Adenoviral-Mediated Thymidine Kinase Gene Transfer into the Primate Brain Followed by Systemic Ganciclovir: Pathologic, Radiologic, and Molecular Studies

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Abstract
Transduction of experimental gliomas with the herpes simplex virus thymidine kinase gene (HSV-tk) using a replication-defective adenoviral vector (ADV/RSV-tk) confers sensitivity to ganciclovir (GCV) leading to tumor destruction and prolonged host survival in rodents. To determine treatment tolerance prior to clinical trials, we conducted toxicity studies in 6 adult baboons (Papio sp.). The animals received intracerebral injections of either a high dose of ADV/RSV-tk [1.5 × 109 plaque-forming units (pfu)] with or without GCV, or a low dose of ADV/RSV-tk (7.5 × 107 pfu) with GCV. The low dose corresponded to the anticipated therapeutic dose; the high dose was expected to be toxic. Magnetic resonance imaging (MRI) of the brain was obtained before treatment and at 3 and 6 weeks after treatment. Animals receiving the high-dose vector and GCV either died or became moribund and required euthanasia during the first 8 days of treatment. Necropsies revealed cavities of coagulative necrosis at the injection sites. Animals receiving only the high-dose vector were clinically normal; however, lesions were detected with MRI at the injection sites corresponding to cystic cavities at necropsy. Animals receiving the low-dose vector and GCV were clinically normal, exhibited small MRI abnormalities, and, although no gross lesions were present at necropsy, microscopic foci of necrosis were present. The vector sequence was detected by polymerase chain reaction (PCR) at the injection sites and in non-adjacent central nervous system tissue in all animals. Recombinant DNA sequence was detected outside of the nervous system in some animals, and persisted up to 6 weeks. The viral vector injections stimulated the production of neutralizing antibodies in the animals. No shedding of the vector was found in urine, feces, or serum 7 days after intracerebral injection. This study suggests that further investigations including clinical toxicity trials of this form of brain tumor therapy are warranted. We examined the clinical, radiologic, and pathologic toxicity in baboons of intracerebral injection of replication-defective adenovirus bearing thymidine kinase followed by intravenous ganciclovir (GCV) administration. A high dose of vector produced significant neurotoxicity that was seriously potentiated by GCV administration. A lower dose of vector corresponding to the upper range of anticipated therapeutic dosages in humans with brain tumors, produced minimal toxicity even when followed by GCV.