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Sub-category:
Molecular/Ligand Targeted Therapies
Category:
Biologic and Targeted Therapies
Meeting:
2002 ASCO Annual Meeting
Abstract No:
26
Citation:
Proc Am Soc Clin Oncol 21: 2002 (abstr 26)
Author(s):
Robert A Baiocchi, Ruoqi Peng, Sameek Roychowdhury, Srinivas Vourganti, Darshna Bhatt, Taryn Sekula, John Grecula, Charles F Eisenbeis, Pierluigi Porcu, Michael A Caligiuri, The Ohio State University, Columbus, OH.
Abstract:
Primary central nervous system lymphomas (PCNSL) that arise in immune deficient patients are aggressive B cell neoplasms universally associated with the Epstein-Barr virus (EBV). PCNSL has a poor prognosis with a mean survival of less than 4 months despite aggressive treatment. We have developed an animal model of EBV+ PCNSL to explore novel strategies specifically targeting EBV-infected B lymphoblasts in vivo. Stereotactic implantation of EBV-transformed lymphoblastoid cell lines (LCL) into the caudate nucleus of the nude rat results in a lethal CNS tumor burden manifested by the onset of focal neurologic symptoms within 21 days. Histologic evaluation at autopsy reveals a multifocal, perivascular human EBV+ lymphoblastic B cell infiltrate displaying a latency type III EBV gene expression profile, a normal karyotype and abundant expression of the bcl-2 protein, similar to the PCNSL that arise in immune deficient patients. The antiviral agents, 3-azido-3-deoxythymidine (AZT) and ganciclovir (GCV), induce apoptosis in EBV+ LCL in vitro in a dose dependent fashion. Furthermore, low-dose irradiation (XRT, 300cGy) of LCLs results in upregulation of the EBV thymidine kinase (vTK) transcript and sensitization to antiviral-induced apoptosis. In the nude rat model, improved survival is seen with combination antiviral-XRT therapy compared to either antiviral therapy or XRT alone. XRT induces EBV-vTK mRNA expression in EBV+ PCNSL tumors in a dose-dependent fashion, which may explain the observed beneficial effect of combined antiviral-XRT therapy in vivo. We have found abundant vTK mRNA expression in a biopsy specimen from a patient with EBV+ post transplant lymphoproliferative disease (PTLD) restricted to the CNS. Despite progressive lymphoma after withdrawal of immunosuppression, this patient achieved a durable, complete response after therapy with high dose AZT and GCV, and remains in remission on oral maintenance AZT/GCV therapy 3 years after diagnosis. These results suggest that novel, EBV-specific therapies can be effectively explored in vivo using a preclinical animal model of human EBV+ PCNSL, with subsequent translation to patients with EBV+ PCNSL.
 Associated Presentation(s):
Other Abstracts in this Sub-Category:
Abstracts by Robert A Baiocchi:
Presentations by Robert A Baiocchi:
Educational Book Manuscripts by Robert A Baiocchi:
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