Monoclonal Antibody Therapy for Follicular Lymphoma

描述(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，为B细胞恶性肿瘤患者开发新的治疗策略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敬业导师团队以及支持和热情的环境应该允许申请者实现独立的研究生涯，例如淋巴瘤治疗领域的“转化型”研究员。 晚期滤泡性非霍奇金淋巴瘤(NHL)患者一般认为常规治疗是无法治愈的，中位生存期在过去30年中无明显变化。因此，需要毒性最小的新方法。利妥昔单抗是一种嵌合的CD20单抗，作为治疗滤泡性非霍奇金淋巴瘤的单一药物，具有显著的尽管有限的活性。 免疫刺激DNA寡核苷酸(ISS)是一类具有抗原递呈和共刺激分子表达、刺激树突状细胞成熟、诱导细胞因子增强抗体依赖细胞介导的细胞毒作用(ADCC)的新型化合物。通过这些对适应性和先天免疫反应的影响，ISS作为单抗治疗的协效剂，如dtuximab，具有显著的前景，增加的毒性最小。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期研究中生物活性的证据，该项目建议在II期研究中测试美妥昔单抗与1018 ISS联合用于复发性滤泡性NHL患者的疗效。详细分析这一组合的体内和体外免疫学效应，包括评估效应细胞的数量和功能、树突状细胞成熟以及肿瘤微环境的变化，将使这一合理组合得到优化，用于进一步的临床开发。

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.