Preclinical trial of the multi‐targeted lenvatinib in combination with cellular immunotherapy for treatment of renal cell carcinoma
Preclinical trial of the multi‐targeted lenvatinib in combination with cellular immunotherapy for treatment of renal cell carcinoma
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多靶点乐伐替尼联合细胞免疫疗法治疗肾细胞癌的临床前试验
DOI：
10.3892/etm.2017.4858
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发表时间：
2017
影响因子：
2.7
通讯作者：
ZHONGQING WEI
中科院分区：
文献类型：
--
作者：
CHENGKUAN CAI;JINGYUAN TANG;BAIXIN SHEN;LIUCHENG DING;YUNPENG SHAO;ZHENGSEN CHEN;YINCHAO MA;HAOLIANG XUE;ZHONGQING WEI
Lenvatinib是一种口服、多靶点酪氨酸激酶抑制剂，可抑制血管内皮生长因子受体1-3、成细胞生长因子受体1- 4、血小板衍生生长因子受体β、RET和KIT。细胞免疫疗法有潜力成为一种高度靶向治疗，对正常组织的毒性低，根除肿瘤组织的能力高。本研究评估了lenvatinib和细胞免疫治疗在小鼠肾细胞癌（RCC）模型中的安全性、最大耐受剂量（MTD）和初步抗肿瘤活性。本研究使用治疗剂量0.12 mg lenvatinib和/或104个大鼠子宫癌腺癌（RuCa）致敏淋巴细胞，每天一次，连续7天周期给药。在lenvatinib和104个ruca致敏淋巴细胞治疗后，观察到RCC小鼠肿瘤消退。MTD设定为每天一次给药0.18 mg lenvatinib和106个ruca致敏淋巴细胞。观察到的最常见的治疗相关不良反应是疲劳（40%）、粘膜紊乱（30%）、蛋白尿、腹泻、呕吐、高血压和恶心（均为40%）。lenvatinib与细胞免疫疗法联合治疗可增强单用治疗的抗肿瘤作用，延长RCC小鼠的生存期。lenvatinib （0.12 mg）联合104个ruca致敏淋巴细胞治疗与可控制的毒性相关，与单个药物一致。需要进一步评估这种联合治疗在晚期肾细胞癌小鼠中的效果。综上所述，lenvatinib和致敏淋巴细胞的协同作用可能会改善肿瘤的细胞免疫治疗和溶瘤治疗。在本研究中，两种药物联合使用可增强其固有的抗肿瘤和免疫刺激特性，为临床治疗RCC患者提供依据。
Lenvatinib is an oral, multi-targeted tyrosine kinase inhibitor of vascular endothelial growth factor receptors 1-3, broblast growth factor receptors 1‐4, platelet‐derived growth factor receptor β, RET and KIT. Cellular immunotherapy has the potential to be a highly targeted treatment, with low toxicity to normal tissues and a high capacity to eradicate tumor tissue. The present study assessed the safety, maximum tolerated dose (MTD) and preliminary antitumor activity of lenvatinib and cellular immunotherapy in a murine model of renal cell carcinoma (RCC). The present study used a thera- peutic dose of 0.12 mg lenvatinib and/or 104 rat uterine cancer adenocarcinoma (RuCa)-sensitized lymphocytes administered once daily continuously in 7-day cycles. Tumor regression was observed in mice with RCC following treatment with lenvatinib and 104 RuCa-sensitized lymphocytes. MTD was established as once daily administration of 0.18 mg lenvatinib and 106 RuCa-sensitized lymphocytes. The most common treatment-related adverse effects observed were fatigue (40%), mucosal in ammation (30%), proteinuria, diarrhea, vomiting, hypertension and nausea (all 40%). Combination therapy using lenvatinib and cellular immunotherapy enhanced the antitumor effect induced by single treatments and prolonged the survival of mice with RCC compared with either of the single treat- ments. Treatment with lenvatinib (0.12 mg) combined with 104 RuCa-sensitized lymphocytes was associated with manageable toxicity consistent with individual agents. Further evaluation of this combination therapy in mice with advanced RCC is required. In conclusion, cellular immunotherapy and oncolytic therapy for cancer may be improved by the synergistic effects of lenvatinib and sensitized lymphocytes. In the present study, the inherent antineoplastic and immune stimulatory properties of the two agents were enhanced when used in combination, which may provide a basis for clinical treatment of patients with RCC.