Introduction: Immune evasion through inhibition of effector T cells is a key survival mechanism of lymphoma cells. We hypothesized that reinstating effector T cell activity through concurrent inhibition of the PD1/PD-L1 axis and of Treg activity will result in a synergistic anti-tumor effect with an acceptable toxicity profile.Methods: Phase I multi-institutional NCI-ETCTN trial aimed to evaluate the safety and tolerability of the combination of mogamulizumab and pembrolizumab in relapsed or refractory non-Hodgkin lymphoma. The study used a 3 + 3 design. Treatment consisted of mogamulizumab 1 mg/kg on days 1, 8, and 15 of cycle 1, followed by 1.5 mg/kg on day 1 of each subsequent 21-day cycle in combination with pembrolizumab 200 mg on day 1 of each cycle. A de-escalation level was defined as a 50% reduction in the dose of mogamulizumab (registered in clinicaltrials.gov NCT03309878).Results: The study was discontinued early, after treating seven patients (two angioimmunoblastic T cell lymphoma, four transformed follicular lymphoma, and one diffuse large B cell lymphoma of germinal center subtype) for concerns of futility and non-tolerability. Only two patients completed the first two cycles of treatment. Three patients presented with an early progression and three withdrew consent in the setting of general deterioration with clinically suspected progression. All six patients expired shortly after withdrawal from the study. The remaining patient experienced stress cardiomyopathy during the third cycle and was taken off the study.Discussion: In striking difference to the observation in solid malignancies, the combination of mogamulizumab with pembrolizumab was associated with low tolerability and suspected hyper-progression in patients with lymphoma.
引言：通过抑制效应T细胞实现免疫逃避是淋巴瘤细胞的关键生存机制。我们假设，通过同时抑制PD1/PD-L1通路与调节性T细胞活性来恢复效应T细胞功能，将产生协同抗肿瘤效应且具有可接受的毒性特征。
方法：这项I期多中心NCI-ETCTN试验旨在评估莫加木利珠单抗联合帕博利珠单抗治疗复发或难治性非霍奇金淋巴瘤的安全性与耐受性。研究采用3+3设计。治疗方案为：第1周期第1、8、15天给予莫加木利珠单抗1 mg/kg，后续每21天周期第1天给予1.5 mg/kg；联合帕博利珠单抗200 mg于每周期第1天给药。剂量递减水平定义为莫加木利珠单抗剂量降低50%（临床试验注册号：NCT0878）。
结果：研究因疗效不足与耐受性问题提前终止，共治疗7例患者（包括2例血管免疫母细胞性T细胞淋巴瘤、4例转化性滤泡性淋巴瘤、1例生发中心亚型弥漫大B细胞淋巴瘤）。仅2例患者完成前两个周期治疗。3例患者出现早期进展，3例在临床疑似进展伴全身状况恶化时撤回知情同意，这6例患者均在退出研究后短期内死亡。剩余1例患者在第三周期出现应激性心肌病而终止研究。
讨论：与实体瘤中的观察结果截然不同，莫加木利珠单抗联合帕博利珠单抗在淋巴瘤患者中表现出较低的耐受性，并疑似引发肿瘤超进展。
肿瘤(癌症)患者之家