OPTIMIZING RADIOIMMUNOTHERAPY FOR NON HODGKIN'S LYMPHOMA

优化非霍奇金淋巴瘤的放射免疫治疗

• 批准号: 6085928
• 负责人: Ajay Gopal
• 金额: $ 13.08万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-21 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6085928
• 关键词: SCID mouse; antileukocyte isoantibody; clinical research; clinical trial phase I; combination cancer therapy; combination chemotherapy; cyclophosphamide; etoposide; human middle age (35-64); human old age (65+); human subject; human therapy evaluation; iodine; neoplasm /cancer chemotherapy; neoplasm /cancer immunotherapy; neoplasm /cancer radiation therapy; neoplasm /cancer relapse /recurrence; neuropsychological tests; nonHodgkin's lymphoma; nonhuman therapy evaluation; nutrition related tag; radionuclides; retinoids; stem cell transplantation

I am a physician-scientist committed to patient-oriented research involving radioimmunotherapy (RIT) for the treatment of non- Hodgkin's lymphoma (NHL). My immediate career development plans include specialized clinical research training in biostatistics, epidemiology, and clinical trial design at the School of Public Health at the University of Washington (UW), as well as didactic and mentored instruction in ethical aspects of clinical research, Quality of Life assessment, and research group involvement at the UW and Fred Hutchinson Cancer Research Center. The overall scientific objectives of this project are to expand and optimize RIT for the treatment of relapsed non-Hodgkin's lymphoma by (1) determining the toxicities and efficacy of myeloablative I-131- anti-CD20 antibody (Ab) combined with cyclophosphamide and etoposide and autologous stem cell transplantation (ASCT) in a Phase II trial for patients (pt) with relapsed NHL, (2) investigating the feasibility, tolerability, and potential efficacy of single agent myeloablative I-131-anti-CD20 Ab followed by ASCT in pt greater than or equal to 60 years old with relapsed NHL in a Phase I/II study, (3) assessing the quality of life (QOL) and neurocognitive function (NCF) of high dose RIT on pt treated in aims 1 and 2, and (4) performing pre-clinical and clinical studies of biological agents with minimal toxicity (cytokines and retinoids) to further augment the efficacy of anti-CD20 antibody therapy. We hypothesize that targeting radiation specifically to B cell lymphomas with I-131-anti-CD20 antibodies will augment the efficacy and decrease the toxicity of therapy compared with transplant regimens containing nonspecific external beam total body irradiation (TBI). We further postulate that I-131-anti-CD20 targeted RIT will improve the post- transplant QOL and NCF compared to those of pt transplanted with traditional conditioning regimens containing TBI (which deliver greater than or equal to 12 Gy to the brain). We anticipate that the tolerable toxicity of single agent I-131-anti-CD20 + ASCT (established in previous trials) will allow us to safely extend this potentially curative therapy to elderly pt who may not otherwise be eligible for stem cell transplantation. Finally, we hypothesize that augmenting CD20 antigen expression on malignant B cells with cytokines such as GM-CSF and enhancing anti-CD20 Ab mediated apoptosis with retinoic acid derivatives will amplify the cytotoxicity of both unmodified and radiolabeled anti-CD20 Ab.. We anticipate that these interventions will ultimately enhance the prognosis for patients with relapsed lymphoma by increasing the response and survival rates, while simultaneously minimizing toxicities.

我是一名内科科学家，致力于以患者为导向的研究，涉及放射免疫疗法(RIT)治疗非霍奇金淋巴瘤(NHL)。我近期的职业发展计划包括在华盛顿大学公共卫生学院接受生物统计学、流行病学和临床试验设计方面的专业临床研究培训，以及在华盛顿大学和弗雷德·哈钦森癌症研究中心教授和指导临床研究的伦理方面、生活质量评估和研究小组参与。这个项目的总体科学目标是扩大和优化RIT治疗复发性非霍奇金淋巴瘤，方法是：(1)在一项复发性NHL患者的II期试验中，确定清髓性I-131-抗CD20抗体(Ab)联合环磷酰胺、依托泊苷和自体干细胞移植(ASCT)对复发性NHL患者的毒性和有效性；(2)在I/II期研究中，研究单剂清髓性I-131-抗CD20抗体在大于或等于60岁的复发性NHL患者中应用ASCT的可行性、耐受性和潜在疗效。(3)评估AIMS 1和AIMS 2中大剂量RIT治疗PT的生活质量(QOL)和神经认知功能(NCF)；(4)开展微毒性生物制剂(细胞因子和维甲酸)的临床前和临床研究，以进一步提高抗CD20抗体治疗的疗效。我们假设，与非特异性外照射(TBI)移植方案相比，I-131-抗CD20抗体定向放射治疗B细胞淋巴瘤将提高疗效并降低毒性。我们进一步假设I-131-抗CD20靶向RIT将改善移植后的QOL和NCF，与传统的含有TBI(向大脑提供大于或等于12Gy射线)的预适应方案相比。我们预计，单剂I-131-抗CD20+ASCT的耐受性毒性(在以前的试验中建立)将使我们能够安全地将这种潜在的根治疗法扩展到老年PT，否则他们可能没有资格接受干细胞移植。最后，我们推测，用GM-CSF等细胞因子增强CD20抗原在恶性B细胞上的表达，并用维甲酸衍生物增强抗CD20抗体介导的细胞凋亡，将增强未经修饰和放射性标记的抗CD20抗体的细胞毒作用。我们预计，这些干预措施最终将通过提高反应和存活率，同时将毒副作用降至最低，从而改善复发淋巴瘤患者的预后。