肿瘤细胞治疗研究
英文原题：Engineered oncolytic herpes simplex virus expressing interleukin 12 suppresses tumorigenicity of hepatocellular carcinoma.
溶瘤病毒（OVs）通过直接溶瘤活性和免疫调节转基因的表达介导抗癌效应。
溶瘤病毒（OVs）通过直接的溶瘤活性和免疫调节转基因的表达介导抗癌效应。Talimogene laherparepvec（T-VEC）是一种经基因修饰的溶瘤单纯疱疹病毒1型（HSV-1），被改造为分泌粒细胞-巨噬细胞集落刺激因子（GM-CSF），已获得美国食品药品监督管理局（FDA）批准用于黑色素瘤治疗。然而，像T-VEC这样的早期世代OVs的临床疗效仍然有限，凸显了增强其抗肿瘤效力和免疫激活能力的必要性。白细胞介素-12（IL-12）是一种强效的免疫刺激性细胞因子，可促进Th1型反应，触发自然杀伤（NK）细胞、CD4+ T细胞和CD8+ T细胞产生干扰素-γ，从而表现出强大的抗肿瘤活性。在本研究中，我们构建了两种重组HSV-1，oHSV-GMCSF和oHSV-IL12，并在H22小鼠肝细胞癌（HCC）模型中评估了它们单独或联合使用的抗肿瘤效果。引人注目的是，oHSV-IL12单药治疗实现了肿瘤完全消退，优于oHSV-GMCSF的疗效。RNA测序分析显示，oHSV-IL12治疗增强了瘤内淋巴细胞浸润和活化，同时上调了免疫相关基因和通路。值得注意的是，oHSV-IL12单药治疗在再攻击和生存实验中均显示出与oHSV-GMCSF和oHSV-IL12联合治疗相当的治疗效果。这些发现使oHSV-IL12成为HCC免疫治疗的一个有前景的新型候选药物。
Oncolytic viruses (OVs) mediate anticancer effects through direct oncolytic activity and the expression of immunomodulatory transgenes. Talimogene laherparepvec (T-VEC), a genetically modified oncolytic herpes simplex virus type 1 (HSV-1) engineered to secrete granulocyte-macrophage colony stimulating factor (GM-CSF), has received United States Food and Drug Administration (FDA) approval for melanoma treatment. However, the clinical efficacy of early generation OVs like T-VEC remains limited, highlighting the need to enhance their antitumor potency and immune activation capacity. Interleukin-12 (IL-12) is a potent immunostimulatory cytokine that promotes Th1-type responses, triggering interferon-γ production by natural killer (NK) cells, CD4 + T cells and CD8 + T cells, thereby exhibiting robust antitumor activity. In this study, we constructed two recombinant HSV-1, oHSV-GMCSF and oHSV-IL12, and evaluated their antitumor effects, alone or in combination, in H22 murine hepatocellular carcinoma (HCC) model. Strikingly, oHSV-IL12 monotherapy achieved complete tumor eradication, surpassing the efficacy of oHSV-GMCSF. RNA sequencing analysis revealed that oHSV-IL12 treatment enhanced intratumoral lymphocyte infiltration and activation while upregulating immune-related genes and pathways. Notably, the oHSV-IL12 monotherapy showed comparable therapeutic outcomes to the combination of oHSV-GMCSF and oHSV-IL12 in both rechallenge and survival experiments. These findings position oHSV-IL12 as a promising novel candidate for HCC immunotherapy.
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