摘要

PURPOSE:Based on the potential for ipilimumab (I) to augment T-cell activation, we hypothesize that ipilimumab would augment the efficacy of rituximab (R) in patients with relapsed/refractory (R/R) CD20+non-Hodgkin's lymphoma (NHL). This phase I study aimed to identify a recommended phase 2 dose, document toxicities, and preliminarily assess efficacy and potential predictive biomarkers.
PATIENTS AND METHODS:Thirty-three patients with R/R CD20+B-cell lymphoma received R at 375 mg/m2weekly for 4 weeks and I at 3 mg/kg on day 1 and every 3 weeks for four doses. Responding patients went on to maintenance with each agent given every 12 weeks. To facilitate correlative analysis, the expansion phase randomized patients to simultaneous R+I versus R with I delayed 2 weeks.
RESULTS:Toxicity was manageable; no dose-limiting toxicity was observed at the doses studied. When considering the entire cohort, efficacy was modest, with an objective response rate (ORR) of 24% and median progression-free survival (PFS) of 2.6 months. However, in follicular lymphoma patients, the ORR was 58% with a median PFS of 5.6 months. The randomized comparison of R with R+I demonstrated that R+I resulted in more effective B-cell depletion (BCD). Both B-cell depletion and the ratio of CD45RA-regulatory T cell (Treg) to Treg were associated with response at all time points.
CONCLUSIONS:The combination of R+I has manageable toxicity and encouraging efficacy in R/R follicular lymphoma. The ratio of CD45RA-Tregs to total Tregs, and peripheral BCD should be studied further as potential predictors of response.

译文

目的: 基于 ipilimumab (I) 增加 T 细胞活化的潜力,我们假设 ipilimumab 将增加利妥昔单抗的疗效 (R) 在复发/难治性 (R/R) CD20 非霍奇金淋巴瘤 (NHL) 患者中。这项 I 期研究旨在确定推荐的 2 期剂量,记录毒性,并初步评估疗效和潜在的预测生物标志物。
患者和方法: 33 名 R/R CD20 b细胞淋巴瘤患者在 4 周内每周接受 375 毫克/平方米的 R,在第一天接受 3 毫克/千克的 I,每 3 周接受 4 剂。有反应的病人继续进行维护,每 12 周给每个代理人一次。为了便于相关分析,扩展阶段随机将患者分为同时 R I 与 R I,延迟 2 周。
结果: 毒性是可控的; 在所研究的剂量下没有观察到剂量限制毒性。当考虑整个队列时,疗效适中,客观反应率 (ORR) 为 24%,中位无进展生存期 (PFS) 为 2.6 个月。然而,在滤泡性淋巴瘤患者中,ORR 为 58%,中位 PFS 为 5.6 个月。R 与 R I 的随机比较表明,R I 导致更有效的 b细胞耗竭 (BCD)。B细胞耗竭和 CD45RA-regulatory T 细胞 (Treg) 与 Treg 的比率均与所有时间点的反应相关。
结论: R I 联合治疗 R/R 滤泡性淋巴瘤具有可控的毒性和令人鼓舞的疗效。应进一步研究 CD45RA-Tregs 与总 Tregs 的比率以及外周 BCD 作为反应的潜在预测因子。

ipilimumab

肿瘤 基础研究 药物
概述  :  

伊匹单抗又叫易普利姆玛,是百时美施贵宝研发的一款免疫检查点抑制剂和单克隆抗体,于2011年3月25日美国FDA批准可用于治疗晚期黑色素瘤。用药方法是静脉注射给药,观察输液反应。治疗时间方面,持续给药直到疾病恶化或出现不可接受的毒性。目前其适应症已经扩展为III期黑色素瘤患者、转移性结直肠癌患者以及晚期肾细胞癌患者,具体来说包括:不可切除或转移性黑色素瘤的成人及儿童患者(12岁及以上);牵涉到局部淋巴结大于1 mm的皮肤黑色素瘤,在完全切除(包括全淋巴结切除术)后的辅助治疗;与niv

Ipilimumab 

       n. 伊匹单抗

       Neoadjuvant treatment with ipilimumab plus nivolumab at the standard dosing schedule induced pathological responses in a high proportion of patients in two small independent early-phase trials, and no patients with a pathological response have relapsed after a median follow up of 32 months. 伊匹单抗联合纳武单抗在标准剂量表下的新辅助治疗在早期两个独立的小型试验结果显示,标准给药方案下新辅助疗法可诱导高比例的患者病理反应,并且在中位随访32个月后,没有病理反应患者复发。

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