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Dendritic cell therapy with CD137L-DC-EBV-VAX in locally recurrent or metastatic nasopharyngeal carcinoma is safe and confers clinical benefit

  • Clinical Trial Report
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Abstract

Introduction

Epstein-Barr virus (EBV) is associated with nasopharyngeal carcinoma (NPC), and provides a target for a dendritic cell (DC) vaccine. CD137 ligand (CD137L) expressed on antigen presenting cells, costimulates CD137-expressing T cells, and reverse CD137L signaling differentiates monocytes to CD137L-DC, a type of DC, which is more potent than classical DC in stimulating T cells.

Methods

In this phase I study, patients with locally recurrent or metastatic NPC were administered CD137L-DC pulsed with EBV antigens (CD137L-DC-EBV-VAX).

Results

Of the 12 patients treated, 9 received full 7 vaccine doses with a mean administered cell count of 23.9 × 106 per dose. Treatment was well tolerated with only 4 cases of grade 1 related adverse events. A partial response was obtained in 1 patient, and 4 patients are still benefitting from a progression free survival (PFS) of currently 2–3 years. The mean pre-treatment neutrophil: lymphocyte ratio was 3.4 and a value of less than 3 was associated with prolonged median PFS. Progressors were characterized by a high frequency of naïve T cells but a low frequency of CD8+ effector T cells while patients with a clinical benefit (CB) had a high frequency of memory T cells. Patients with CB had lower plasma EBV DNA levels, and a reduction after vaccination.

Conclusion

CD137L-DC-EBV-VAX was well tolerated. The use of CD137L-DC-EBV-VAX is demonstrated to be safe. Consistent results were obtained from all 12 patients, indicating that CD137L-DC-EBV-VAX induces an anti-EBV and anti-NPC immune response, and warranting further studies in patients post effective chemotherapy.

Precis.

The first clinical testing of CD137L-DC, a new type of monocyte-derived DC, finds that CD137L-DC are safe, and that they can induce an immune response against Epstein-Barr virus-associated nasopharyngeal carcinoma that leads to tumor regression or prevents tumor progression.

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Acknowledgements

We are grateful to the patients who participated. We thank the many people who translated an initial PCR fragment to a clinical application, most notably Joachim Langstein, Daniela Drenkard, Shaqireen Kwajah and Zulkarnain Harfuddin. We thank the Life Sciences Institute flow cytometry core facility for excellent assistance. We thank Lingzhi Wang, Amelia Lau, and Shiwen Qiu for help with analysing EBV plasma DNA levels.

Funding

This research was supported by a grant (NMRC/BnB/018b/2015) from the National Medical Research Council, Singapore.

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Authors and Affiliations

  1. Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    Emily Nickles, Bhushan Dharmadhikari, Li Yating & Herbert Schwarz

  2. Life Sciences Institute, Immunology Programme, National University of Singapore, Singapore, Singapore

    Emily Nickles, Bhushan Dharmadhikari, Li Yating & Herbert Schwarz

  3. Immunology Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    Emily Nickles, Bhushan Dharmadhikari, Li Yating & Herbert Schwarz

  4. Department of Haematology-Oncology, National University Cancer Institute, National University Health System, Singapore, Singapore

    Robert J. Walsh, Liang Piu Koh, Michelle Poon, Lip Kun Tan, Yvonne Ang, Yugarajah Asokumaran, Wan Qin Chong, Yiqing Huang, Kwok Seng Loh, Ross Soo & Boon Cher Goh

  5. Health Sciences Authority, Singapore, Singapore

    Mickey Koh, Liam Pock Ho, Marieta Chan, Madelaine Niam, Melissa Soh & Yen Hoon Luah

  6. Department of Otolaryngology – Head and Neck Surgery, Singapore General Hospital, Singapore, Singapore

    Chwee Ming Lim

  7. Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore, Singapore

    Nivashini Kaliaperumal, Veonice B. Au, Najwa Binte Said Nasir Talib, Reina Sng & John E. Connolly

  8. Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA

    John E. Connolly

  9. Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore

    Ling-Zhi Wang

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  1. Emily Nickles
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Contributions

Conception and design: Herbert Schwarz, Boon Cher Goh. Financial support: Herbert Schwarz, Boon Cher Goh. Administrative support: Michelle Poon, Yvonne Ang, Yugarajah Asokumaran, Wan Qin Chong, Yiqing Huang, Kwok Seng Loh, Ross Soo. Provision of study materials: Emily Nickles, Bhushan Dharmadhikari, Li Yating, Lip Kun Tan, Mickey Koh, Liam Pock Ho, Marieta Chan, Madelaine Niam, Melissa Soh, Yen Hoon Luah. Provision of patients: Boon Cher Goh, Chwee Ming Lim, J. Walsh, Liang Piu Koh. Collection and assembly of data: Emily Nickles, Li Yating, Robert J. Walsh, Bhushan Dharmadhikari, John E. Connolly, Nivashini Kaliaperumal, Veonice B. Au. Data analysis and interpretation: Herbert Schwarz, Boon Cher Goh, Emily Nickles, Bhushan Dharmadhikari, Li Yating, John E. Connolly, Nivashini Kaliaperumal, Najwa Binte Said Nasir Talib, Reina Sg. Manuscript writing: Herbert Schwarz. Revision and final approval of manuscript: All authors.

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Correspondence to Boon Cher Goh or Herbert Schwarz.

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Emily Nickles and Bhushan Dharmadhikari authors contributed equally

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Nickles, E., Dharmadhikari, B., Yating, L. et al. Dendritic cell therapy with CD137L-DC-EBV-VAX in locally recurrent or metastatic nasopharyngeal carcinoma is safe and confers clinical benefit. Cancer Immunol Immunother 71, 1531–1543 (2022). https://doi.org/10.1007/s00262-021-03075-3

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