Monoclonal Antibody Therapy for Follicular Lymphoma

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，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。 在拟议的资助期间，一个正式的教学计划，具有培训研究人员历史的专门导师团队，以及一个支持性的，热情的环境，应允许申请人实现独立的研究生涯，作为淋巴瘤治疗领域的“翻译”研究者。 晚期滤泡性非霍奇金淋巴瘤（NHL）患者的中位生存期在过去的30年中没有显著变化，一般认为常规治疗是无法治愈的。 因此，需要具有最小毒性的新方法。 利妥昔单抗是一种嵌合CD20单克隆抗体，作为治疗滤泡性NHL的单一药物具有显著但有限的活性。 免疫刺激性DNA寡核苷酸（ISS）是一类新型化合物，具有多种免疫学效应，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，诱导细胞因子产生增强的抗体依赖性细胞介导的细胞毒性（ADCC）。 通过对适应性和先天性免疫应答的这些作用，ISS作为与单克隆抗体治疗如dtuximab的协同剂具有显著的前景，具有最小的附加毒性。 鉴于利妥昔单抗与ISS（1018）的I期研究中有利的安全性特征和生物活性证据，该项目建议在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。详细分析该联合治疗的体内和体外免疫学效应，包括评价效应细胞数量和功能，树突状细胞成熟和肿瘤微环境的变化将允许优化这种合理的组合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.