Division of Pulmonary, Thoracic Oncology Research Laboratory, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Mol Ther. 2012 Apr;20(4):736-48. doi: 10.1038/mt.2011.228. Epub 2011 Oct 18.
Since previous work using a nonreplicating adenovirus-expressing mouse interferon-β (Ad.mIFNβ) showed promising preclinical activity, we postulated that a vector-expressing IFNβ at high levels that could also replicate would be even more beneficial. Accordingly a replication competent, recombinant vaccinia viral vector-expressing mIFNβ (VV.mIFNβ) was tested. VV.mIFNβ-induced antitumor responses in two syngeneic mouse flank models of lung cancer. Although VV.mIFNβ had equivalent in vivo efficacy in both murine tumor models, the mechanisms of tumor killing were completely different. In LKRM2 tumors, viral replication was minimal and the tumor killing mechanism was due to activation of immune responses through induction of a local inflammatory response and production of antitumor CD8 T-cells. In contrast, in TC-1 tumors, the vector replicated well, induced an innate immune response, but antitumor activity was primarily due to a direct oncolytic effect. However, the VV.mIFNβ vector was able to augment the efficacy of an antitumor vaccine in the TC-1 tumor model in association with increased numbers of infiltrating CD8 T-cells. These data show the complex relationships between oncolytic viruses and the immune system which, if understood and harnessed correctly, could potentially be used to enhance the efficacy of immunotherapy.
由于先前使用表达鼠干扰素-β（Ad.mIFNβ）的非复制型腺病毒的工作显示出有希望的临床前活性，我们推测能够高水平复制的表达 IFNβ 的载体将会更有益。因此，测试了一种复制型、重组痘苗病毒载体表达的 mIFNβ（VV.mIFNβ）。VV.mIFNβ 在两种肺癌同基因小鼠侧翼模型中诱导抗肿瘤反应。尽管 VV.mIFNβ 在两种小鼠肿瘤模型中具有同等的体内疗效，但肿瘤杀伤机制完全不同。在 LKRM2 肿瘤中，病毒复制很少，肿瘤杀伤机制是通过诱导局部炎症反应和产生抗肿瘤 CD8 T 细胞来激活免疫反应。相比之下，在 TC-1 肿瘤中，该载体复制良好，诱导先天免疫反应，但抗肿瘤活性主要归因于直接溶瘤作用。然而，VV.mIFNβ 载体能够增强 TC-1 肿瘤模型中抗肿瘤疫苗的疗效，同时增加浸润的 CD8 T 细胞数量。这些数据显示了溶瘤病毒与免疫系统之间的复杂关系，如果能够正确理解和利用，可能会增强免疫疗法的疗效。
