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: 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
• 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

 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）具有治愈希望，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，这在少数族裔群体中尤其严重。我们的目标是使用一种新的半相合 HCT 放射免疫治疗 (RIT) 策略来克服这些限制，使用我们的临床前小鼠同基因 AML 模型只需要一个匹配的 HLA 单倍型。我们已经证明，RIT 使用 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，我们建议通过在靶向抗 CD45 RIT 中使用更高能量的放射性核素砹-211 (211At) 来代替半相合 HCT 期间的全身照射，以改善当前的 AML 治疗方案。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：使用新型数字放射自显影成像技术评估白血病小鼠脾脏和骨髓中 α 和 β 发射体的微观生物分布，并估计促进 211At 和 90Y 抗 CD45 RIT 提供的单倍体 HCT 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，表征当抗 CD45 RIT 靶向白血病细胞时，α 和 β 发射体 211At 和 90Y 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使用 211At-抗 CD45 RIT 且无需 TBI 的新型单倍体 HCT 预处理方案，该方案的毒性低于目前的方法，但有利于单倍体供体的造血植入。这些目标不仅将确定使用新型数字放射自显影成像技术进行半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，以在未来的研究中改善白血病的治疗选择。这项 NCI 指导研究科学家 K01 奖提案建立在 Orozco 博士之前在优化抗 CD45 RIT 放射性核素方面的成果的基础上，并得到了深思熟虑的职业发展计划的支持，并在他的职业咨询委员会的指导下增加了翻译和临床培训。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，他是一名医师科学家，也是血液恶性肿瘤放射免疫治疗领域无可争议的领导者；何塞·洛佩兹 (Jose Lopez) 博士是一位著名的拉丁裔医师科学家，现任西北 Bloodworks（前身为普吉特海湾血液中心）的首席科学官； Janine McCune 博士，华盛顿大学药学系教授，以抗癌药物药代动力学和药效学研究而闻名；华盛顿大学免疫学系教授 Ed Clark 博士，以 B 淋巴细胞和树突状细胞调节研究而闻名。 Fred Hutchinson 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的理想地点，成为一名成功的独立研究者，优化血液恶性肿瘤的基于抗体的治疗方案，并有机会改善单倍体 HCT 的结果。