Bertino Erin M, McMichael Elizabeth L, Mo Xiaokui, Trikha Prashant, Davis Melanie, Paul Bonnie, Grever Michael, Carson William E, Otterson Gregory A
Division of Medical Oncology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio.
Biomedical Sciences Graduate Program, College of Medicine, The Ohio State University, Columbus, Ohio.
Mol Cancer Ther. 2016 Sep;15(9):2244-50. doi: 10.1158/1535-7163.MCT-15-0879. Epub 2016 Jul 25.
mAbs can induce antibody-dependent cellular cytotoxicity (ADCC) via the innate immune system's ability to recognize mAb-coated cancer cells and activate immune effector cells. Lenalidomide is an immunomodulatory agent with the capacity to stimulate immune cell cytokine production and ADCC activity. This phase I trial evaluated the combination of cetuximab with lenalidomide for the treatment of advanced colorectal and head and neck squamous cell cancers (HNSCC). This trial included patients with advanced colorectal cancer or HNSCC. Treatment consisted of cetuximab 500 mg/m(2) i.v. every two weeks with lenalidomide given orally days 1-21 on a 28-day cycle. Three dose levels of lenalidomide were evaluated (15, 20, 25 mg). Correlative studies included measurement of ADCC, FcγRIIIA polymorphism genotyping, measurement of serum cytokine levels, and flow cytometric analysis of immune cell subtypes. Twenty-two patients were enrolled (19 colorectal cancer, 3 HNSCC). Fatigue was the only dose-limiting toxicity. One partial response was observed and 8 patients had stable disease at least 12 weeks. The recommended phase II dose is cetuximab 500 mg/m(2) with lenalidomide 25 mg daily, days 1-21. Correlative studies demonstrated a dose-dependent increase in natural killer cytotoxic activity with increasing doses of lenalidomide. Cetuximab and lenalidomide were well tolerated. There was a lenalidomide dose-dependent increase in ADCC with higher activity in patients enrolled in cohort 3 than those enrolled in cohorts 1/2. Although response was not a primary endpoint, there was evidence of antitumor activity for the combination therapy. Further investigation of lenalidomide as an immunomodulator in solid tumors is warranted. Mol Cancer Ther; 15(9); 2244-50. ©2016 AACR.
单克隆抗体（mAbs）可通过先天免疫系统识别包被有mAb的癌细胞并激活免疫效应细胞的能力来诱导抗体依赖性细胞毒性（ADCC）。来那度胺是一种免疫调节剂，能够刺激免疫细胞产生细胞因子并具有ADCC活性。这项I期试验评估了西妥昔单抗与来那度胺联合用于治疗晚期结直肠癌和头颈部鳞状细胞癌（HNSCC）的疗效。该试验纳入了晚期结直肠癌或HNSCC患者。治疗方案为每两周静脉注射西妥昔单抗500mg/m²，同时来那度胺在第1 - 21天口服，每28天为一个周期。评估了三个来那度胺剂量水平（15、20、25mg）。相关研究包括ADCC测定、FcγRIIIA多态性基因分型、血清细胞因子水平测定以及免疫细胞亚群的流式细胞术分析。共入组22例患者（19例结直肠癌，3例HNSCC）。疲劳是唯一的剂量限制性毒性。观察到1例部分缓解，8例患者疾病稳定至少12周。推荐的II期剂量为西妥昔单抗500mg/m²，来那度胺25mg每日，第1 - 21天。相关研究表明，随着来那度胺剂量增加，自然杀伤细胞的细胞毒性活性呈剂量依赖性增加。西妥昔单抗和来那度胺耐受性良好。来那度胺剂量依赖性地增加ADCC，第3组入组患者的活性高于第1/2组入组患者。尽管缓解不是主要终点，但有证据表明联合治疗具有抗肿瘤活性。有必要进一步研究来那度胺作为实体瘤免疫调节剂的作用。《分子癌症治疗》；15(9)；2244 - 50。©2016美国癌症研究协会。
