Radioimmunotherapy of Acute Leukemia

描述(申请人提供)：该奖项的主要目的是使候选人能够获得必要的技能，成为急性白血病骨髓移植领域的独立临床研究员。该研究奖项旨在评估放射性标记单抗疗法作为改善急性髓系(AML)和淋巴细胞性白血病(ALL)患者造血干细胞移植(HSCT)结果的方法。将131I-抗CD45抗体与传统的HSCT方案相结合的研究表明，这种抗体可以在相对节省正常器官的情况下向造血组织提供显著的靶向辐射。一项对首次缓解的AML患者接受抗体、白花丹和环磷酰胺治疗以及随后进行相关的造血干细胞移植的初步结果令人鼓舞。相比之下，许多晚期AML或ALL患者接受了放射性标记抗体、环磷酰胺和全身照射，随后进行了相关或非相关的HSCT，这些患者已经复发。这些初步结果表明，需要进一步确定首次缓解的AML患者使用131I-抗CD45抗体的方案对无病生存的影响，并进行扩展的II期研究和后续的III期研究，正如Aim 1中建议的那样。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对造血组织的靶向性，而不增加额外的毒性。初步的临床前研究表明，替代的能量更高、半衰期更短的放射性同位素，如Y-90(90Y)，可能会改善对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抗体在非人类灵长类动物中的相对器官定位和保留来确定，这种动物模型已经非常好地预测了放射性标记的抗CD45抗体在人类体内的生物分布。如果这些临床前研究表明90Y具有潜在的治疗优势，它们将提供在I期临床研究中启动该方法评估所需的背景知识，作为对拟议的指导性研究活动的补充，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.