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必要的技能，成为急性白血病骨髓移植领域的独立临床研究者。该研究奖项旨在评估放射标记单克隆抗体治疗作为改善急性髓系（AML）和淋巴系（ALL）白血病患者造血干细胞移植（HSCT）结果的手段。131I-anti-CD45抗体联合常规造血干细胞移植方案的研究表明，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。一项首次缓解的AML患者接受抗体、丁硫凡和环磷酰胺治疗后进行相关造血干细胞移植的初步研究结果令人鼓舞。相比之下，许多晚期AML或ALL患者接受放射性标记抗体、环磷酰胺和全身照射后进行相关或不相关的HSCT后复发。这些初步结果表明，需要进一步确定在首次缓解的AML患者中使用131I-anti-CD45抗体的方案对无病生存的影响，如Aim 1中提出的延长II期研究和随后的III期研究。晚期急性白血病患者的高复发率和移植相关死亡率表明，需要找到方法来提高造血组织的靶向性，而不增加过量的毒性，正如Aim 2所提出的那样。初步临床前研究表明，比131I能量更高、半衰期更短的替代放射性同位素，如钇-90 (90Y)，可能会改善靶向造血组织的相对辐射。这种同位素的潜在益处可以通过研究90y -抗cd45抗体在非人灵长类动物中的相对器官定位和保留来确定，这种动物模型非常能预测放射性标记的抗cd45抗体在人类中的生物分布。如果这些临床前研究表明90Y具有潜在的治疗优势，它们将为在I期临床研究中启动该方法的评估提供必要的背景。为了补充建议的指导研究活动，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.