Radiolabeled Antibody Therapy of Acute Leukemia

急性白血病的放射性标记抗体治疗

• 批准号: 6913346
• 负责人: FREDERICK APPELBAUM
• 金额: $ 22.62万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6913346
• 关键词: acute leukemia; acute lymphocytic leukemia; acute myelogenous leukemia; antitumor antibody; bone marrow purging; clinical trial phase II; hematopoietic tissue transplantation; human subject; human therapy evaluation; immunosuppressive; iodine; monoclonal antibody; neoplasm /cancer radioimmunotherapy; patient oriented research; preneoplastic state; radionuclides; stem cell transplantation

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.

同种异体造血细胞移植（HCT）治疗恶性血液病患者经常失败，因为疾病复发。由于大多数调理剂的非特异性，其相关毒性限制了强化预备方案的尝试。项目3的总体目标是通过向白血病受累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，同时不增加毒性。通过临床前模型，我们已经证明131I-anti-CD45抗体（Ab）可以向造血组织提供靶向辐射，与肝、肺或肾相比，向骨髓提供的辐射多2至3倍，向脾脏提供的辐射多12倍，向淋巴结提供的辐射多2至8倍。这种临床前观察已转化为人类研究，证明了联合靶向