Anti-4-1BB scFv immunogene therapy and low dose cyclophosphamide exhibit a synergistic antitumor effect in established murine lung tumors
Anti-4-1BB scFv immunogene therapy and low dose cyclophosphamide exhibit a synergistic antitumor effect in established murine lung tumors
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抗 4-1BB scFv 免疫基因疗法和低剂量环磷酰胺在已建立的小鼠肺部肿瘤中表现出协同抗肿瘤作用
DOI：
10.4161/cbt.8.8.7916
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发表时间：
2009-04
影响因子：
3.6
通讯作者：
Chen Hong-Zhuan
中科院分区：
文献类型：
--
作者：
Qi Hong;Liu Fang;Ye Xun;Zhang Wei-Wei;Lu Qin;Fang Chao;Xie Jing;Lieber Andre;Yu De-Hong;Chen Hong-Zhuan
T细胞共刺激分子如4-1BB可能为促进积极的免疫调节提供独特而重要的信号。4-1BB被认为具有作为癌症免疫药物的潜在用途。在我们之前的研究中，携带针对4-1BB基因的单链抗体（anti-4- 1BB scFv）的非复制型腺病毒（Ad.4 - 1BB scFv）具有显著的体内抗肝癌效果。然而，通过触发4-1BB信号传导实现的单一疗法不足以在低免疫原性肿瘤中诱导根除性抗肿瘤活性。探索4-1BB信号传导与低剂量环磷酰胺（CTX）组合的任何可能的协同抗肿瘤作用是非常有趣的，这被充分证明可以抑制小鼠和人中调节性T细胞的抑制能力。在本研究中，重组非复制型腺病毒携带的抗4-1BB单链抗体基因的产生，其特征在于，并探讨其刺激抗肺肿瘤（TC-1）免疫的免疫活性C57 BL/6小鼠。与单独使用腺病毒和环磷酰胺相比，腺病毒介导的抗4-1BB单链抗体联合小剂量CTX治疗可明显增强抗肿瘤活性，部分已建立的TC-1肿瘤被根除，小鼠生存期明显延长。这种协同抗肿瘤作用在很大程度上归因于低剂量CTX诱导的T调节细胞的耗竭。这些发现可能为肿瘤的免疫基因治疗提供一种新的有前途的策略。
T-cell costimulatory molecules such as 4-1BB may provide a distinct and important signal for promoting positive immune regulation. 4-1BB is thought to have potential use as a cancer immunotherapeutic drug. In our previous study, a nonreplicative adenovirus (Ad.4-1BB scFv) carrying single-chain Fv fragments (scFv) specific for the 4-1BB gene (anti-4-1BB scFv) possessed remarkable in vivo anti-hepatoma efficacy. However, monotherapy achieved by triggering 4-1BB signaling was not sufficient to induce eradicative anti-tumor activities in low immunogenic tumors. It is of great interest to explore any possible synergistic antitumor effect of 4-1BB signaling combined with low dose cyclophosphamide (CTX), which is well documented to inhibit the suppressive capability of regulatory T cells in mice and humans. In the present study, recombinant nonreplicative adenoviruses carrying an anti-4-1BB scFv gene were generated, characterized, and explored for their stimulation of anti-lung tumor (TC-1) immunity in immunocompetent C57BL/6 mice. Compared to adenovirus and cyclophosphamide alone, adenovirus-mediated anti-4-1BB scFv in combination with low dose CTX treatment could obviously augment the anti-tumor activity, in which some established TC-1 tumors were eradicated and the survival of mice was significantly extended. This synergistic antitumor effect could be largely attributed to the depletion of T regulatory cells induced by low dose CTX. These findings may provide a new and promising strategy for immunogene therapy against cancer.
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