Page 111 - Haematologica-April 2018

Hodgkin Lymphoma
CD83 is a new potential biomarker and therapeutic target for Hodgkin lymphoma
Ziduo Li,1,2 Xinsheng Ju,1,2 Kenneth Lee,2,3 Candice Clarke,3 Jennifer L. Hsu,1,2 Edward Abadir,1,2 Christian E. Bryant,1,4 Suzanne Pears,5 Neroli Sunderland,5 Scott Heffernan,5 Annemarie Hennessy,5 Tsun-Ho Lo,1,2 Geoffrey A. Pietersz,6,7 Fiona Kupresanin,1 Phillip D. Fromm,1,2 Pablo A. Silveira,1,2 Con Tsonis,1 Wendy A. Cooper,2,8,9 Ilona Cunningham,10 Christina Brown,2,4
Ferrata Storti Foundation
Georgina J. Clark1,2 and Derek N.J. Hart,1,2
1Dendritic Cell Research, ANZAC Research Institute, Sydney; 2Sydney Medical School, University of Sydney; 3Department of Anatomical Pathology, Concord Repatriation General Hospital, Sydney; 4Institute of Haematology, Royal Prince Alfred Hospital, Sydney; 5Animal Facility, Royal Prince Alfred Hospital, Sydney; 6Burnet Institute, Melbourne; 7Baker Heart and Diabetes Institute, Melbourne; 8Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney; 9School of Medicine, University of Western Sydney and 10Department of Haematology, Concord Repatriation General Hospital, Sydney, Australia
ABSTRACT
Chemotherapy and hematopoietic stem cell transplantation are effective treatments for most Hodgkin lymphoma patients, how- ever there remains a need for better tumor-specific target therapy in Hodgkin lymphoma patients with refractory or relapsed disease. Herein, we demonstrate that membrane CD83 is a diagnostic and ther- apeutic target, highly expressed in Hodgkin lymphoma cell lines and Hodgkin and Reed-Sternberg cells in 29/35 (82.9%) Hodgkin lymphoma patient lymph node biopsies. CD83 from Hodgkin lymphoma tumor cells was able to trogocytose to surrounding T cells and, interestingly, the trogocytosing CD83+T cells expressed significantly more programmed death-1 compared to CD83– T cells. Hodgkin lymphoma tumor cells secreted soluble CD83 that inhibited T-cell proliferation, and anti-CD83 antibody partially reversed the inhibitory effect. High levels of soluble CD83 were detected in Hodgkin lymphoma patient sera, which returned to normal in patients who had good clinical responses to chemotherapy confirmed by positron emission tomography scans. We generated a human anti-human CD83 antibody, 3C12C, and its toxin monomethyl auristatin E conjugate, that killed CD83 positive Hodgkin lymphoma cells but not CD83 negative cells. The 3C12C antibody was tested in dose escalation studies in non-human primates. No toxicity was observed, but there was evidence of CD83 positive target cell depletion. These data establish CD83 as a potential biomarker and therapeutic tar- get in Hodgkin lymphoma.
Introduction
Hodgkin lymphoma (HL) is a B-cell neoplasm that is defined by the presence of Hodgkin Reed-Sternberg cells (HRS). During recent decades, the long-term survival of HL patients has increased, and most patients can be cured through multi-agent chemotherapy, radiotherapy and/or hematopoietic stem cell transplantation.1 Despite this, 25-30% of patients experience either disease relapse or are refractory to chemotherapy and their survival is substantially reduced, especially for elderly patients who do not tolerate intensive therapy.2,3 New targeted therapies for HL are warranted, especially for refractory/relapsed patients and elderly patients where limiting treatment toxicity is essential. Recent studies have focused on the devel- opment of therapeutic agents that target HL-specific antigens or regulate the natu- ral immune response in patients. Antibodies targeting HL surface antigens such as CD25 (daclizumab),4 CD20 (rituximab, tositumomab)5,6 or CD30 (brentuximab)7-10 have shown promising results. The programmed death-1(PD-1)/PD-ligand 1 (PD- L1) checkpoint inhibitors (nivolumab, pembrolizumab), that reverse the suppres-
Haematologica 2018 Volume 103(4):655-665
Correspondence:
xinsheng.ju@sydney.edu.au
Received: August 22, 2017. Accepted: January 10, 2018. Pre-published: January 19, 2018.
doi:10.3324/haematol.2017.178384
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/4/655
©2018 Ferrata Storti Foundation
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