Emily Nickles1,2,3, Bhushan Dharmadhikari1,2,3, Li Yating1,2,3, Robert J Walsh4, Liang Piu Koh4, Michelle Poon4, Lip Kun Tan4, Ling-Zhi Wang5, Yvonne Ang4, Yugarajah Asokumaran4, Wan Qin Chong4, Yiqing Huang4, Kwok Seng Loh4, Joshua Tay, Ross Soo4, Mickey Koh6, Liam Pock Ho6, Marieta Chan6, Madelaine Niam6, Melissa Soh6, Yen Hoon Luah6, Chwee Ming Lim7, Nivashini Kaliaperumal8, Veonice B Au8, Najwa Binte Said Nasir Talib8, Reina Sng8, John E Connolly8,9, Boon Cher Goh10, Herbert Schwarz11,12,13. 1. Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. 2. Life Sciences Institute, Immunology Programme, National University of Singapore, Singapore, Singapore. 3. Immunology Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. 4. Department of Haematology-Oncology, National University Cancer Institute, National University Health System, Singapore, Singapore. 5. Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore. 6. Health Sciences Authority, Singapore, Singapore. 7. Department of Otolaryngology - Head and Neck Surgery, Singapore General Hospital, Singapore, Singapore. 8. Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore, Singapore. 9. Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. 10. Department of Haematology-Oncology, National University Cancer Institute, National University Health System, Singapore, Singapore. phcgbc@nus.edu.sg. 11. Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. phssh@nus.edu.sg. 12. Life Sciences Institute, Immunology Programme, National University of Singapore, Singapore, Singapore. phssh@nus.edu.sg. 13. Immunology Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. phssh@nus.edu.sg.
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.
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.
Authors: Carol S Leung; Michael A Maurer; Sonja Meixlsperger; Anne Lippmann; Cheolho Cheong; Jianmin Zuo; Tracey A Haigh; Graham S Taylor; Christian Münz Journal: Blood Date: 2013-01-07 Impact factor: 22.113
Authors: Beatris Mastelic-Gavillet; Klara Balint; Caroline Boudousquie; Philippe O Gannon; Lana E Kandalaft Journal: Front Immunol Date: 2019-04-11 Impact factor: 7.561
Authors: Raquel S Laureano; Jenny Sprooten; Isaure Vanmeerbeerk; Daniel M Borras; Jannes Govaerts; Stefan Naulaerts; Zwi N Berneman; Benoit Beuselinck; Kalijn F Bol; Jannie Borst; An Coosemans; Angeliki Datsi; Jitka Fučíková; Lisa Kinget; Bart Neyns; Gerty Schreibelt; Evelien Smits; Rüdiger V Sorg; Radek Spisek; Kris Thielemans; Sandra Tuyaerts; Steven De Vleeschouwer; I Jolanda M de Vries; Yanling Xiao; Abhishek D Garg Journal: Oncoimmunology Date: 2022-07-04 Impact factor: 7.723