Section for Studies on Host-Immune Response, National Cancer Center Research Institute, Tokyo, Japan.
Cancer Sci. 2010 Jul;101(7):1686-94. doi: 10.1111/j.1349-7006.2010.01578.x. Epub 2010 Mar 25.
Type I interferon (IFN) protein is a cytokine with pleiotropic biological functions that include induction of apoptosis, inhibition of angiogenesis, and immunomodulation. We have demonstrated that intratumoral injection of an IFN-alpha-expressing adenovirus effectively induces cell death of cancer cells and elicits a systemic tumor-specific immunity in several animal models. On the other hand, reports demonstrated that an elevation of IFN in the serum following an intramuscular delivery of a vector is able to activate antitumor immunity. In this study, we compared the intratumoral and systemic routes of IFN gene transfer with regard to the effect and safety of the treatment. Intratumoral injection of an IFN-alpha adenovirus effectively activated tumor-responsive lymphocytes and caused tumor suppression not only in the gene-transduced tumors but also in distant tumors, which was more effective than the intravenous administration of the same vector. The expression of co-stimulatory molecules on CD11c(+) cells isolated from regional lymph nodes was enhanced by IFN gene transfer into the tumors. Systemic toxicity such as an elevation of hepatic enzymes was much lower in mice treated by intratumoral gene transfer than in those treated by systemic gene transfer. Our data suggest that the intratumoral route of the IFN vector is superior to intravenous administration, due to the effective induction of antitumor immunity and the lower toxicity.
I 型干扰素（IFN）蛋白是一种细胞因子，具有多种生物学功能，包括诱导细胞凋亡、抑制血管生成和免疫调节。我们已经证明，在肿瘤内注射表达 IFN-α的腺病毒可以有效地诱导癌细胞死亡，并在几种动物模型中引发全身性肿瘤特异性免疫。另一方面，有报道表明，在肌肉内递送载体后血清中 IFN 的升高能够激活抗肿瘤免疫。在这项研究中，我们比较了 IFN 基因转移的肿瘤内和系统途径，以评估治疗的效果和安全性。肿瘤内注射 IFN-α腺病毒可以有效地激活肿瘤反应性淋巴细胞，并不仅在转导肿瘤中而且在远处肿瘤中抑制肿瘤，其效果优于静脉内给予相同的载体。从区域淋巴结中分离出的 CD11c（+）细胞上共刺激分子的表达通过肿瘤内基因转移增强。与全身基因转移相比，肿瘤内基因转移治疗的小鼠的肝酶升高等全身毒性要低得多。我们的数据表明，由于有效的抗肿瘤免疫诱导和较低的毒性，IFN 载体的肿瘤内途径优于静脉内给药。
