Experimental treatment of Epstein-Barr virus-associated primary central nervous system lymphoma.
Primary central nervous system lymphoma (PCNSL) that arises in immune-deficient patients is an aggressive B-cell neoplasm that is universally associated with the EBV. Patients with EBV(+) PCNSL face a particularly poor prognosis with median survival times of 2-12 months despite aggressive management with radiation therapy. We have developed a preclinical model of EBV(+) PCNSL to explore strategies that specifically target EBV-infected B lymphoblasts in vivo. Stereotactic implantation of EBV-transformed human lymphoblastoid B-cell lines into the caudate nucleus of the nude rat resulted in lethal CNS tumor burden manifested by the onset of focal neurological symptoms within 21 days. Histological evaluation at autopsy revealed a multifocal, perivascular human EBV(+) lymphoblastic B-cell infiltrate that displayed a latency type III EBV gene expression profile similar to PCNSL that develops in some immune-deficient patients. Radiation (1600 cGy) of lymphoblastoid B-cell lines resulted in up-regulation of the EBV thymidine kinase (EBV-TK) transcript and sensitization of these cells to drug-induced apoptosis using nucleoside analogs. Enhanced expression of EBV-TK mRNA in EBV(+) PCNSL tumors by radiation therapy occurred in a dose-dependent fashion. In vivo trials using the nude rat PCNSL model demonstrated significantly improved mean survival time (MST) with single fraction whole-brain radiotherapy (WBRT) and antiviral therapy consisting of zidovudine (AZT) and ganciclovir (GCV; MST 41.3 +/- 3.3 days; P = 0.05), compared with either antiviral therapy (MST 32.1 +/- 1.1 days) or WBRT alone (MST 22 +/- 0.8 days). We found constitutive and abundant EBV-TK mRNA expression in a stereotactic core biopsy specimen from a solid organ transplant patient with EBV(+) PCNSL. Withdrawal of immunosuppression did not result in disease regression. This patient achieved a complete response after therapy with high-dose AZT and GCV in the absence of WBRT, and remains in remission on oral maintenance AZT/GCV therapy 3 years after diagnosis. These results suggest that antiviral therapies can be effectively explored in vivo using a preclinical animal model of human EBV(+) PCNSL with subsequent translation to patients with EBV(+) PCNSL.
Roychowdhury
Sameek
S
Department of Molecular Virology, Immunology, Medical Genetics, The Ohio State University, Columbus, Ohio, 43210, USA.
Peng
Ruoqi
R
Baiocchi
Robert A
RA
Bhatt
Darshna
D
Vourganti
Srinivas
S
Grecula
John
J
Gupta
Nilendu
N
Eisenbeis
Charles F
CF
Nuovo
Gerard J
GJ
Yang
Weilian
W
Schmalbrock
Petra
P
Ferketich
Amy
A
Moeschberger
Melvin
M
Porcu
Pierluigi
P
Barth
Rolf F
RF
Caligiuri
Michael A
MA
D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D001932:Brain Neoplasms / Q000378:metabolism / Q000628:therapy* / Q000821:virology*; D003131:Combined Modality Therapy; D020031:Epstein-Barr Virus Infections / Q000150:complications / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D015774:Ganciclovir / Q000493:pharmacokinetics / Q000494:pharmacology; D004854:Herpesvirus 4, Human / Q000201:enzymology / Q000235:genetics / Q000528:radiation effects; D006801:Humans; D016030:Kidney Transplantation / Q000009:adverse effects; D016393:Lymphoma, B-Cell / Q000378:metabolism / Q000628:therapy* / Q000821:virology*; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D013937:Thymidine Kinase / Q000096:biosynthesis / Q000235:genetics; D015854:Up-Regulation / Q000528:radiation effects; D023041:Xenograft Model Antitumor Assays; D015215:Zidovudine / Q000493:pharmacokinetics / Q000494:pharmacology
D000998:Antiviral Agents; D012333:RNA, Messenger; D015215:Zidovudine; D013937:Thymidine Kinase; D015774:Ganciclovir