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的日益复杂，b细胞恶性肿瘤患者的新治疗策略的开发需要临床研究人员和基础科学家的共同努力。在建议的资助期内，一个正式的教学项目，一个具有培训研究者历史的专门导师团队，以及一个支持性的、热情的环境，应该允许申请人作为淋巴瘤治疗领域的“转化”研究者实现独立的研究事业。

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.