CpG Plus Rituximab Therapy in Follicular Lymphoma

描述(申请人提供)：尽管已经开发出治疗滤泡性淋巴瘤(FL)的新的治疗方法，但总体存活率尚未显著提高。抗CD20单抗利妥昔单抗作为治疗FL的单一药物具有显著的活性，但活性有限。免疫刺激DNA寡核苷酸(ISS)具有抗原递呈和共刺激分子表达、刺激树突状细胞成熟、诱导细胞因子和增强抗体依赖细胞介导的细胞毒作用。通过对适应性免疫和先天免疫的影响，我们推测ISS可能与利妥昔单抗有协同作用。考虑到良好的安全性，以及在用利妥昔单抗进行ISS(1018)的I期研究中有生物活性的证据，我们计划在复发性FL患者的II期研究中评估用1018 ISS进行的利妥昔单抗。我们提出了三个目标。首先，对复发性FL患者进行1018次ISS联合利妥昔单抗的临床试验。第二，研究1018ISS联合利妥昔单抗对效应细胞和肿瘤微环境的影响。第三，观察1018ISS和利妥昔单抗对体外免疫应答的影响。这项研究是治疗FL的一种新方法，在FL中，增加抗原提呈和效应细胞可能会导致利妥昔单抗的细胞毒作用增强，并诱导抗肿瘤免疫。

DESCRIPTION (provided by applicant): Although novel therapeutic approaches have been developed for treating follicular lymphomas (FL), the overall survival has not yet been significantly improved. The anti-CD20 monoclonal antibody rituximab, has significant, albeit limited activity as a single agent for treatment of FL. Immunostimulatory DNA oligonucleotides (ISS) have pleotropic effects, including enhancement of antigen presentation and co-stimulatory molecule expression, stimulation of dendritic cell maturation, and induction of cytokines and augmented antibody-dependent cell-mediated cytotoxicity. Through effects on both adaptive and innate immunity, we hypothesize ISS may synergize with rituximab. Given a favorable safety profile, and evidence of biologic activity in a phase I study of ISS (1018) with rituximab, we plan to evaluate rituximab with 1018 ISS in a phase II study for relapsed FL patients. We propose three aims. First, to undertake a clinical trial of 1018 ISS with rituximab for patients with relapsed FL. Second, to investigate in situ effects of the combination 1018 ISS and rituximab on effector cells and the tumor microenvironment. Third, to investigate effects of 1018 ISS and rituximab on the immune response in vitro. This study is a novel approach to treating FL, where augmenting antigen presentation and effector cells may lead to enhanced cytotoxic effects of rituximab and induce anti-tumor immunity.