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Oncolytic Activity of the E1B-55 kDa-deleted Adenovirus ONYX-015 Is Independent of Cellular p53 Status in Human Malignant Glioma Xenografts¹

Department of Pediatrics [B. G., J. G., G. V.], Laboratory of Pharmacotoxicology and Pharmacogenetics (UMR 8532) [B. G., J. G., J. M., G. A., G. V.], Vectorology and Gene Transfer (UMR 1582) [P. O.], Department of Pathology [M-J. T-L.], Genetic Unit [B. B-D. P., M. B.], Genetic Oncology (UMR 1599) [J. F.], Institut Gustave-Roussy, 94 805 Villejuif, France; Division of Gene Therapy, Department of Medical Oncology, Vrije Universiteit Medical Center, 1007 MB Amsterdam, The Netherlands [J. G.]; and ONYX Pharmaceuticals, Richmond, California 94806 [D. H. K.].

Treatment of malignant gliomas remains a major challenge in adults and children because of high treatment failure. The E1B 55 kDa-gene deleted adenovirus, ONYX-015 (ONYX Pharmaceuticals), was demonstrated to replicate selectively in and lyse tumor cells. Currently ongoing clinical trials of ONYX-015 in head and neck tumors are promising.

Here, we demonstrate ONYX-015-mediated cell lysis and antitumor activity in three of four s.c. human malignant glioma xenografts deriving from primary tumors. Intratumoral injections of ONYX-015, 1 x 10⁸ plaque-forming units daily for 5 consecutive days, yielded significant tumor growth delay in the p53 mutant xenografts IGRG88 and the p53 wild-type IGRG93 and IGRG121 treated at an advanced tumor stage. The p53 wild-type tumors IGRG93 and IGRG121 experienced 45% and 82% complete tumor regressions. Four and 8 of 11 animals, respectively, survived tumor free 4 months after treatment. Widespread intratumoral adenoviral replication was observed in tumor cells of these two xenografts compared with only scattered replication in the p53-mutant tumors. In addition to a fast tumor growth rate, wild-type p53 status was associated with increased antitumor activity of the E1B-attenuated virus, and induction of functional p53 may therefore determine adenoviral cytolysis in tumor cells.

In conclusion, ONYX-015 displayed a major antitumor activity in human xenografts derived from primary malignant glioma supporting its development in the treatment of these highly malignant tumors.

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