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Targeted Therapy for Glioblastoma Multiforme Neoplastic Meningitis with Intrathecal Delivery of an Oncolytic Recombinant Poliovirus

Authors' Affiliations: ¹ Division of Neurosurgery, Department of Surgery; Departments of ² Molecular Genetics and Microbiology and ³ Pathology, Duke University Medical Center, Durham, North Carolina; and ⁴ Center of Biologics Evaluation and Research, Food and Drug Administration, Rockville, Maryland

Requests for reprints: John H. Sampson, Division of Neurosurgery, Duke University Medical Center, Box 3050, Durham, NC 27710. Phone: 919-684-9041; Fax: 919-684-9045; E-mail: john.sampson{at}duke.edu.

Purpose: The toxicity and antitumor activity of regional intrathecal delivery of an oncolytic recombinant poliovirus, PVS-RIPO, was evaluated in rodent models of glioblastoma multiforme neoplastic meningitis.

Experimental Design: To evaluate for toxicity, PVS-RIPO was administered into the spinal cord of transgenic mice that express the human poliovirus receptor, CD155, and into the intrathecal space of athymic rats without tumor. To evaluate efficacy, two different doses of PVS-RIPO were administered intrathecally 3 days after athymic rats were inoculated intrathecally with an aggressive human glioblastoma multiforme xenograft.

Results: No clinical or histologic evidence of toxicity was found. In efficacy studies, median survival was increased by 174.47% from 8.5 days in the group treated with UV light-inactivated virus to 15 days in the rats treated with 1.0 x 10⁷ plaque-forming units (pfu) of PVS-RIPO (P < 0.0001). A similar increase in median survival was seen in the group receiving 1.0 x 10⁹ pfu PVS-RIPO (P < 0.0001); however, there was no statistically significant dose-response relationship (P = 0.345). In addition, 1 of 10 rats in lower-dose PVS-RIPO–treated group and 3 of 10 rats in higher-dose PVS-RIPO–treated group survived >60 days after tumor cell inoculation and had no evidence of residual tumor at autopsy.

Conclusion: These results suggest that intrathecal treatment with PVS-RIPO may be useful for treatment of neoplastic meningitis in patients with glioblastoma multiforme and provides a rationale for clinical trials in this area.

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