Monoclonal Antibody Therapy for Follicular Lymphoma

滤泡性淋巴瘤的单克隆抗体治疗

• 批准号: 7101820
• 负责人: JONATHAN W FRIEDBERG
• 金额: $ 13.08万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7101820
• 关键词: B cell lymphoma; DNA; antineoplastics; clinical research; clinical trial phase II; dendritic cells; drug resistance; drug screening /evaluation; flow cytometry; gene expression; human subject; human therapy evaluation; immunocytochemistry; interferons; monoclonal antibody; neoplasm /cancer chemotherapy; neoplasm /cancer immunotherapy; neoplasm /cancer relapse /recurrence; nonHodgkin' s lymphoma; patient oriented research; polymerase chain reaction; positron emission tomography

DESCRIPTION (provided by applicant): As both basic laboratory research and clinical research become increasingly complex, development of novel therapeutic strategies for patients with B-cell malignancies requires collaborative efforts between clinical researchers and basic scientists. During the proposed funding period, a formal didactic program, dedicated team of mentors with a history of training investigators, and a supportive, enthusiastic environment should allow the applicant to achieve an independent research career as such a "translational" investigator in the field of lymphoma therapy. Patients with advanced stage follicular non-Hodgkin's lymphoma (NHL) are generally accepted to be incurable with conventional treatment, and the median survival has not changed significantly in the past thirty years. Novel approaches with minimal toxicity are therefore needed. Rituximab, a chimeric CD20 monoclonal antibody, has significant, albeit limited activity as a single agent for treatment of follicular NHL. Immunostimulatory DNA oligonucleotides (ISS) are novel compounds that have pleotropic immunological effects, including enhancement of antigen presentation and costimulatory molecule expression, stimulation of dendritic cell maturation, and induction of cytokines resulting in enhanced antibody-dependent cell-mediated cytotoxicity (ADCC). Through these effects on both the adaptive and innate immune response, ISS have significant promise as synergistic agents with monoclonal antibody therapy such as dtuximab, with minimal added toxicity. Given a favorable safety profile, and evidence of biologic activity in an ongoing phase I study of ISS (1018) with rituximab, this project proposes to test the efficacy of rituximab in combination with 1018 ISS in a phase II study for patients with relapsed follicular NHL Detailed analysis of the immunological effects of this combination both in vivo and in vitro, including evaluation of effector cell number and function, dendritic cell maturation, and changes in the tumor microenvironment, will allow optimization of this rational combination for further clinical development.

描述（由申请人提供）：随着基础实验室研究和临床研究变得越来越复杂，针对 B 细胞恶性肿瘤患者的新型治疗策略的开发需要临床研究人员和基础科学家之间的合作努力。 在拟议的资助期内，正式的教学计划、具有培训研究人员历史的专门导师团队以及支持性、热情的环境应该使申请人能够实现独立的研究生涯，成为淋巴瘤领域的“转化”研究人员治疗。 晚期滤泡性非霍奇金淋巴瘤（NHL）患者通常被认为采用常规治疗无法治愈，并且中位生存期在过去三十年中没有显着变化。 因此需要毒性最小的新方法。 利妥昔单抗是一种嵌合 CD20 单克隆抗体，作为治疗滤泡性 NHL 的单一药物，其活性虽然有限，但仍显着。 免疫刺激性 DNA 寡核苷酸 (ISS) 是具有多效性免疫效应的新型化合物，包括增强抗原呈递和共刺激分子表达、刺激树突状细胞成熟以及诱导细胞因子，从而增强抗体依赖性细胞介导的细胞毒性 (ADCC)。 通过对适应性和先天免疫反应的这些影响，ISS 作为单克隆抗体疗法（如 dtuximab）的协同药物具有重大前景，且附加毒性最小。 鉴于良好的安全性以及正在进行的 ISS (1018) 与利妥昔单抗的 I 期研究中的生物活性证据，该项目建议在一项 II 期研究中测试利妥昔单抗与 1018 ISS 联合治疗复发性滤泡性 NHL 患者的疗效详细分析该组合在体内和体外的免疫学作用，包括评估效应细胞数量和功能、树突状细胞成熟以及肿瘤微环境的变化，将允许优化这种合理的组合以进行进一步的临床开发。