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Epstein–Barr virus-targeted therapy in nasopharyngeal carcinoma

  • Original Article – Clinical Oncology
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Purpose

Despite successful primary treatment of nasopharyngeal carcinoma (NPC), the incidence of distant metastasis remains 25–34 %. Treatment options are limited, and survival is poor. Intratumoural Epstein–Barr virus (EBV) was used as treatment target. In NPC, EBV is present in a latent state, expressing only few non-immunogenic viral products. Gemcitabine and valproic acid can trigger EBV to the lytic state, wherein viral kinases are expressed, making EBV-positive tumour cells susceptible for antiviral therapy with, i.e. valganciclovir, and inducing an EBV-specific immune response.

Methods

This drug combination was applied in eight patients with EBV-positive NPC, refractory to conventional treatment. The primary endpoints were safety, tolerability and clinical response. Secondary endpoint was to get proof of concept based on biomarkers, i.e. pharmacokinetics, EBV-DNA load in whole blood and nasopharyngeal brushes, EBV-RNA profiling for proof of lytic induction, EBV-IgG and EBV-IgA levels and diversity and EBV-specific T cell response.

Results

The best observed clinical response was partial in two patients (25 %) and stable disease in three patients (37.5 %). The median survival was 9 months (95 % confidence interval 7–17 months). Effective dose levels were reached. Peaking of EBV-DNA loads in blood and brush proved the biological effect on EBV during most treatment cycles. In one patient, RNA profiling confirmed lytic EBV induction. EBV-IgG and EBV-IgA antibody levels were already high before treatment and did not change during treatment. No changes in EBV-specific T cell response were detected.

Conclusion

The treatment was safe with manageable side effects, clinical response was observed, and viral activation corroborated.

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Acknowledgments

This study was supported by Grant ZonMW 95110069 from the Netherlands Government and Grants KWF VU2011-4555, KWF-VU2010-4809 from the Netherlands Cancer Society.

Conflict of interest

The authors declare that they have no conflict of interest.

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Author notes

    Authors and Affiliations

    1. Department of Head and Neck Surgery and Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands

      Sharon D. Stoker, Maarten A. Wildeman & I. Bing Tan

    2. Department of Pathology, VU University Medical Centre, Amsterdam, The Netherlands

      Zlata Novalić, Sandra A. W. M. Verkuijlen, Hedy Juwana, Astrid E. Greijer & Jaap M. Middeldorp

    3. Department of Otolaryngology, Academic Medical Centre, Amsterdam, The Netherlands

      Maarten A. Wildeman

    4. Department of Pharmacy and Pharmacology, Netherlands Cancer Institute, Amsterdam, The Netherlands

      Alwin D. R. Huitema

    5. Department of Maxillofacial Surgery, Academic Medical Centre, Amsterdam, The Netherlands

      I. Bing Tan

    6. Ear Nose and Throat Department, Faculty of Medicine/Dr. Sardjito Hospital, Gadjah Mada University, Yogyakarta, Indonesia

      I. Bing Tan

    7. Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands

      Jan Paul de Boer

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    1. Sharon D. Stoker
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    Correspondence to Sharon D. Stoker.

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    Sharon D. Stoker and Zlata Novalić have contributed equally.

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    Stoker, S.D., Novalić, Z., Wildeman, M.A. et al. Epstein–Barr virus-targeted therapy in nasopharyngeal carcinoma. J Cancer Res Clin Oncol 141, 1845–1857 (2015). https://doi.org/10.1007/s00432-015-1969-3

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