Pretargeted Radioimmunotherapy for Hematologic Malignancies

血液系统恶性肿瘤的靶向放射免疫治疗

• 批准号: 8719025
• 负责人: Oliver W. Press
• 金额: $ 30.48万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8719025
• 关键词: Achievement; Acute Lymphocytic Leukemia; Acute Myelocytic Leukemia; Allogenic; Antibodies; Autologous; Binding; Biodistribution; Blood; Bone Marrow; Chimeric Proteins; Conduct Clinical Trials; Cyclophosphamide; DOTA-biotin; Dose; Dose-Limiting; Drug Kinetics; Dysmyelopoietic Syndromes; Etoposide; Excretory function; Goals; Grant; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Hour; In complete remission; Infusion procedures; Lead; Lymphoma; Macaca; Malignant Neoplasms; Maximum Tolerated Dose; Modeling; Monoclonal Antibodies; Morbidity - disease rate; Mus; Myelosuppression; Non-Hodgkin' s Lymphoma; Normal tissue morphology; Organ; PTPRC gene; Patients; Phase I Clinical Trials; Progression-Free Survivals; Radiation; Radioactivity; Radioimmunoconjugate; Radioimmunotherapy; Radioisotopes; Radiolabeled; Reagent; Refractory; Regimen; Relapse; Relative (related person); Reporting; Research Personnel; Site; Streptavidin; Technology; Testing; Toxic effect; Transplantation; Treatment Effectiveness; VP 16; Whole-Body Irradiation; chemical conjugate; chemoradiation; conditioning; dosimetry; fludarabine; hematopoietic cell transplantation; high risk; improved; leukemia; leukemia/lymphoma; lymph nodes; mortality; neoplastic cell; phase 1 study; radiotracer; response; therapeutic target; tositumomab; tumor; urinary

The objective of Project 3 (Pretargeted Radioimmunotherapy for Hematologic Malignancies) is to improve the efficacy and diminish the toxicity of radioimmunotherapy (RIT) by removing the proportion of radioisotope that fails to bind to tumor and remains in the blood perfusing normal organs. This goal will be achieved by employing a multi-step "pretargeted" RIT (PRIT) approach in which conjugates of the anti-CD45 BCS Ab and streptavidin are injected first into patients with CD45-expressing hematologic malignancies followed by infusion of radiolabeled DOTA-biotin 48 hours later. In Aim 1, we will conduct a phase I trial of non-myeloablative allogeneic hematopoietic cell transplantation (HCT) using PRIT with BCS-SA and radiobiotin followed by fludarabine (FLU) and 2 Gy total body irradiation (TBI) for relapsed or refractory acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or high risk myelodysplasia (MDS). The primary objective of this Aim is to estimate the maximum tolerated dose (MTD) of [90]Y-DOTA-biotin when given with this transplant conditioning regimen. Secondary objectives include defining the pharmacokinetics (PK) and biodistributions of the BCS-SA and radiolabeled-DOTA-biotin reagents and examining their potential efficacy. In Aim 2, we will conduct a phase I trial of myeloablative autologous HCT for relapsed lymphoma using PRIT with BCS-SA and radiobiotin followed by etoposide (VP16) and cyclophosphamide (CY). The primary objective of this study is to estimate the MTD of [90]Y-DOTA-biotin using pre-targeting technology followed by autologous HCT in patients with relapsed lymphoma. In Aim 3 we will compare and contrast the biodistributions and dosimetries of radiobiotin pretargeted using anti-CD45 BCS-SA with those observed with directly radiolabeled anti-CD45 BCS Ab in patients with leukemia and lymphoma. The overall goal of Project 1 is to improve the delivery of radiation to tumor cells compared to normal tissues, thereby allowing escalation of the tumor dose while maintaining well-defined, tolerable upper limits on the doses to critical normal organs. Successful execution of this Project should lead to improvements in the cure rates of patients with relapsed and refractory AML, ALL, MDS and NHL undergoing HCT.

项目 3（血液恶性肿瘤的靶向放射免疫治疗）的目标是 通过去除比例提高放射免疫治疗（RIT）的疗效并降低毒性 无法与肿瘤结合并保留在灌注正常器官的血液中的放射性同位素。这个目标 将通过采用多步骤“预定目标”RIT（PRIT）方法来实现，其中缀合物 首先将抗 CD45 BCS Ab 和链霉亲和素注射到表达 CD45 的患者体内 血液恶性肿瘤，48 小时后输注放射性标记的 DOTA-生物素。在目标 1 中，我们 将进行非清髓性同种异体造血细胞移植（HCT）的 I 期试验 使用 PRIT 结合 BCS-SA 和放射性生物素，然后进行氟达拉滨 (FLU) 和 2 Gy 全身照射 (TBI) 用于治疗复发性或难治性急性髓系白血病 (AML)、急性淋巴细胞白血病 (ALL)，或 高风险骨髓增生异常（MDS）。该目标的主要目标是估计最大容忍度 当与这种移植预处理方案一起给予时，[90]Y-DOTA-生物素的剂量（MTD）。中学 目标包括定义 BCS-SA 的药代动力学 (PK) 和生物分布 放射性标记的 DOTA 生物素试剂并检查其潜在功效。在目标 2 中，我们将进行 使用 PRIT 结合 BCS-SA 进行清髓性自体 HCT 治疗复发性淋巴瘤的 I 期试验 放射性生物素，其次是依托泊苷 (VP16) 和环磷酰胺 (CY)。本次活动的首要目标 研究的目的是使用预靶向技术和自体同源技术来估计 [90]Y-DOTA-生物素的 MTD 复发性淋巴瘤患者的 HCT。在目标 3 中，我们将比较和对比生物分布 以及使用抗 CD45 BCS-SA 预靶向的放射性生物素的剂量测定以及直接观察到的剂量测定 放射性标记的抗 CD45 BCS 抗体用于白血病和淋巴瘤患者。项目1总体目标 与正常组织相比，改善肿瘤细胞的辐射传递，从而允许 增加肿瘤剂量，同时保持明确的、可耐受的剂量上限 重要的正常器官。该项目的成功执行应该会改善治疗效果 复发性和难治性 AML、ALL、MDS 和 NHL 患者接受 HCT 的比例。