OPTIMIZING RADIOIMMUNOTHERAPY FOR NON HODGKIN'S LYMPHOMA

我是一名医生兼科学家，致力于以患者为导向的研究，包括放射免疫疗法（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接受临床研究伦理方面的教学和指导指导，生活质量评估，以及研究小组的参与。该项目的总体科学目标是通过(1)在复发性NHL患者（pt）的II期试验中确定清髓性I-131-抗cd20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)调查其可行性、耐受性、可持续性和可移植性，以扩大和优化RIT治疗复发性非霍奇金淋巴瘤的效果。和潜在的单药的功效骨髓I - 131 -抗- cd20 Ab ASCT紧随其后在pt大于或等于60岁与复发NHL I / II期研究,(3)评估生活质量(QOL)和神经认知功能(NCF)高剂量RIT对pt治疗的目标是1和2,和(4)执行生物制剂的临床前和临床研究以最小的毒性(细胞因子和类维生素a)进一步增强anti-CD20抗体疗法的疗效。我们假设，与含有非特异性外束全身照射（TBI）的移植方案相比，用i- 131抗cd20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的毒性。我们进一步假设i- 131抗cd20靶向RIT将改善移植后的QOL和NCF，而传统的治疗方案中含有TBI（向大脑输送大于或等于12 Gy的能量）。我们预计，单药i- 131抗cd20 + ASCT的可耐受毒性（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老年患者，否则他们可能不符合干细胞移植的条件。最后，我们假设使用细胞因子如GM-CSF增强CD20抗原在恶性B细胞上的表达，并使用维甲酸衍生物增强抗CD20 Ab介导的凋亡，将增强未修饰和放射性标记的抗CD20 Ab的细胞毒性。我们预计这些干预措施将最终通过增加反应和生存率来改善复发性淋巴瘤患者的预后，同时将毒性降到最低。

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.