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Updated: Jan 18, 2026
Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo
Published on: January 7, 2019
Engineered oncolytic herpes simplex virus expressing interleukin 12 suppresses tumorigenicity of hepatocellular
Jingwen Lv1, Wei Zhu1, Xin Xie1
1School of Pharmacy, Yantai University, Yantai, Shandong, 264005, China.
Abstract:
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.
Insights
A novel oncolytic virus, oHSV-IL12, demonstrated complete tumor eradication in a hepatocellular carcinoma model. This interleukin-12 expressing virus outperformed oHSV-GMCSF, offering a promising new immunotherapy strategy.
Area of Science:
- Oncolytic virotherapy
- Immunotherapy
- Hepatocellular carcinoma research
Background:
- Oncolytic viruses (OVs) offer dual anticancer mechanisms: direct tumor lysis and immune stimulation via transgenes.
- Talimogene laherparepvec (T-VEC), an OV secreting granulocyte-macrophage colony-stimulating factor (GM-CSF), is FDA-approved for melanoma but has limitations.
- Interleukin-12 (IL-12) is a potent cytokine that enhances Th1 immune responses and exhibits strong antitumor activity.
Purpose of the Study:
- To construct and evaluate recombinant herpes simplex virus type 1 (HSV-1) vectors expressing IL-12 (oHSV-IL12) and GM-CSF (oHSV-GMCSF).
- To assess the monotherapy and combination efficacy of oHSV-IL12 and oHSV-GMCSF in a murine hepatocellular carcinoma (HCC) model.
- To investigate the underlying immune mechanisms of oHSV-IL12 therapy.
Main Methods:
- Construction of two recombinant HSV-1 vectors: oHSV-GMCSF and oHSV-IL12.
- Evaluation of antitumor effects in the H22 murine HCC model via monotherapy and combination treatments.
- RNA sequencing analysis to assess intratumoral immune cell infiltration, activation, and gene expression changes.
Main Results:
- oHSV-IL12 monotherapy achieved complete tumor eradication in the HCC model, outperforming oHSV-GMCSF.
- RNA sequencing revealed that oHSV-IL12 significantly enhanced intratumoral lymphocyte infiltration and activation.
- oHSV-IL12 monotherapy demonstrated therapeutic outcomes comparable to the combination therapy in rechallenge and survival studies.
Conclusions:
- oHSV-IL12 exhibits potent antitumor activity as a monotherapy, surpassing the efficacy of oHSV-GMCSF in the H22 HCC model.
- IL-12-expressing oncolytic HSV-1 is a promising candidate for hepatocellular carcinoma immunotherapy.
- Further development of oHSV-IL12 holds potential for enhancing cancer treatment strategies.
