Bone Marrow Transplantation for Hematologic Malignancies using Novel Radioimmunot

描述（由申请人提供）：急性髓性白血病（AML）和骨髓增生异常综合征（MDS）目前杀死大多数患病患者，尽管用联合化疗和造血细胞移植（HCT）治疗。HCT用于急性白血病潜在治疗的选择必须进一步扩展到没有现成HLA匹配供体的患者，例如少数民族患者。放射性标记的抗CD 45单克隆抗体（Ab）已被证明可以改善HCT背景下AML和MDS的结局，但毒性仍然很高，治愈率也不理想。本研究计划的目的是开发一种策略，以提高AML和MDS的治愈率，使用预先靶向CD 45细胞抗原的放射免疫治疗（RIT）。在目标1中，我们将通过比较90 Y和177 Lu标记的生物素在比较生物分布、剂量测定和治疗实验中的相对优点来优化预靶向RIT方法的治疗功效和毒性，以确定177 Lu的较短路径长度B发射是否比90 Y可实现的肿瘤与正常器官比率更有利。在目标2中，我们将评估采用MHC-半相合干细胞的HCT的相对优点，所述造血干细胞利用清髓性预靶向RIT与抗CD 45 Ab（30 F11）-链霉亲和素（SA）缀合物，随后是90 Y-或177 Lu-标记的DOTA-生物素（根据目标1确定，将使用最佳放射性核素），与在临床相关的播散性AML小鼠白血病模型中使用直接放射性标记的抗CD 45 Ab（30 F11）的常规RIT相比，在该模型中白血病细胞和正常造血细胞均表达CD 45。我们预计，从这个目标的结果将证明，预先靶向RIT是上级常规RIT，并将使我们能够提高单倍体相合BMT的治疗效果，具有可耐受的毒性。在目标3中，我们将表征并最大化通过90 Y-或177 Lu-标记的生物素递送至淋巴造血组织的辐射的骨髓抑制和免疫抑制作用。（如从目的1确定的）与优化的补充剂量的全身照射（TBI）和氟达拉滨（FLU）组合，在采用环磷酰胺（CY）移植后移植物-vs-宿主疾病预防。减少TBI和FLU剂量，同时给予高剂量的预靶向90 Y-或177 Lu-生物素作为骨髓HCT准备方案的一部分，将取决于证明这种方法能够：1）消融骨髓空间，和2）产生足够的免疫抑制。因此，在目的3中，我们还将在鼠白血病模型中使用抗mCD 45 Ab-SA缀合物（30 F11 Ab-SA）和放射性生物素，随后降低剂量的TBI和/或FLU和输注MHC-半倍相合BM和移植后CY，评价造血和免疫细胞重建的动力学和持久性。我们假设，与常规RIT联合标准预处理试剂相比，本提案中定义的预靶向RIT策略将放大递送至白血病细胞的辐射量，减少递送至肝、肺和其他正常器官的辐射，提高缓解率和治愈率，延长生存期，并显著减轻毒性。因此，我们预期将优化的有希望的预靶向RIT快速转化为我们用于AML和MDS的临床RIT HCT计划。 公共卫生相关性：急性髓性白血病（AML）和骨髓增生异常综合征（MDS）目前杀死大多数患者的疾病，尽管治疗与化疗和造血细胞移植（HCT）。在这个项目中，我们计划通过使用一种新的预处理方案和一种称为预靶向放射免疫治疗的新方法，针对白血病细胞进行靶向放射治疗，以提高接受HCT但没有现成的HLA匹配供体的患者（如少数民族患者）的AML和MDS的治愈率。我们预计，这些方法将治愈更多的患者，并导致比目前可用的疗法更少的毒性。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) currently kill the majority of patients with the disease despite treatment with chemotherapy and hematopoietic cell transplantation (HCT). In this project, we plan to improve the cure rate of AML and MDS for patients undergoing HCT without a readily available HLA-matched donor, such as patients in ethnic minority groups, by targeting radiation therapy to the leukemia cells using a novel conditioning regimen and a new method called pretargeted radioimmunotherapy. We anticipate that these approaches will cure more patients and cause fewer toxicities than currently available therapies.