Radioimmunotherapy of Acute Leukemia

描述（由申请人提供）：该奖项的主要目的是使候选人获得成为急性白血病骨髓移植领域独立临床研究者所需的技能。 该研究奖旨在评估放射性标记的单克隆抗体治疗作为改善急性髓细胞（AML）和淋巴细胞（ALL）白血病患者造血干细胞移植（HSCT）结果的一种手段。 131 I-抗-CD 45抗体与常规HSCT方案组合的研究表明，该抗体可以向造血组织提供显著的靶向辐射，同时相对保留正常器官。 一项对首次缓解的AML患者进行的研究的初步结果令人鼓舞，该患者接受了抗体、白消安和环磷酰胺，随后接受了相关的HSCT。 相比之下，许多接受放射性标记抗体、环磷酰胺和全身照射后接受相关或不相关HSCT的晚期AML或ALL患者复发。 这些初步结果表明，需要通过扩展的II期研究和后续的III期研究，进一步确定使用131 I-抗CD 45抗体的方案对首次缓解的AML患者的无病生存期的影响，如目的1所述。 晚期急性白血病患者的高复发率和移植相关死亡率表明，需要找到方法来改善造血组织的靶向，而不增加过量的毒性，如目标2中所提出的。 初步的临床前研究表明，比131 I能量更高、半衰期更短的替代放射性同位素，如钇-90（90 Y），可能会改善靶向造血组织的相对辐射。 该同位素的潜在获益可通过研究90 Y-抗CD 45抗体在非人灵长类动物中的相对器官定位和保留来确定，这是一种非常可预测放射性标记抗CD 45抗体在人体中生物分布的动物模型。 如果这些临床前研究表明90 Y具有潜在的治疗优势，则它们将提供在I期临床研究中启动该方法评估所需的背景，为了补充拟议的指导研究活动，候选人还将参加临床研究和核医学的结构化教学计划。

DESCRIPTION (provided by applicant): The main objective of this award is to enable the candidate to acquire the skills necessary to become an independent clinical investigator in the field of marrow transplantation for acute leukemia. This research award is intended to evaluate radiolabeled monoclonal antibody therapy as a means to improve the outcome of hematopoietic stem cell transplant (HSCT) for patients with acute myeloid (AML) and lymphoid (ALL) leukemia. Studies of 131I-anti-CD45 antibody combined with conventional HSCT regimens have shown that this antibody can deliver significant targeted radiation to hematopoietic tissues while relatively sparing normal organs. Preliminary results of a study of patients with AML in first remission receiving antibody, busulfan and cyclophosphamide followed by related HSCT are encouraging. In contrast, many patients with advanced AML or ALL receiving radiolabeled antibody, cyclophosphamide and total body irradiation followed by related or unrelated HSCT have relapsed. These preliminary results indicate the need to further define the impact on disease free-survival of a regimen using 131I-anti-CD45 antibody in patients with AML in first remission with an extended Phase II study and a subsequent Phase III study, as proposed in Aim 1. The high relapse rates and transplant-related mortality in patients with advanced acute leukemia suggest the need to find methods to improve targeting of hematopoietic tissues without adding excess toxicity, as proposed in Aim 2. Preliminary pre-clinical studies have suggested that alternative radioisotopes of higher energy and shorter half-life than 131I such as yttrium-90 (90Y) may improve the relative radiation delivered to target hematopoietic tissues. The potential benefit of this isotope can be determined by studying the relative organ localization and retention of 90Y-anti-CD45 antibody in non-human primates, an animal model that has been very predictive of the biodistribution of radiolabeled anti-CD45 antibody in humans. If these pre-clinical studies suggest a potential therapeutic advantage for 90Y, they will provide the background necessary to initiate the evaluation of this approach in a Phase I clinical study, To complement the proposed mentored research activities, the candidate will also participate in a structured didactic program in clinical research and nuclear medicine.