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: 6630491
• 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/6630491
• 关键词: SCID mouse; antileukocyte isoantibody; clinical research; clinical trial phase I; clinical trial phase II; 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 radioimmunotherapy; neoplasm /cancer relapse /recurrence; neuropsychological tests; nonHodgkin's lymphoma; nonhuman therapy evaluation; nutrition related tag; patient oriented research; 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.

我是一名医生，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（UW）的公共卫生学院进行生物统计学，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UW和Fred哈钦森癌症研究中心进行临床研究伦理方面的教学和指导教学。 本项目的总体科学目标是通过以下方式扩展和优化RIT治疗复发性非霍奇金淋巴瘤：（1）在复发性NHL患者（pt）的II期试验中确定清髓性I-131-抗CD 20抗体（Ab）联合环磷酰胺和依托泊苷以及自体干细胞移植（ASCT）的毒性和疗效，（2）研究可行性，在I/II期研究中，在年龄大于或等于60岁的复发性NHL患者中，单药清髓性I-131-抗-CD 20 Ab随后ASCT的耐受性和潜在疗效，（3）评估高剂量RIT对目标1和2中治疗的患者的生活质量（QOL）和神经认知功能（NCF），和（4）进行具有最小毒性的生物制剂（细胞因子和类维生素A）的临床前和临床研究，以进一步增强抗CD 20抗体治疗的功效。 我们假设，与包含非特异性外部束全身照射（TBI）的移植方案相比，使用I-131-抗CD 20抗体特异性靶向B细胞淋巴瘤的放射治疗将增加疗效并降低治疗毒性。 我们进一步假设，与接受含TBI的传统预处理方案（向大脑输送大于或等于12戈伊）移植的患者相比，I-131-抗-CD 20靶向RIT将改善移植后QOL和NCF。 我们预计，单药I-131-抗CD 20 + ASCT的可耐受毒性（在既往试验中确立）将使我们能够安全地将这种潜在的治愈性治疗扩展至可能不适合干细胞移植的老年患者。 最后，我们假设用细胞因子如GM-CSF增加恶性B细胞上的CD 20抗原表达和用视黄酸衍生物增强抗CD 20 Ab介导的细胞凋亡将放大未修饰的和放射性标记的抗CD 20 Ab的细胞毒性。 我们预计，这些干预措施将最终提高复发性淋巴瘤患者的预后，提高反应率和生存率，同时最大限度地减少毒性。