The median time of survival for patients with the acquired immune deficiency syndrome diagnosed with primary central nervous system lymphoma (AIDS PCNSL) is less than four months, despite radio- and chemotherapy and recent improvements in the suppression of HIV-1 replication. Essentially no advances have been made in the clinical management of this disorder since its initial characterization in 1991 as a lymphoma associated with the Epstein-Barr virus (EBV) in virtually 100 percent of cases. Death in patients with AIDS PCNSL results as often from therapy-induced toxicity and complications of AIDS as it does from progression of the PCNSL. To the best of our knowledge, an in vivo preclinical animal model to explore novel strategies for the treatment of AIDS PCNSL has not been described. The current proposal is a revised application. In our initial proposal, there was considerable enthusiasm for our discovery and characterization of Fas expression on AIDS PCNSL in the absence of Fas expression in human brain parenchyma, and our single specific aim to develop an animal model of PCNSL to explore anti-Fas therapy. Over the last year our laboratory has worked to successfully develop a model of human PCNSL in the nude rat through a multidisciplinary collaboration involving several investigators at our university. The model utilizes human EBV+ B cell tumors that arise spontaneously in the setting of immune deficiency to implant into the CNS of the nude NIH rat. Within 13 days of implantation, the rat develops irreversible neurologic symptoms from an expanding tumor mass within the CNS. Histologic evaluation at autopsy reveals an infiltrating human EBV+ B cell tumor. Magnetic resonance imaging is used to document progression in tumor growth and provide accurate assessment of tumor volume. Commercial instrumentation allows reproducible implantation and therapeutic delivery into the rat CNS that is comparable to delivery of CNS therapies in humans. The first specific aim of the revised proposal will focus on refinement of the preclinical animal model to best assess toxicity and efficacy of novel antitumor strategies in vivo. We hypothesize that novel therapies which target EBV+ lymphoma cells in vitro can be meaningfully explored in a preclinical in vivo animal model of PCNSL prior to early clinical development in patients with AIDS PCNSL. The model should, therefore, assist in determining which in vitro observations are too toxic or simply ineffective to pursue in vivo, and provide support for the transition of promising basic observations to clinical trials for the treatment of AIDS PCNSL. In the second and third specific aims of this revised proposal, two such in vitro observations will be pursed in the in vivo animal model: 1) a combination of antiviral therapy and cytokine therapy that induces apoptosis of EBV+ cell lines in vitro and has shown promising results in a few patients with AIDS PCNSL in vivo, and 2) anti-Fas therapy that induces apoptosis of AIDS PCNSL in vitro. The limitations of the animal model preclude its use for studying the pathogenesis of AIDS PCNSL.
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