Oncolytic activity of the E1B-55 kDa-deleted adenovirus ONYX-015 is independent of cellular p53 status in human malignant glioma xenografts.
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 10(8) 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.
Geoerger
Birgit
B
Department of Pediatrics, Laboratory of Pharmacotoxicology, Institut Gustave-Roussy, 39 Rue Camille Desmoulins, 94 805 Villejuif, France.
Grill
Jacques
J
Opolon
Paule
P
Morizet
Jackie
J
Aubert
Geneviève
G
Terrier-Lacombe
Marie-José
MJ
Bressac De-Paillerets
Brigitte
B
Barrois
Michel
M
Feunteun
Jean
J
Kirn
David H
DH
Vassal
Gilles
G
D000256:Adenoviridae / Q000235:genetics / Q000502:physiology*; D017501:Adenovirus E1B Proteins / Q000235:genetics*; D000818:Animals; D003588:Cytopathogenic Effect, Viral; D005260:Female; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000378:metabolism / Q000628:therapy* / Q000821:virology*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D011991:Receptors, Virus / Q000096:biosynthesis; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays
D017501:Adenovirus E1B Proteins; D011991:Receptors, Virus; D016159:Tumor Suppressor Protein p53; C085301:adenovirus receptor