Immunological Effects of Low-dose Cyclophosphamide in Cancer Patients Treated With Oncolytic Adenovirus
Immunological Effects of Low-dose Cyclophosphamide in Cancer Patients Treated With Oncolytic Adenovirus
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DOI：
10.1038/mt.2011.113
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发表时间：
2011-09-01
影响因子：
12.4
通讯作者：
Hemminki, Akseli
中科院分区：
文献类型：
--
作者：
Cerullo, Vincenzo;Diaconu, Iulia;Hemminki, Akseli
采用三种不同方案的小剂量环磷酰胺(CP)联合溶瘤腺病毒治疗经常规治疗无效或进展的晚期实体瘤患者。CP口服节律剂量(50 mg/d，N=21)、静脉注射(单次1000 mg，N=7)或两者兼用(N=7)。病毒被注射到肿瘤内。对照组(N=8)接受不含CP的病毒感染。治疗耐受性良好，无论计划如何，都是安全的。CP对抗体形成和病毒复制无明显影响。节律CP(口服和口服+静脉给药方案)减少了调节性T细胞(T-regs)，而不影响抗肿瘤或抗病毒T细胞反应的诱导。在大多数患者中，溶瘤腺病毒联合节律CP可增加细胞毒性T细胞，并在系统水平上诱导Th1型免疫。所有CP方案的疾病控制率均高于单纯病毒方案(均P<；0.0001)，口服+静脉组的无进展(PFS)和总存活率(OS)最好。一年的PFS和OS分别为53%和42%(P=0.0016和P<；0.02与病毒相比)，这对于化疗难治的患者来说都是异常高的。我们的结论是，低剂量的CP具有免疫学效应，适合于溶瘤病毒治疗。虽然这些首创的人类数据显示出良好的安全性、耐人寻味的疗效和延长的生存期，但这些结果应该在随机试验中得到证实。
Patients with advanced solid tumors refractory to and progressing after conventional therapies were treated with three different regimens of low-dose cyclophosphamide (CP) in combination with oncolytic adenovirus. CP was given with oral metronomic dosing (50 mg/day, N = 21), intravenously (single 1,000 mg dose, N = 7) or both (N = 7). Virus was injected intratumorally. Controls (N = 8) received virus without CP. Treatments were well tolerated and safe regardless of schedule. Antibody formation and virus replication were not affected by CP. Metronomic CP (oral and oral + intravenous schedules) decreased regulatory T cells (T-regs) without compromising induction of antitumor or antiviral T-cell responses. Oncolytic adenovirus given together with metronomic CP increased cytotoxic T cells and induced Th1 type immunity on a systemic level in most patients. All CP regimens resulted in higher rates of disease control than virus only (all P < 0.0001) and the best progression-free (PFS) and overall survival (OS) was seen in the oral + intravenous group. One year PFS and OS were 53 and 42% (P = 0.0016 and P < 0.02 versus virus only), respectively, both which are unusually high for chemotherapy refractory patients. We conclude that low-dose CP results in immunological effects appealing for oncolytic virotherapy. While these first-in-human data suggest good safety, intriguing efficacy and extended survival, the results should be confirmed in a randomized trial.