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Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo
Published on: January 7, 2019
Enhanced anti-tumor response elicited by a novel oncolytic HSV-1 engineered with an anti-PD-1 antibody
Chao Tian1, Jiajia Liu2, Hua Zhou2
1Center of Biological Sciences, School of Advanced Interdisciplinary Studies, Peking University, Beijing, 100871, China; Beijing WellGene Company Ltd., Beijing, 100085, China.
Abstract:
Oncolytic viruses as cancer vaccines modulate the tumor microenvironment and act synergistically with immune checkpoint inhibitors to overcome resistance. Taking advantage of the loading capacity for exogenous genes, we generated a recombinant herpes simplex virus type 1 (HSV-1), HSV-aPD-1, carrying a full-length humanized anti-PD-1 monoclonal antibody (anti-PD-1 mAb) that replicates and expresses anti-PD-1 mAbs in tumor cells in vitro and in vivo. Its anti-tumor effect was assessed in human PD-1 knock-in mice by analyzing tumor inhibition, cell populations and RNA expression in tumors, and serum cytokine levels. Enhanced anti-tumor immune responses and T-cell infiltration were induced by HSV-aPD-1 compared with unloaded virus or anti-PD-1 therapy in both MC38 and B16-F10 models, resulting in improved treatment efficacy in the latter. Moreover, compared with unloaded HSV-1 or HSV-1 loaded with GM-CSF/IL-2 combined with anti-PD-1 mAbs, HSV-aPD-1 displayed similar therapeutic control of tumor growth. Finally, tumor RNAseq analysis in the B16-F10 model showed upregulated IFN pathway and antigen processing and presentation genes, and downregulated angiogenesis and cell adhesion genes, which all contribute to tumor inhibition. These findings indicate the clinical potential of HSV-aPD-1 as monotherapy or combination therapy, especially in tumors resistant to immune checkpoint inhibitors.
Insights
A novel oncolytic virus, HSV-aPD-1, engineered to express an anti-PD-1 antibody, enhances anti-tumor immunity and T-cell infiltration. This engineered virus shows promise for treating cancers resistant to current immunotherapies.
Area of Science:
- Oncolytic virotherapy
- Cancer immunotherapy
- Molecular oncology
Background:
- Oncolytic viruses can be engineered as cancer vaccines to modulate the tumor microenvironment.
- Synergy between oncolytic viruses and immune checkpoint inhibitors (ICIs) is crucial for overcoming treatment resistance.
- Recombinant herpes simplex virus type 1 (HSV-1) offers a platform for delivering therapeutic genes due to its large loading capacity.
Purpose of the Study:
- To generate a recombinant HSV-1 (HSV-aPD-1) capable of expressing a humanized anti-PD-1 monoclonal antibody (mAb).
- To evaluate the anti-tumor efficacy and immune-modulating effects of HSV-aPD-1 in preclinical cancer models.
- To assess the potential of HSV-aPD-1 as a monotherapy or in combination with other treatments for ICI-resistant tumors.
Main Methods:
- Construction of a recombinant HSV-1 (HSV-aPD-1) carrying a gene for a full-length humanized anti-PD-1 mAb.
- In vitro and in vivo replication and expression of anti-PD-1 mAb by HSV-aPD-1 in tumor cells.
- Assessment of anti-tumor effects in human PD-1 knock-in mice using MC38 and B16-F10 tumor models, analyzing tumor inhibition, immune cell populations, RNA expression, and serum cytokines.
Main Results:
- HSV-aPD-1 demonstrated enhanced anti-tumor immune responses and increased T-cell infiltration compared to unloaded virus or anti-PD-1 therapy alone.
- Improved treatment efficacy was observed with HSV-aPD-1 in the B16-F10 model.
- Tumor RNA sequencing revealed upregulated interferon (IFN) pathways, antigen processing and presentation genes, and downregulated angiogenesis and cell adhesion genes, contributing to tumor inhibition.
Conclusions:
- HSV-aPD-1 effectively replicates and expresses anti-PD-1 mAb, inducing potent anti-tumor immune responses.
- The engineered virus shows significant therapeutic potential as a monotherapy or combination therapy, particularly for tumors resistant to immune checkpoint inhibitors.
- HSV-aPD-1 represents a promising strategy for enhancing cancer immunotherapy by reprogramming the tumor microenvironment.
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