Radiolabeled Antibody Therapy of Acute Leukemia

异基因造血细胞移植（HCT）治疗恶性血液病患者经常因疾病复发而失败。由于大多数调理剂的非特异性性质，加强制备方案的尝试受到相关毒性的限制。项目3的总体目标是通过向白血病累及部位提供靶向治疗来克服这一限制，以降低HCT后复发的风险，而不增加毒性。使用临床前模型，我们已经表明，131 I-抗-CD 45抗体（Ab）可以将靶向辐射传递到造血组织，与肝脏、肺或肾脏相比，传递到骨髓的辐射多2至3倍，传递到脾脏的辐射多12倍，传递到淋巴结的辐射多2至8倍。这一临床前观察结果已转化为人类研究，证明了联合靶向治疗的可行性。 年轻患者采用消融性预备方案进行放疗，老年患者采用非消融性方案进行放疗。此外，我们已经证明了令人鼓舞的结果，在年轻的AML患者首次缓解接受匹配的相关HCT使用I31 I-抗-CD 45抗体结合白消安（BU）和环磷酰胺（CY）预处理。最后，我们已经开发了一种预靶向方法，在动物模型中，使用CD 45作为靶点， 一个目标为了进一步发展靶向放射治疗人类白血病的前景，我们现在建议将这些初步观察扩展到三个具体目标。在目标1中，我们将单中心II期研究扩展为多中心II期研究，以检查131 I-抗CD 45 Ab联合BU和CY治疗首次缓解的年轻AML患者的可行性并进一步确定其疗效。在目标2中，我们将确定以下MTD： 131 I-抗CD 45 Ab联合非清髓性HCT预处理方案治疗老年AML患者，并将该应用扩展至II期研究，以评估该方法的疗效。在目标3中，使用项目1作为平台，我们将确定用于预靶向RTF方法的药物的最佳剂量，该方法可在I期试验中与非清髓性方案联合治疗复发性或难治性AML、ALL或高危MDS患者。 我们预计，在以后的几年里，这些研究将使我们能够进行重要的III期研究，其中采用131 I-抗-CD 45 Ab的同种异体HCT方法与标准HCT方法进行比较。通过与本申请的其他项目合作，这些干预措施有望最终改善患有以下疾病的患者的预后： 急性白血病和MDS，提高反应率和生存率，同时尽量减少毒性。

Allogeneic hematopoietic cell transplantation (HCT) for treatment of patients with hematological malignancies frequently fails because of disease recurrence. Attempts at intensifying the preparative regimen have been limited by associated toxicities due to the non-specific nature of most conditioning agents. The overall goal of Project 3 is to overcome this limitation by delivering targeted therapy to sites of leukemic involvement to decrease the risk of relapse after HCT without increased toxicity. Using preclinical models we have shown that 131I-anti-CD45 antibody (Ab) can deliver targeted radiation to hematopoietic tissues, with two to three times more radiation delivered to marrow, up to 12 times more to spleen, and two to eight times more to lymph nodes as compared to liver, lung or kidney. This preclinical observation has been translated to human studies that have demonstrated the feasibility of combining targeted radiotherapy with ablative preparative regimens in younger patients and with non-ablative regimens in older patients. Additionally, we have demonstrated encouraging outcomes in younger patients with AML in first remission receiving matched related HCT using I31I-anti-CD45 Ab combined with busulfan (BU) and cytoxan (CY) conditioning. Finally we have developed an approach of pretargeting that, in animal models, promises even greater specificity using CD45 as a target. To further develop the promise of targeted radiotherapy for the treatment of human leukemia, we now propose to extend these preliminary observations with three specific aims. In Aim 1 we will extend our single-center Phase II study to a multi-center Phase II study to examine the feasibility and further define the efficacy of using 131I-anti-CD45 Ab combined with BU and CY in younger patients with first remission AML. In Aim 2 we will establish the MTD of 131I-anti-CD45 Ab combined with a non-myeloablative HCT conditioning regimen for older AML patients and extend this application to Phase II studies in order to estimate the efficacy of this approach. In Aim 3 using Project 1 as a platform, we will determine the optimal doses of the agents for a pretargeted RTF approach that can be combined with a non-myeloablative regimen in a Phase I trial to treat patients with relapsed or refractory AML, ALL, or high risk MDS. We anticipate that in later years these studies will allow us to carry out important Phase III studies in which allogeneic HCT approaches employing l31I-anti-CD45 Ab are compared to standard HCT methods. In collaboration with the other Projects of this application, these interventions hold high promise to ultimately enhance the prognosis for patients with acute leukemias and MDS by increasing the response and survival rates, while simultaneously minimizing toxicities.