Bone Marrow Transplantation for Hematologic Malignancies using Novel Radioimmunot

使用新型放射免疫进行骨髓移植治疗血液系统恶性肿瘤

• 批准号: 8209292
• 负责人: JOHN M PAGEL
• 金额: $ 35.42万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-09 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8209292
• 关键词: 90Y; Ablation; Acute; Acute Myelocytic Leukemia; Acute leukemia; Allogenic; Antibodies; Antigens; Attenuated; Beryllium; Biodistribution; Biotin; Bone Marrow; Bone Marrow Transplantation; Cells; Characteristics; Clinical; Clonal Deletion; Combination Drug Therapy; Cyclophosphamide; DOTA-biotin; Disease; Disease model; Disease remission; Dose; Dysmyelopoietic Syndromes; Engraftment; Exhibits; Goals; Granulocyte Colony-Stimulating Factor; Guidelines; HLA Antigens; Haplotypes; Hematologic Neoplasms; Hematopoietic; Human; Immune; Immunosuppression; Immunosuppressive Agents; Infusion procedures; International; Isotopes; Kinetics; Label; Length; Leukemic Cell; Liver; Lung; Major Histocompatibility Complex; Malignant Neoplasms; Marrow; Methods; Minority Groups; Modeling; Modification; Monoclonal Antibodies; Mus; Organ; Outcome; PTPRC gene; Palpable; Patients; Procedures; Prophylactic treatment; Radiation; Radiation therapy; Radio; Radioactivity; Radioimmunotherapy; Radioisotopes; Radiolabeled; Reagent; Regimen; Relative (related person); Research Proposals; Residual Neoplasm; SCID Mice; Site; Spleen; Stem cells; Streptavidin; T-Lymphocyte; Technology; Testing; Therapeutic; Time; Tissues; Toxic effect; Translations; Transplantation; Treatment Efficacy; United States National Institutes of Health; Whole-Body Irradiation; Xenograft procedure; abstracting; biotin 2; chemotherapy; clinically relevant; comparative; conditioning; disorder control; dosimetry; ethnic minority population; fludarabine; graft vs host disease; hematopoietic cell transplantation; high risk; improved; in vivo; keratinocyte growth factor; killings; leukemia; novel; pre-clinical; programs; public health relevance; radiotracer; reconstitution; research study; response; transplant registry; tumor

ABSTRACT Project summary: Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) currently kill the majority of afflicted patients despite treatment with combination chemotherapy and hematopoietic cell transplantation (HCT). The option of HCT for potential therapy of acute leukemias must be further extended to patients who do not have a readily available HLA-matched donor, such as patients in ethnic minority groups. Radiolabeled anti-CD45 monoclonal antibodies (Ab) have been shown to improve outcomes for AML and MDS in the setting of HCT, but toxicity remains high and cure rates are suboptimal. The objective of this research proposal is to develop a strategy to improve the cure rate of AML and MDS using radioimmunotherapy (RIT) pretargeted to the CD45 cell antigen. In Aim 1 we will optimize the therapeutic efficacy and toxicities of the pretargeted RIT approach by comparing the relative merits of 90Y- and 177Lu-labeled biotin in comparative biodistribution, dosimetry and therapy experiments to determine if the shorter path length b emissions of 177Lu afford more favorable tumor-to-normal organ ratios than those achievable with 90Y. In Aim 2 we will assess the relative merits of HCT employing MHC-haploidentical stem cells utilizing myeloablative pretargeted RIT with an anti-CD45 Ab (30F11)-streptavidin (SA) conjugate followed by either 90Y- or 177Lu-labeled DOTA-biotin (as determined from aim 1 the best radionuclide will be used), compared to conventional RIT using a directly radiolabeled anti-CD45 Ab (30F11) in clinically relevant disseminated AML murine leukemia model in which both leukemic cells and normal hematopoietic cells express CD45. We anticipate that the results from this aim will demonstrate that pretargeted RIT is superior to conventional RIT and will allow us to improve the therapeutic efficacy of haploidentical BMT, with tolerable toxicity. In Aim 3 we will characterize and maximize the myelosuppressive and immunosuppressive effects of radiation delivered to lymphohematopoietic tissues via either 90Y- or 177Lu-labeled biotin (as determined from aim 1) in combination with optimized supplemental doses of total body irradiation (TBI) and Fludarabine (FLU) in a preclinical murine haploidentical HCT model employing cyclophosphamide (CY) post-transplant graft-vs-host disease prophylaxis. Reducing the TBI and FLU doses, while administering high doses of pretargeted 90Y- or 177Lu-biotin as part of a preparative regimen for marrow HCT, would depend upon the demonstration of the ability of such an approach to: 1) ablate the marrow space, and 2) produce adequate immunosuppression. Thus, in aim 3 we will also evaluate the kinetics and durability of hematopoietic and immune cell reconstitution using an anti-mCD45 Ab-SA conjugate (30F11 Ab-SA) and radiobiotin, followed by reduced doses of TBI and/or FLU and infusion of MHC-haploidentical BM and post-transplantation CY in a murine leukemia model. We hypothesize that the pretargeted RIT strategy defined in this proposal will amplify the amount of radiation delivered to leukemia cells, decrease the radiation delivered to the liver, lungs, and other normal organs, improve remission and cure rates, prolong survival, and markedly attenuate toxicities compared to conventional RIT combined with standard conditioning reagents. We therefore anticipate rapid translation of the optimized promising pretargeted RIT into our clinical RIT HCT program for AML and MDS.

抽象的 项目摘要：急性髓性白血病（AML）和骨髓增生综合征（MDS）当前杀死 尽管结合化疗和造血细胞治疗，大多数患者大多数患者 移植（HCT）。 HCT在潜在急性白血病的潜在治疗中的选择必须进一步扩展到 没有随时可用的HLA匹配供体的患者，例如少数民族群体中的患者。 已显示放射标记的抗CD45单克隆抗体（AB）可改善AML和MDS的预后 在HCT的情况下，但是毒性保持较高，治愈率是次优的。这项研究的目的 建议是制定一种使用放射免疫疗法（RIT）提高AML和MD的治疗速率的策略 预先靶向CD45细胞抗原。在AIM 1中，我们将优化的治疗功效和毒性 通过比较比较90y和177lu标记的生物素的相对优点，预先定位的RIT方法 生物分布，剂量法和治疗实验，以确定较短的路径长度B排放量是否177LU 比90年代可实现的肿瘤与正常器官比率更高。在AIM 2中，我们将评估 使用MHC-Haploidentic Stem细胞的HCT的相对优点，利用有髓性的预先掌握RIT 抗CD45 AB（30F11）-streptavidin（SA）结合物，其次是90y-或177lu标记的Dota-Biotin（AS 从AIM 1确定的最佳放射性核素将使用），与传统的RIT相比 临床相关的AML鼠白血病模型中的放射标记的抗CD45 AB（30F11），其中 白血病细胞和正常造血细胞都表达CD45。我们预计这个目标的结果 将证明，有限的RIT优于常规RIT，将使我们能够改善 单倍体BMT的治疗功效，具有可耐受性的毒性。在AIM 3中，我们将表征和最大化 辐射的骨髓抑制和免疫抑制作用递送到淋巴瘤组织 通过90y-或177lu标记的生物素（根据AIM 1确定）与优化的补充合并 临床前鼠单倍型HCT模型中的全身辐照剂量（TBI）和氟达拉滨（流感） 采用环磷酰胺（CY）移植后移植物为宿主疾病预防。减少TBI和 流感剂量，同时服用高剂量的90y-或177lu-biotin作为制备方案的一部分 对于骨髓HCT，将取决于这种方法的能力的证明：1）消融 骨髓空间和2）产生足够的免疫抑制。因此，在AIM 3中，我们还将评估动力学 使用抗MCD45 AB-SA结合物（30F11）的造血和免疫细胞重建的耐用性 AB-SA）和放射性植物素，随后降低了TBI剂量和/或流感和输注MHC-Haploidential BM 在鼠白血病模型中移植后CY。我们假设有预定的RIT策略 在此提案中定义的将扩大传递给白血病细胞的辐射量，减少辐射 递送到肝脏，肺部和其他正常器官，提高缓解和治愈率，延长生存率以及 与常规RIT和标准调节试剂相比，显着减弱毒性。 因此，我们预计将优化有希望的有前途的RIT快速翻译到我们的临床RIT HCT中 AML和MD的程序。