Neoadjuvant interleukin-12 immunogene therapy protects against cancer recurrence after liver resection in an animal model
Neoadjuvant interleukin-12 immunogene therapy protects against cancer recurrence after liver resection in an animal model
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DOI：
10.1097/00000658-200005000-00017
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发表时间：
2000-05-01
影响因子：
9
通讯作者：
Fong, Y
中科院分区：
文献类型：
--
作者：
Jarnagin, WR;Delman, K;Fong, Y
目的评价单纯疱疹病毒（HSV）表达小鼠白细胞介素-12 （IL-12）基因扩增子载体在新辅助治疗中的应用。背景手术是肝恶性肿瘤最有效的治疗方法。复发是常见的，最常发生在残肝，部分原因是术后宿主细胞免疫功能障碍下残留的显微病变的生长。作者假设，工程肿瘤在体内分泌IL-12将引发针对残余肿瘤的免疫反应，并减少切除后的复发率。方法在Buffalo大鼠肝脏中建立孤立肝癌，直接注射10(6)个携带IL-12、β -半乳糖苷酶（lacZ）基因的HSV颗粒或生理盐水。注射一周后，对动物进行10(6)个肿瘤细胞的门静脉内注射，随后切除含有先前建立的宏观肿瘤结节的肝叶，重现显微残留肿瘤的临床场景。结果转染HSV-IL-12的肝癌细胞在体外和体内均产生高水平的IL-12。肿瘤中CD4（+）和CD8（+）淋巴细胞数量的逐渐增加证明了显著的局部免疫反应。用HSV-IL-12治疗肝癌可防止肝切除术后显微残留癌的生长。接受HSV-IL-12治疗的动物中，64%的动物没有肿瘤或只有一个肿瘤，而接受HSV-IL-12治疗的动物中，这一比例为30%，接受盐碱治疗的动物中为24%。结论这种新辅助免疫策略可能有助于降低肝切除术后肿瘤的复发率。
ObjectiveTo evaluate the neoadjuvant use of a herpes simplex viral (HSV) amplicon vector expressing the murine interleukin-12 (IL-12) gene.Summary Background DataSurgery is the most effective therapy for hepatic malignancy. Recurrences, which are common, most often occur in the remnant liver and are due partly to growth of residual microscopic disease in the setting of postoperative host cellular immune dysfunction. The authors hypothesized that engineering tumors to secrete IL-12 in vivo would elicit an immune response directed at residual tumor and would reduce the incidence of recurrence after resection.MethodsSolitary hepatomas were established in Buffalo rat livers and directly injected with 10(6) particles of HSV carrying the gene for IL-12, lacZ (beta-galactosidase) or with saline. One week after injection, the animals were challenged with an intraportal injection of 10(6) tumor cells, with subsequent resection of the hepatic lobe containing the previously established macroscopic tumor nodule, recreating the clinical scenario of residual microscopic cancer.ResultsHepatoma cells transfected with HSV-IL-12 produced high levels of IL-12 in vitro and in vivo. A significant local immune response developed, as evidenced by a progressive increase in the number of CD4(+) and CD8(+) lymphocytes in the tumor. Treatment of established hepatomas with HSV-IL-12 protected against growth of microscopic residual cancer after hepatic resection. Sixty-four percent of the animals treated with HSV-IL-12 had zero or one tumors compared with 30% of HSVlac-treated and 24% of saline-treated animals.Conclusions This neoadjuvant immune strategy may prove useful in reducing the incidence of cancer recurrence after hepatic resection.