; career development; chemotherapy; conditioning; digital; disorder control; ethnic minority population; hematopoietic cell transplantation; high risk; improved; interest; leukemia; leukemia treatment; leukemia/lymphoma; mouse model; novel; particle; pre-clinical; preclinical study; professor; radiation absorbed dose; radiotracer; sound

 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）具有治愈前景，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，这在少数民族群体中是一个特别严重的问题。我们的目标是克服这些限制，使用一种新的放射免疫治疗（RIT）策略，单倍体相合HCT，只需要一个匹配的HLA单倍型，使用我们的临床前小鼠同基因AML模型。我们已经证明，使用90 Y和131 I放射性标记的抗CD 45抗体的RIT将辐射靶向白血病部位，以放大对靶组织的辐射，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具有局限性，为此，我们建议通过在靶向抗CD 45 RIT中使用更高能量的放射性核素<$-211（211 At）代替在单倍体相合HCT期间的全身照射来改善当前AML治疗选择。这项建议将：目标1：在小鼠白血病模型中，比较211 At-抗CD 45 RIT与90 Y-抗CD 45 RIT或标准TBI在单倍相合HCT中观察到的植入动力学、毒性和存活率。目标二：使用新型数字放射自显影成像技术评价白血病小鼠脾脏和骨髓中α和β发射体的显微生物分布，并估计促进211 At和90 Y抗CD 45 RIT递送的单倍相合HCT的疾病控制和植入的辐射需求。目标3：在播散性小鼠AML模型中，通过抗CD 45 RIT靶向白血病细胞时，表征α和β发射体211 At和90 Y诱导的细胞损伤的程度和机制。我们预计这些临床前研究将定义一种新的单倍相合HCT预处理方案，该方案使用211 At-抗CD 45 RIT而不使用TBI，其毒性低于当前方法，但有利于来自单倍相合供体的造血移植。这些目标不仅将使用新型数字放射自显影成像技术定义单倍体相合植入所需的靶组织的最小吸收辐射剂量，阐明细胞损伤的机制，而且还将确定其他潜在的治疗干预措施，以改善未来研究中的白血病治疗方案。这个NCI指导研究科学家K 01奖的提案建立在Orozco博士之前优化抗CD 45 RIT放射性核素的结果基础上，并得到了深思熟虑的职业发展计划的支持，增加了翻译和临床培训，并得到了他的职业咨询委员会的指导。该委员会是由全国著名的调查人员，如：博士奥罗斯科的导师，博士奥利弗W。Press，一位内科医生科学家和无可争议的血液恶性肿瘤放射免疫治疗领域的领导者; Jose洛佩斯博士，一位成熟的拉丁裔内科医生科学家，他是Bloodworks Northwest（前身为Puget Sound血液中心）的首席科学官; Janine McCune博士，华盛顿大学药学系教授，她以抗癌药物的药代动力学和药效学研究而闻名;艾德克拉克博士，华盛顿大学免疫学系教授，他以B淋巴细胞和树突细胞调节的研究而闻名。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，使西雅图成为一个理想的位置，从那里开始职业生涯，成为一个成功的独立研究者，在工作台上优化基于抗体的血液恶性肿瘤治疗方案，并有机会改善单倍相合HCT的结果。