A phase I trial of Ad.hIFN-beta gene therapy for glioma.
Interferon-beta (IFN-beta) is a pleiotropic cytokine with antitumoral activity. In an effort to improve the therapeutic index of IFN-beta by providing local, sustained delivery of IFN-beta to gliomas, the safety and biological activity of a human IFN-beta (hIFN-beta)-expressing adenovirus vector (Ad.hIFN-beta) was evaluated in patients with malignant glioma by stereotactic injection, followed 4-8 days later by surgical removal of tumor with additional injections of Ad.hIFN-beta into the tumor bed. Eleven patients received Ad.hIFN-beta in cohorts of 2 x 10(10), 6 x 10(10), or 2 x 10(11) vector particles (vp). The most common adverse events were considered by the investigator as being unrelated to treatment. One patient, who was enrolled in the cohort with the highest dose levels, experienced dose-limiting, treatment-related Grade 4 confusion following the post-operative injection. Ad.hIFN-beta DNA was detected within the tumor, blood, and nasal swabs in a dose-dependent fashion and hIFN-beta protein was detectable within the tumor. At the highest doses tested, a reproducible increase in tumor cell apoptosis in post-treatment versus pre-treatment biopsies with associated tumor necrosis was observed. Direct Ad.hIFN-beta injection into the tumor and the surrounding normal brain areas after surgical removal was feasible and associated with apoptosis induction.
Chiocca
E Antonio
EA
Department of Neurosurgery, Dardinger Neuro-oncology Center, James Comprehensive Cancer Center, The Ohio State University Medical Center, Columbus, Ohio 43210-1240, USA. EA.Chiocca@osumc.edu
Smith
Katie M
KM
McKinney
Byron
B
Palmer
Cheryl A
CA
Rosenfeld
Steven
S
Lillehei
Kevin
K
Hamilton
Allan
A
DeMasters
Betty K
BK
Judy
Kevin
K
Kirn
David
D
D000256:Adenoviridae / Q000235:genetics*; D000328:Adult; D000368:Aged; D001921:Brain / Q000473:pathology; D001932:Brain Neoplasms / Q000097:blood / Q000473:pathology / Q000628:therapy*; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D005910:Glioma / Q000097:blood / Q000473:pathology / Q000628:therapy*; D006801:Humans; D016899:Interferon-beta / Q000235:genetics* / Q000276:immunology / Q000502:physiology; D016753:Interleukin-10 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D008875:Middle Aged; D016019:Survival Analysis
D015850:Interleukin-6; D016753:Interleukin-10; D016899:Interferon-beta