A Phase I Trial to Evaluate Antibody-Dependent Cellular Cytotoxicity of Cetuximab and Lenalidomide in Advanced Colorectal and Head and Neck Cancer.
A Phase I Trial to Evaluate Antibody-Dependent Cellular Cytotoxicity of Cetuximab and Lenalidomide in Advanced Colorectal and Head and Neck Cancer.
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DOI：
10.1158/1535-7163.mct-15-0879
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发表时间：
2016-09
影响因子：
5.7
通讯作者：
Otterson GA
中科院分区：
文献类型：
--
作者：
Bertino EM;McMichael EL;Mo X;Trikha P;Davis M;Paul B;Grever M;Carson WE;Otterson GA
mAb可以通过先天免疫系统识别mAb包被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，具有刺激免疫细胞细胞因子产生和ADCC活性的能力。这项I期试验评估了西妥昔单抗与来那度胺联合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。治疗包括西妥昔单抗500 mg/m2静脉注射，每2周一次，来那度胺口服给药，第1 - 21天，28天为1周期。评价了来那度胺的三个剂量水平（15、20、25 mg）。相关研究包括ADCC测定、Fc γ RIIIA多态性基因分型、血清细胞因子水平测定和免疫细胞亚型流式细胞术分析。22例患者入组（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例患者病情稳定至少12周。II期推荐剂量为西妥昔单抗500 mg/m2，每日一次，来那度胺25 mg，第1 - 21天。相关研究表明，随着来那度胺剂量的增加，自然杀伤细胞毒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。ADCC呈来那度胺剂量依赖性增加，入组队列3的患者活性高于入组队列1/2的患者。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。需要进一步研究来那度胺作为实体瘤的免疫调节剂。
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/m2 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/m2 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 ½. 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.