Journal
CANCER LETTERS
Volume 518, Issue -, Pages 49-58Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2021.06.005
Keywords
Oncolytic virus; HSV-1; PD-1; Tumor microenvironment
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Funding
- Top Talents Program for One Case One Discussion of Shandong Province
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HSV-aPD-1, a recombinant herpes simplex virus type 1 carrying anti-PD-1 monoclonal antibodies, demonstrates enhanced anti-tumor immune responses and T-cell infiltration, leading to effective tumor inhibition and potential clinical applications in tumors resistant to immune checkpoint inhibitors.
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 antiPD-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.
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