OPTIMIZING RADIOIMMUNOTHERAPY FOR NON HODGKIN'S LYMPHOMA

优化非霍奇金淋巴瘤的放射免疫治疗

基本信息

批准号：
6699974
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
项目类别：
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

项目摘要

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）。我的直接职业发展计划包括华盛顿大学（UW）公共卫生学院生物统计学，流行病学和临床试验设计的专业临床研究培训，以及在UW和UW Hutchinson Cancer Cancer Cancer Research Center的临床研究，生活质量评估以及临床研究，生活质量评估的道德方面的教学教学。该项目的总体科学目标是通过（1）确定骨髓性I-131-抗CD20抗体（AB）的毒性和功效来扩展和优化RIT，以治疗复发的非霍奇金淋巴瘤（1）与环磷酰胺和依托磷酰胺和依托磷酰胺和自动型静脉植物（ASCT）相关性（ASCT）的毒性和功效（AB），以置于II的相关性（ASCT）中，并在II阶段（ASCT），均与II阶段相关（PT）（2）调查单个药物骨髓的可行性，耐受性和潜在功效对具有最小毒性（细胞因子和类维生素类动物）的生物学剂的临床和临床研究，以进一步增强抗CD20抗体疗法的疗效。我们假设使用I-131-ANTI-CD20抗体专门针对B细胞淋巴瘤靶向辐射将增强疗效并降低治疗的毒性，而与含有非特异性外束全身辐照（TBI）的移植方案相比。我们进一步假设，与用含有TBI的传统调节方案移植的PT相比，I-131-ANTI-CD20靶向RIT将改善移植后QOL和NCF（向大脑提供大于或等于12 Gy）。我们预计，单药I-131-ANTI-CD20 + ASCT的耐受性毒性（在先前的试验中建立）将使我们能够安全地将这种潜在的治愈性治疗扩展到可能不符合干细胞移植资格的老年PT。最后，我们假设使用细胞因子（例如GM-CSF）增强CD20抗原表达，并增强与视黄酸衍生物的抗CD20 AB介导的凋亡相关的凋亡，并扩大未修饰和放射性抗CD20 AB的细胞毒性，我们将最终与抗CD20 AB相互融合。反应和存活率，同时最大程度地减少毒性。