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: 8403556
• 负责人: JOHN M PAGEL
• 金额: $ 33.3万
• 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/8403556
• 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.

摘要 项目摘要：急性髓系白血病(AML)和骨髓增生异常综合征(MDS)目前杀死了 大多数患者尽管接受了联合化疗和造血细胞治疗，但仍受到影响 移植(HCT)。HCT用于急性白血病潜在治疗的选择必须进一步扩大到 没有现成的人类白细胞抗原配型供者的患者，如少数民族患者。 放射性标记的抗CD45单抗可改善急性髓系白血病和骨髓增生异常综合征的预后 在HCT环境中，但毒性仍然很高，治愈率也不是最理想的。这项研究的目的是 建议开发一种策略，使用放射免疫疗法(RIT)提高AML和MDS的治愈率 预先靶向CD45细胞抗原。在目标1中，我们将优化治疗效果和毒性 比较~(90)Y和~(177)Lu标记生物素的相对优劣的预靶向RIT方法 生物分布、剂量测定和治疗实验，以确定较短路径长度b发射的177Lu 提供比90Y更有利的肿瘤与正常器官比率。在目标2，我们将评估 使用MHC-半相合干细胞的HCT的相对优点，使用清髓性预靶向RIT联合 抗CD45抗体(30F11)-链霉亲和素(SA)结合后90Y或177Lu标记的DOTA-生物素(AS) 根据目标1确定将使用最好的放射性核素)，与直接使用 放射性标记抗CD45抗体(30F11)在临床相关播散性AML小鼠白血病模型中的应用 白血病细胞和正常造血细胞均表达CD45。我们预计，这一目标的结果 将证明预先确定的RIT优于传统的RIT，并将使我们能够提高 半相合骨髓移植的疗效，毒性可耐受。在目标3中，我们将描述并最大化 淋巴造血组织辐射的骨髓抑制和免疫抑制效应 通过90Y或177Lu标记的生物素(根据Aim 1测定)与优化的补充剂相结合 临床前小鼠半相合红细胞移植模型中全身照射(TBI)和氟达拉滨(Flu)的剂量 移植后应用环磷酰胺(CY)预防移植物抗宿主病。降低总拥有成本和 流感剂量，同时作为准备方案的一部分，使用高剂量的预靶向90Y-或177Lu-生物素 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，2)产生足够的免疫抑制。因此，在目标3中，我们也将评估动力学 使用抗mCD45抗体-SA结合物(30F11)重建造血和免疫细胞的持久性 AB-SA)和放射性生物素，随后减少TBI和/或Flu剂量并输注MHC-半相合BM 以及移植后CY在小鼠白血病模型中的作用。我们假设预先确定目标的RIT策略 这项提案中定义的将放大向白血病细胞传递的辐射量，减少辐射 输送到肝脏、肺和其他正常器官，提高缓解和治愈率，延长生存时间，以及 与传统的RIT结合标准的调理试剂相比，毒性显著减弱。 因此，我们期待着将优化的前景看好的预靶向RIT快速转化为我们的临床RIT HCT 针对AML和MDS的计划。