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The efficacy of a third-generation oncolytic herpes simplex viral therapy for an HPV-related uterine cervical cancer model

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Abstract

Purpose

Cervical cancer is the fourth most common cancer in women and the seventh most common of all human cancers. Development of new treatments is mandatory to improve the outcome of this disease. Replication-selective oncolytic herpes simplex viruses (HSVs) have emerged as a new platform for cancer therapy. The therapeutic potential of a triple-mutated oncolytic HSV (T-01) for human papillomavirus (HPV)-related cervical cancer was evaluated with immunodeficient and immune-complete models.

Methods

(1) The in vitro efficacy of T-01 on human cervical cancer cell lines, TC-1, HeLa, CaSki, and SKG IIIa was evaluated. (2) The in vivo efficacy of T-01 was examined in human HeLa xenograft and TC-1 syngeneic models of human cervical cancer. After flank tumors reached 5 mm in diameter, the first intratumoral (i.t.) administration of T-01 was performed. Intratumoral administration of T-01 was performed with a 5 day interval a total of 6 times.

Results

In the in vitro study, T-01 was highly cytotoxic for all cell lines (48 h after infection with T-01 at 1 × 105 PFU, T-01 killing HeLa: 67.5%, Caski: 62.8%, SKG IIIa: 43.2%). Furthermore, in the human HeLa xenograft and TC-1 syngeneic models, T-01 resulted in a significant reduction of tumor growth. In addition, tumor-bearing mice treated with T-01 showed significantly increased numbers of CD8 + T-cells precursors than the control mice (p = 0.03).

Conclusions

These results demonstrate that T-01 has cytotoxic efficacy and inhibited against HPV-related cervical cancer cells. These findings indicate that T-01 has therapeutic potential for HPV-related cervical cancer.

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References

  1. Cancer. IAfRo CANCER FACT SHEETS: CERVICAL CANCER. https://gco.iarc.fr/today/data/pdf/fact-sheets/cancers/cancer-fact-sheets-16.pdf. Accessed July 11 2019

  2. Continue NCCN Guidelines Panel Disclosures Emily Wyse Patient Advocate NCCN Guidelines Version 2.2018 Cervical Cancer. https://www.nccn.org/professionals/physician_gls/pdf/cervical.pdf.

  3. Martuza RL, Malick A, Markert JM et al (1991) Experimental therapy of human glioma by means of a genetically engineered virus mutant. Science 252(5007):854–856

    Article  CAS  Google Scholar 

  4. Fukuhara H, Ino Y, Todo T (2016) Oncolytic virus therapy: a new era of cancer treatment at dawn. Cancer Sci 107(10):1373–1379. https://doi.org/10.1111/cas.13027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Todo T (2012) Active immunotherapy: oncolytic virus therapy using HSV-1. Adv Exp Med Biol 746:178–186

    Article  CAS  Google Scholar 

  6. Todo T, Martuza RL, Rabkin SD et al (2001) Oncolytic herpes simplex virus vector with enhanced MHC class I presentation and tumor cell killing. Proc Natl Acad Sci USA 98(11):6396–6401. https://doi.org/10.1073/pnas.101136398

    Article  CAS  PubMed  Google Scholar 

  7. Scheffner M, Werness BA, Huibregtse JM et al (1990) The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell 63:1129–1136. https://doi.org/10.1016/0092-8674(90)90409-8

    Article  CAS  PubMed  Google Scholar 

  8. Dyson N, Howley PM, Münger K et al (1989) The human papilloma virus-16 E7 oncoprotein is able to bind to the retinoblastoma gene product. Science 243:934–937. https://doi.org/10.1126/science.2537532

    Article  CAS  PubMed  Google Scholar 

  9. Fernandes J (2016) Oncogenes: the passport for viral oncolysis through PKR inhibition. Biomark Cancer 8:101–110

    Article  CAS  Google Scholar 

  10. Coukos G, Makrigiannakis A, Kang EH et al (2000) Oncolytic herpes simplex virus-1 lacking ICP34.5 induces p53-independent death and is efficacious against chemotherapy-resistant ovarian cancer. Clin Cancer Res 6:3342–3353

    CAS  PubMed  Google Scholar 

  11. Matsushima H, Kaibori M, Hatta M et al (2019) Efficacy of a third-generation oncolytic herpes simplex virus in neuroendocrine tumor xenograft models. Oncotarget 10:7132–7141. https://doi.org/10.18632/oncotarget.27391

    Article  PubMed  PubMed Central  Google Scholar 

  12. Lin KY, Guarnieri FG, Staveley-O’Carroll KF et al (1996) Treatment of established tumors with a novel vaccine that enhances major histocompatibility class II presentation of tumor antigen. Cancer Res 56:21–26

    CAS  PubMed  Google Scholar 

  13. Tseng CW, Hung CF, Alvarez RD et al (2008) Pretreatment with cisplatin enhances E7-specific CD8+ T-Cell-mediated antitumor immunity induced by DNA vaccination. Clin Cancer Res 14:3185–3192. https://doi.org/10.1158/1078-0432.CCR-08-0037

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Sundaresan P, Hunter WD, Martuza RL et al (2000) Attenuated, replication-competent herpes simplex virus type 1 mutant G207: safety evaluation in mice. J Virol 74:3832–3841

    Article  CAS  Google Scholar 

  15. Blank SV, Rubin SC, Coukos G et al (2002) Replication-selective herpes simplex virus type 1 mutant therapy of cervical cancer is enhanced by low-dose radiation. Hum Gene Ther 13:627–639. https://doi.org/10.1089/10430340252837224

    Article  CAS  PubMed  Google Scholar 

  16. Desaintes C, Hallez S, Van Alphen P et al (1992) Transcriptional activation of several heterologous promoters by the E6 protein of human papillomavirus type 16. J Virol 66:325–333

    Article  CAS  Google Scholar 

  17. Pol J, Bloy N, Obrist F et al (2014) Trial watch: oncolytic viruses for cancer therapy. Oncoimmunology 3:e28694. https://doi.org/10.4161/onci.28694

    Article  PubMed  PubMed Central  Google Scholar 

  18. Piersma SJ, Jordanova ES, van Poelgeest MI et al (2007) High number of intraepithelial CD8+ tumor-infiltrating lymphocytes is associated with the absence of lymph node metastases in patients with large early-stage cervical cancer. Cancer Res 67:354–361. https://doi.org/10.1158/0008-5472.CAN-06-3388

    Article  CAS  PubMed  Google Scholar 

  19. Jordanova ES, Gorter A, Ayachi O et al (2008) Human leukocyte antigen class I, MHC class I chain-related molecule A, and CD8+/regulatory T-cell ratio: which variable determines survival of cervical cancer patients? Clin Cancer Res 14:2028–2035. https://doi.org/10.1158/1078-0432.CCR-07-4554

    Article  CAS  PubMed  Google Scholar 

  20. Fukuhara H, Todo T (2007) Oncolytic herpes simplex virus type 1 and host immune responses. Curr Cancer Drug Targets 7:149–155

    Article  CAS  Google Scholar 

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Acknowledgements

The authors would like to thank Professor T-C. Wu for providing the TC-1 cell line and for helpful information regarding this line. The authors would also like to thank Professor T. Todo and Dr Y. Ino for providing the T-01 virus and for helpful information regarding this virus. This work was supported by JSPS KAKENHI Grant-in-Aid for Challenging Exploratory Research, Number JP16K15711.

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Iwate Medical University School of Medicine, 2-1-1 Idaidori, Yahaba-chou, Shiwa, Iwate, 028-3695, Japan

    Masahiro Kagabu, Tatsunori Saito, Yuki Miura, Ryosuke Takeshita, Kazuyuki Murakami, Hideki Kawamura, Tsukasa Baba & Toru Sugiyama

  2. Division of Infectious Diseases and Immunology, Department of Microbiology, Iwate Medical University School of Medicine, 1-1-1 Idaidori, Yahaba-cho, Shiwa, Iwate, 028-3694, Japan

    Naoto Yoshino

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  1. Masahiro Kagabu
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  2. Naoto Yoshino
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All authors contributed to data analysis, drafting and revising the article, gave final approval of the version to be published, and agree to be accountable for all aspects of the work.

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Correspondence to Masahiro Kagabu.

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Kagabu, M., Yoshino, N., Saito, T. et al. The efficacy of a third-generation oncolytic herpes simplex viral therapy for an HPV-related uterine cervical cancer model. Int J Clin Oncol 26, 591–597 (2021). https://doi.org/10.1007/s10147-020-01823-6

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  • DOI: https://doi.org/10.1007/s10147-020-01823-6

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