Study of the efficacy, biodistribution, and safety profile of therapeutic gutless adenovirus vectors as a prelude to a phase I clinical trial for glioblastoma.
Glioblastoma multiforme (GBM) is the most common and most aggressive primary brain tumor in humans. Systemic immunity against gene therapy vectors has been shown to hamper therapeutic efficacy; however, helper-dependent high-capacity adenovirus (HC-Ad) vectors elicit sustained transgene expression, even in the presence of systemic anti-adenoviral immunity. We engineered HC-Ads encoding the conditional cytotoxic herpes simplex type 1 thymidine kinase (TK) and the immunostimulatory cytokine fms-like tyrosine kinase ligand 3 (Flt3L). Flt3L expression is under the control of the regulatable Tet-ON system. In anticipation of a phase I clinical trial for GBM, we assessed the therapeutic efficacy, biodistribution, and clinical and neurotoxicity with escalating doses of HC-Ad-TetOn-Flt3L + HC-Ad-TK in rats. Intratumoral administration of these therapeutic HC-Ads in rats bearing large intracranial GBMs led to long-term survival in approximately 70% of the animals and development of antiglioma immunological memory without signs of neuropathology or systemic toxicity. Systemic anti-adenoviral immunity did not affect therapeutic efficacy. These data support the idea that it would be useful to develop HC-Ad vectors further as a therapeutic gene-delivery platform to implement GBM phase I clinical trials.
Muhammad
A K M G
AK
Gene Therapeutics Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Puntel
M
M
Candolfi
M
M
Salem
A
A
Yagiz
K
K
Farrokhi
C
C
Kroeger
K M
KM
Xiong
W
W
Curtin
J F
JF
Liu
C
C
Lawrence
K
K
Bondale
N S
NS
Lerner
J
J
Baker
G J
GJ
Foulad
D
D
Pechnick
R N
RN
Palmer
D
D
Ng
P
P
Lowenstein
P R
PR
Castro
M G
MG
D000256:Adenoviridae / Q000235:genetics* / Q000276:immunology; D000276:Adjuvants, Immunologic / Q000627:therapeutic use; D000818:Animals; D001522:Behavior, Animal; D001932:Brain Neoplasms / Q000523:psychology / Q000628:therapy*; D017321:Clinical Trials, Phase I as Topic; D004306:Dose-Response Relationship, Immunologic; D018628:Gene Dosage; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D005909:Glioblastoma / Q000523:psychology / Q000628:therapy*; D006801:Humans; D007150:Immunohistochemistry; D007267:Injections; D009368:Neoplasm Transplantation; D051381:Rats; D016019:Survival Analysis; D014018:Tissue Distribution; D019076:Transgenes / Q000235:genetics
D000276:Adjuvants, Immunologic