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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的项目概要：急性髓系白血病（AML）和骨髓增生异常综合征（MDS）目前杀死尽管接受联合化疗和造血细胞治疗，大多数患病患者移植（HCT）。 HCT 作为急性白血病潜在治疗的选择必须进一步扩展到没有现成的 HLA 匹配供体的患者，例如少数民族患者。放射性标记的抗 CD45 单克隆抗体 (Ab) 已被证明可以改善 AML 和 MDS 的结果在 HCT 的情况下，但毒性仍然很高，治愈率也不是最理想的。本研究的目的建议制定一项策略，利用放射免疫疗法（RIT）提高 AML 和 MDS 的治愈率预靶向 CD45 细胞抗原。在目标 1 中，我们将优化治疗效果和毒性通过比较 90Y 和 177Lu 标记生物素的相对优点，开发了预靶向 RIT 方法生物分布、剂量测定和治疗实验，以确定 177Lu 的较短路径长度 b 排放是否有效与 90Y 相比，可提供更有利的肿瘤与正常器官比率。在目标 2 中，我们将评估使用 MHC-半相合干细胞的 HCT 的相对优点，利用清髓性预靶向 RIT 和抗 CD45 Ab (30F11)-链霉亲和素 (SA) 缀合物，然后是 90Y 或 177Lu 标记的 DOTA-生物素（如与使用直接放射性核素的传统 RIT 相比，从目标 1 确定将使用最好的放射性核素）临床相关的播散性 AML 小鼠白血病模型中放射性标记的抗 CD45 Ab (30F11) 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定位 RIT 优于传统 RIT，并使我们能够改进单倍体BMT治疗效果好，毒性可耐受。在目标 3 中，我们将描述并最大化放射治疗淋巴造血组织的骨髓抑制和免疫抑制作用通过 90Y 或 177Lu 标记的生物素（根据目标 1 确定）结合优化的补充临床前小鼠单倍相合 HCT 模型中全身照射 (TBI) 和氟达拉滨 (FLU) 的剂量采用环磷酰胺（CY）预防移植后移植物抗宿主病。减少 TBI 和 FLU 剂量，同时作为准备方案的一部分施用高剂量的预靶向 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）骨髓空间，2) 产生足够的免疫抑制。因此，在目标 3 中，我们还将评估动力学使用抗 mCD45 Ab-SA 缀合物 (30F11 Ab-SA）和放射性生物素，然后减少 TBI 和/或 FLU 剂量并输注 MHC-半相合 BM 以及小鼠白血病模型中的移植后 CY。我们假设预定 RIT 策略该提案中定义的将放大传递到白血病细胞的辐射量，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，延长生存期，与传统 RIT 结合标准调节试剂相比，毒性显着减弱。因此，我们预计将优化后的有前景的预靶向 RIT 快速转化为我们的临床 RIT HCT AML 和 MDS 计划。