Human adenovirus type 35 vector for gene therapy of brain cancer: improved transduction and bypass of pre-existing anti-vector immunity in cancer patients.
Clinical trials in malignant glioma have demonstrated excellent safety of recombinant adenovirus type 5 (Ad5) but lack of convincing efficacy. The overall low expression levels of the Coxsackie and Adenovirus receptor and the presence of high anti-Ad5-neutralizing antibody (NAb) titers in the human population are considered detrimental for consistency of clinical results. To identify an adenoviral vector better suited to infect primary glioma cells, we tested a library of fiber-chimeric Ad5-based adenoviral vectors on 12 fresh human glioma cell suspensions. Significantly improved marker gene expression was obtained with several Ad5-chimeric vectors, predominantly vectors carrying fiber molecules derived from B-group viruses (Ad11, Ad16, Ad35 and Ad50). We next tested Ad35 sero prevalence in sera derived from 90 Dutch cancer patients including 30 glioma patients and investigated the transduction efficiency of this vector in glioma cell suspensions. Our results demonstrate that the sero prevalence and the titers of NAb against Ad35 are significantly lower than against Ad5. Also, recombinant Ad35 has significantly increased ability to transfer a gene to primary glioma cells compared to Ad5. We thus conclude that Ad35 represents an interesting candidate vector for gene therapy of malignant glioma.
Brouwer
E
E
Department of Neurology, Erasmus University Medical Center, Dr Molewaterplein 40, 3015 GD Rotterdam, The Netherlands.
Havenga
M J
MJ
Ophorst
O
O
de Leeuw
B
B
Gijsbers
L
L
Gillissen
G
G
Hoeben
R C
RC
ter Horst
M
M
Nanda
D
D
Dirven
C
C
Avezaat
C J
CJ
Goudsmit
J
J
Sillevis Smitt
P
P
D000256:Adenoviridae / Q000235:genetics*; D001483:Base Sequence; D001932:Brain Neoplasms / Q000276:immunology / Q000628:therapy*; D017931:DNA Primers; D015316:Genetic Therapy; D005822:Genetic Vectors; D005910:Glioma / Q000276:immunology / Q000628:therapy*; D006801:Humans; D014161:Transduction, Genetic
D017931:DNA Primers