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A novel oncolytic virus engineered with PD-L1 scFv effectively inhibits tumor growth in a mouse model

Cellular & Molecular Immunology volume 16, pages 780–782 (2019)Cite this article

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The adoptive transfer of engineered chimeric antigen receptor (CAR) T cells has yielded impressive clinical results for targeting hematological cancers.1 However, the advancement of CAR T-cell therapy in solid tumors remains limited, due to the scarcity of tumor antigens that are deemed safe for targeting. Moreover, the requirement of patient-specific autologous T cells for the current standard treatment has also hampered its application. Oncolytic virus (OV) therapy has been classified as another form of novel immunotherapy. In particular, Talimogene laherparepvec (T-VEC, Imlygic), a genetically modified herpes simplex virus expressing GM-CSF, is the first OV-based drug approved by the US Food and Drug Administration.2 In addition, monoclonal antibodies targeting immune checkpoint molecules have also recently been used to make substantial progress in the treatment of cancer therapy. In particular, antibodies blocking the programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) pathway have displayed promising results in a wide variety of cancers and other diseases.3,4,5 A recent study found that T-VEC virotherapy combined with anti-PD-1 resulted in a high response rate in patients with metastatic melanoma in a phase 1b trial.6 Thus, in this study, we sought to generate an OV bearing an antibody against an immune checkpoint, PD-L1, and evaluated its ability to modulate anticancer effects in mice as well as in the immunosuppressive tumor microenvironment.

Vesicular stomatitis virus (VSV) preferentially replicates in cancer cells, which commonly exhibit defects in type I IFN signaling, making it an ideal oncolytic immunotherapy vector. Although laboratory strains of recombinant VSV are not usually pathogenic in humans, an attenuated VSV was generated as a therapeutic vector to avoid the potential for VSV to cause disease in humans. An M51R substitution in the VSV M gene has been reported to prevent VSV from inhibiting host gene expression, thus allowing cells to mount an antiviral response, as previously described.7 Therefore, we generated an M51R mutation in the M gene of the VSV viral backbone, and the attenuated virus (VSVM51R) was recovered in BHK cells.8 The viral replication curve indicated that VSVM51R replicated more slowly than the WT VSV-GFP virus in 293T cells, indicating its attenuation (Supplementary Data S1A). In Vero cells, which are type I IFN-deficient, VSVM51R replication was comparable with that of VSV-GFP (Supplementary Data S1B). Moreover, in mice intranasally infected with 107 pfu of the virus, VSVM51R exhibited substantially attenuated toxicity in vivo (Supplementary Data S1C). Taken together, these data indicate that we successfully generated an attenuated VSVM51R immunotherapy vector.

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References

  1. Porter, D. L. et al. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci. Transl. Med 7, 303ra139 (2015).

    Article  Google Scholar 

  2. Andtbacka, R. H. et al. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J. Clin. Oncol. 33, 2780–2788 (2015).

    Article  CAS  Google Scholar 

  3. Luo, L. et al. Selection and characterization of the novel anti-human PD-1 FV78 antibody from a targeted epitope mammalian cell-displayed antibody library. Cell. Mol. Immunol. 15, 146–157 (2018).

    Article  CAS  Google Scholar 

  4. Chen, L. & Han, X. Anti-PD-1/PD-L1 therapy of human cancer: past, present, and future. J. Clin. Invest 125, 3384–3391 (2015).

    Article  Google Scholar 

  5. Zhang, Y. et al. The altered PD-1/PD-L1 pathway delivers the ‘one-two punch’ effects to promote the Treg/Th17 imbalance in pre-eclampsia. Cell. Mol. Immunol. 15, 710–723 (2018).

    Article  CAS  Google Scholar 

  6. Ribas, A. et al. Oncolytic virotherapy promotes intratumoral T cell infiltration and improves anti-PD-1 immunotherapy. Cell 170, 1109–1119 (2017). e1110.

    Article  CAS  Google Scholar 

  7. Smedberg, J. R., Westcott, M. M., Ahmed, M. & Lyles, D. S. Signaling pathways in murine dendritic cells that regulate the response to vesicular stomatitis virus vectors that express flagellin. J. Virol. 88, 777–785 (2014).

    Article  Google Scholar 

  8. Lawson, N. D., Stillman, E. A., Whitt, M. A. & Rose, J. K. Recombinant vesicular stomatitis viruses from DNA. Proc. Natl Acad. Sci. USA 92, 4477–4481 (1995).

    Article  CAS  Google Scholar 

  9. Liu, K. et al. Structural basis of anti-PD-L1 monoclonal antibody avelumab for tumor therapy. Cell Res. 27, 151–153 (2017).

    Article  Google Scholar 

  10. Iwasa, M. et al. PD-L1 upregulation in myeloma cells by panobinostat in combination with interferon-gamma. Oncotarget 10, 1903–1917 (2019).

    Article  Google Scholar 

  11. Badovinac, V. P., Porter, B. B. & Harty, J. T. Programmed contraction of CD8(+) T cells after infection. Nat. Immunol. 3, 619–626 (2002).

    Article  CAS  Google Scholar 

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Acknowledgements

We greatly thank Ph.D. Tan in George Gao’s lab at the Institute of Microbiology, CAS for providing PD-L1 scFv. We also thank Prof. John Rose at Yale University for providing the VSV reverse genetic system. This work was supported by the National Natural Science Foundation of China (31470848, 31470880, 31670898, 81802083 and 31870867), State Key Laboratory of Veterinary Biotechnology Foundation (SKLVBF201916), and Jiangsu Provincial Innovative Research Team, the Priority Academic Program Development of Jiangsu Higher Education Institutions.

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  1. Jiangsu Key Laboratory of Infection and Immunity, The Institutes of Biology and Medical Sciences, Soochow University, 199 Ren-Ai Road, Suzhou, 215123, Jiangsu, China

    Chuanjian Wu, Manman Wu, Minglong Liang, Sidong Xiong & Chunsheng Dong

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  1. Chuanjian Wu
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Correspondence to Sidong Xiong or Chunsheng Dong.

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Wu, C., Wu, M., Liang, M. et al. A novel oncolytic virus engineered with PD-L1 scFv effectively inhibits tumor growth in a mouse model. Cell Mol Immunol 16, 780–782 (2019). https://doi.org/10.1038/s41423-019-0264-7

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