Selective replication and oncolysis in p53 mutant tumors with ONYX-015, an E1B-55kD gene-deleted adenovirus, in patients with advanced head and neck cancer: a phase II trial.
ONYX-015 is an E1B-55kDa gene-deleted adenovirus engineered to selectively replicate in and lyse p53-deficient cancer cells. To evaluate the selectivity of ONYX-015 replication and cytopathic effects for the first time in humans, we carried out a Phase II clinical testing of intratumoral and peritumoral ONYX-015 injection in 37 patients with recurrent head and neck carcinoma. Patients received ONYX-015 at a daily dose of 1 x 10(10) plaque-forming units (pfu) via intratumoral injection for 5 days during week 1 of each 3-week cycle (n = 30; cohort A), or 1 x 10(10) pfu twice a day for 10 days during weeks 1 and 2 of each 3-week cycle. Posttreatment biopsies documented selective ONYX-015 presence and/or replication in the tumor tissue of 7 of 11 patients biopsied on days 5-14, but not in immediately adjacent normal tissue (0 of 11 patients; P = 0.01). Tissue destruction was also highly selective; significant tumor regression (>50%) occurred in 21% of evaluable patients, whereas no toxicity to injected normal peritumoral tissues was demonstrated. p53 mutant tumors were significantly more likely to undergo ONYX-015-induced necrosis (7 of 12) than were p53 wild-type tumors (0 of 7; P = 0.017). High neutralizing antibody titers did not prevent infection and/or replication within tumors. ONYX-015 is the first genetically engineered replication-competent virus to demonstrate selective intratumoral replication and necrosis in patients. This agent demonstrates the promise of replication-selective viruses as a novel therapeutic platform against cancer.
Nemunaitis
J
J
US Oncology, Dallas, Texas 75246, USA. John.Nemunaitis@USOncology.com
Ganly
I
I
Khuri
F
F
Arseneau
J
J
Kuhn
J
J
McCarty
T
T
Landers
S
S
Maples
P
P
Romel
L
L
Randlev
B
B
Reid
T
T
Kaye
S
S
Kirn
D
D
D017501:Adenovirus E1B Proteins / Q000235:genetics; D000260:Adenoviruses, Human / Q000235:genetics / Q000502:physiology*; D000368:Aged; D000912:Antibodies, Neoplasm / Q000096:biosynthesis / Q000097:blood; D001706:Biopsy; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000473:pathology / Q000628:therapy* / Q000821:virology; D005260:Female; D016158:Genes, p53 / Q000235:genetics*; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy* / Q000821:virology; D006801:Humans; D015552:Injections, Intralesional; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000473:pathology / Q000628:therapy* / Q000821:virology; D014779:Virus Replication
D017501:Adenovirus E1B Proteins; D000912:Antibodies, Neoplasm