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.

我是一名医师科学家，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) 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，以及临床研究伦理方面、临床研究质量方面的教学和指导指导。华盛顿大学和 Fred Hutchinson 癌症研究中心的生命评估和研究小组参与。 该项目的总体科学目标是通过 (1) 确定清髓性 I-131-抗 CD20 抗体 (Ab) 联合环磷酰胺和依托泊苷的毒性和疗效，扩大和优化 RIT 用于治疗复发性非霍奇金淋巴瘤针对复发性 NHL 患者 (pt) 的 II 期试验中的自体干细胞移植 (ASCT)，(2) 研究可行性、耐受性和潜在疗效在一项 I/II 期研究中，对大于或等于 60 岁的复发性 NHL 患者使用单药清髓性 I-131-抗 CD20 Ab 进行 ASCT，(3) 评估生活质量 (QOL) 和神经认知功能(NCF) 对目标 1 和 2 中接受治疗的患者进行高剂量 RIT，以及 (4) 对毒性最小的生物制剂（细胞因子和类维生素A）进一步增强抗CD20抗体疗法的功效。 我们假设，与包含非特异性外束全身照射 (TBI) 的移植方案相比，使用 I-131-抗 CD20 抗体对 B 细胞淋巴瘤进行特异性靶向放疗将增强疗效并降低治疗毒性。 我们进一步假设，与接受包含 TBI 的传统调理方案（向大脑输送大于或等于 12 Gy）的患者相比，I-131-抗 CD20 靶向 RIT 将改善移植后的 QOL 和 NCF。 我们预计单药 I-131-抗 CD20 + ASCT（在之前的试验中确定）的可耐受毒性将使我们能够安全地将这种潜在的治愈疗法扩展到可能不适合干细胞移植的老年患者。 最后，我们假设用 GM-CSF 等细胞因子增强恶性 B 细胞上的 CD20 抗原表达，并用视黄酸衍生物增强抗 CD20 Ab 介导的细胞凋亡，将放大未修饰和放射性标记的抗 CD20 Ab 的细胞毒性。这些干预措施最终将通过提高缓解率和生存率来改善复发性淋巴瘤患者的预后，同时最大限度地减少毒性。