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Antitumor effects of IL-12 and GM-CSF co-expressed in an engineered oncolytic HSV-1

Gene Therapy volume 28, pages 186–198 (2021)Cite this article

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Abstract

Oncolytic viruses selectively replicate and destroy cancer cells while sparing normal cells, prompting their recognition as promising antitumor agents. Herpes simplex virus (HSV) is suitable as an anticancer agent, given its considerable therapeutic gene capacity and excellent safety profile in clinical trials. Interleukin (IL)-12 induces a Th1-type immune response that mediates interferon (IFN)-γ release from natural killer (NK), CD4+ and CD8+ T cells. Granulocyte-macrophage colony-stimulating factor (GM-CSF) induces the generation of antigen-presenting cells and promotes dendritic cell differentiation. We established a novel oncolytic HSV-1 (∆6/GM/IL12) co-expressing IL-12 and GM-CSF and tested its effects against a B16-F10 murine melanoma model. ∆6/GM/IL12 administration diminished tumor growth and prolonged survival compared to treatment with ∆6/GM or ∆6/IL12 expressing each individual cytokine. Flow cytometry and histological analysis showed increased activation of CD4+ and CD8+ T cells in ∆6/GM/IL12-treated mice. Enzyme-linked immunosorbent spot assay showed an increase in the phenotypically characterized IFN-γ-producing cell population in ∆6/GM/IL12-treated mice. Moreover, ∆6/GM/IL12 induced a B16-F10-specific cytotoxic immune response that enhanced IFN-γ production by CD3+CD8+ T cells. Therefore, IL-12 and GM-CSF from an engineered oncolytic HSV have a synergistic effect, boosting the immune response to increase their antitumor effects.

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Fig. 1: Construction of recombinant HSV-1 strains.
Fig. 2: Characterization of cytokine-expressing oHSV-1 strains.
Fig. 3: Antitumor effects and survival rates in B16-F10 tumor-bearing mice.
Fig. 4: Immune response to treatment with cytokine-expressing oHSV-1.
Fig. 5: Cancer cell-specific immune responses to cytokine-expressing oHSV-1 strains.
Fig. 6: Histology of tumors from mice injected with PBS, ∆6, ∆6/GM, ∆6/IL12, or ∆6/GM/IL12.

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Acknowledgements

We thank Professor David A. Leib (Geisel School of Medicine at Dartmouth) for providing us with the KOS-37 BAC and Cre-Vero cell lines.

Funding

This study was supported by the Basic Science Research Program of the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2016R1D1A1B03935312).

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Authors and Affiliations

  1. Laboratory of Gene Therapy, Department of Microbiology, CHA Bundang Medical Center, CHA University, Seongnam, Korea

    Kyoung-Ju Kim, Dahye Moon, Youngeun Yoo, Soyoung Kim & Kyung-Ju Choi

  2. Graduate School of the Department of Biomedical Science, CHA University, Seongnam, Korea

    Kyoung-Ju Kim, Dahye Moon, Yu Seong Lee, Youngeun Yoo & Kyung-Ju Choi

  3. Laboratory of Translational Immuno-Oncology, CHA University, Seongnam, Korea

    So Jung Kong, Yu Seong Lee, Chan Kim & Hong Jae Chon

  4. Medical Oncology, CHA Bundang Medical Center, CHA University, Seongnam, Korea

    So Jung Kong, Chan Kim & Hong Jae Chon

  5. Laboratory of Gene Therapy, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea

    Joo-Hang Kim

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Kim, KJ., Moon, D., Kong, S.J. et al. Antitumor effects of IL-12 and GM-CSF co-expressed in an engineered oncolytic HSV-1. Gene Ther 28, 186–198 (2021). https://doi.org/10.1038/s41434-020-00205-x

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