Immune modulation with weekly dosing of an agonist CD40 antibody in a phase I study of patients with advanced solid tumors
Immune modulation with weekly dosing of an agonist CD40 antibody in a phase I study of patients with advanced solid tumors
复制标题
DOI：
10.4161/cbt.10.10.13251
复制
发表时间：
2010-11-15
影响因子：
3.6
通讯作者：
Vonderheide, Robert H.
中科院分区：
文献类型：
--
作者：
Rueter, Jens;Antonia, Scott J.;Vonderheide, Robert H.
背景资料：单剂量输注的激动性抗CD 40单克隆抗体（mAb）CP-870，893完成免疫激活和临床反应的晚期癌症患者，但这种药物的重复给药还没有reported.Results：27例患者参加。最常见的不良事件是短暂的输注相关细胞因子释放综合征（CRS）。剂量限制性毒性包括3级CRS和3级荨麻疹;最大耐受剂量（MTD）估计为0.2 mg/kg。7例患者（26%）的最佳临床缓解为疾病稳定;未观察到部分或完全缓解。在MTD时，患者B淋巴细胞表现出持续增加的共刺激分子和粘附分子表达，剂量之间未重置至基线。在MTD评估的8名患者中的4名（50%）中，总CD 3（+）T淋巴细胞以及CD 4（+）和CD 8（+）亚群显著下降。安全性和免疫药效学进行了assessed.Conclusions：每周输注的激动剂CD 40抗体CP-870，893耐受性良好，但在晚期癌症患者的临床活动很少。相关研究表明慢性B细胞活化，在某些患者中，T细胞耗竭。为了获得最佳免疫药效学，可能需要更长的给药间隔。
Background: Single-dose infusion of the agonistic anti-CD40 monoclonal antibody (mAb) CP-870,893 accomplishes immune activation and clinical responses in patients with advanced cancers, but repeat dosing of this agent has not been reported.Results: Twenty-seven patients were enrolled. The most common adverse event was transient, infusion-related cytokine release syndrome (CRS). Dose-limiting toxicities included grade 3 CRS and grade 3 urticaria; the maximum tolerated dose (MTD) was estimated to be 0.2 mg/kg. Seven patients (26%) had stable disease as the best clinical response; no partial or complete responses were observed. At the MTD, patient B lymphocytes exhibited persistently increased expression of costimulatory and adhesion molecules without resetting to baseline between doses. In 4 of 8 patients (50%) evaluated at the MTD, there were marked declines in total CD3(+) T lymphocytes, as well as CD4(+) and CD8(+) subsets.Patients and Methods: Patients with advanced solid tumor malignancies received weekly intravenous infusions of CP-870,893 in four dose level cohorts. Safety and immune pharmacodynamics were assessed.Conclusions: Weekly infusions of the agonist CD40 antibody CP-870,893 were well-tolerated, but there was little clinical activity in advanced cancer patients. Correlative studies demonstrate chronic B cell activation and in some patients, T cell depletion. Longer dosing intervals may be desirable for optimal immune pharmacodynamics.