UCSF Helen Diller Family Comprehensive Cancer Center, Cardiovascular Research Institute and Department of Anatomy, University of California, San Francisco, San Francisco, California.
Ignite Immunotherapy, Alameda, California.
Mol Cancer Ther. 2021 Aug;20(8):1481-1494. doi: 10.1158/1535-7163.MCT-20-0863. Epub 2021 May 27.
Oncolytic vaccinia viruses have promising efficacy and safety profiles in cancer therapy. Although antitumor activity can be increased by manipulating viral genes, the relative efficacy of individual modifications has been difficult to assess without side-by-side comparisons. This study sought to compare the initial antitumor activity after intravenous administration of five vaccinia virus variants of the same Western Reserve backbone and thymidine kinase gene deletion in RIP-Tag2 transgenic mice with spontaneous pancreatic neuroendocrine tumors. Tumors had focal regions of infection at 5 days after all viruses. Natural killer (NK) cells were restricted to these sites of infection, but CD8 T cells and tumor cell apoptosis were widespread and varied among the viruses. Antitumor activity of virus VV-A34, bearing amino acid substitution A34 to increase viral spreading, and virus VV-IL2v, expressing a mouse IL2 variant (mIL2v) with attenuated IL2 receptor alpha subunit binding, was similar to control virus VV-GFP. However, antitumor activity was significantly greater after virus VV-A34/IL2v, which expressed mIL2v together with A34 mutation and viral B18R gene deletion, and virus VV-GMCSF that expressed mouse GM-CSF. Both viruses greatly increased expression of CD8 antigens and cytotoxicity genes granzyme A, granzyme B, Fas ligand, and perforin-1 in tumors. VV-A34/IL2v led to higher serum IL2 and greater tumor expression of death receptor ligand TRAIL, but VV-GMCSF led to higher serum GM-CSF, greater expression of leukocyte chemokines and adhesion molecules, and more neutrophil recruitment. Together, the results show that antitumor activity is similarly increased by viral expression of GM-CSF or IL2v combined with additional genetic modifications.
溶瘤痘苗病毒在癌症治疗中具有良好的疗效和安全性。虽然通过操纵病毒基因可以提高抗肿瘤活性，但如果没有平行比较，就很难评估单个修饰的相对疗效。本研究旨在比较静脉注射同一 Western Reserve 骨架和胸苷激酶基因缺失的五种痘苗病毒变体在 RIP-Tag2 转基因小鼠自发性胰腺神经内分泌肿瘤中的初始抗肿瘤活性。所有病毒在 5 天后肿瘤均有局部感染区域。自然杀伤 (NK) 细胞局限于这些感染部位，但 CD8 T 细胞和肿瘤细胞凋亡广泛存在，且在不同病毒之间存在差异。携带氨基酸替代 A34 以增加病毒传播的病毒 VV-A34 和表达具有减弱的 IL2 受体 alpha 亚单位结合的小鼠 IL2 变体 (mIL2v) 的病毒 VV-IL2v 的抗肿瘤活性与对照病毒 VV-GFP 相似。然而，表达 mIL2v 与 A34 突变和病毒 B18R 基因缺失以及表达小鼠 GM-CSF 的病毒 VV-GMCSF 的病毒 VV-A34/IL2v 的抗肿瘤活性显著增加。两种病毒均显著增加了肿瘤中 CD8 抗原和细胞毒性基因 granzyme A、granzyme B、Fas 配体和 perforin-1 的表达。VV-A34/IL2v 导致血清中 IL2 水平升高和肿瘤中死亡受体配体 TRAIL 表达增加，但 VV-GMCSF 导致血清中 GM-CSF 水平升高、白细胞趋化因子和黏附分子表达增加以及更多的中性粒细胞募集。综上所述，结果表明病毒表达 GM-CSF 或 IL2v 与其他遗传修饰相结合可同等提高抗肿瘤活性。
