Recombinant adenovirus shedding after intratumoral gene transfer in lung cancer patients.
We conducted two phase 1 trials of direct intratumoral injection of a recombinant E1E3-deleted adenovirus (AdR) encoding either the bacterial enzyme beta-galactosidase (Ad.RSVbetagal) or interleukin 2 (IL2, AdTG5327) into primary nonsmall-cell lung cancers of 21 patients. We report here virus shedding and the duration of virus expression in the tumor after intrabronchial injection of 10(7), 10(8) or 10(9) PFU of adenovirus. The infectious AdR and the viral DNA were detected in PBL, plasma, stool and aerodigestive samples in a dose-dependent manner, since cell cultures and PCRs were found to be positive mainly for samples from patients who received the highest AdR dose (10(9) PFU). We detected beta-galactosidase activity in the tumor biopsy samples of 66% of the patients, seemingly dose related, and only low levels of IL2 mRNA could be detected in tumor biopsy samples. E1 sequences were not detected by PCR in any of the PBL and bronchial samples collected after virus delivery, except in one patient. In this patient, E1 sequences were detected in PBL as well as in tumor biopsy samples collected at days 8, 30 and 60 and were correlated with longer beta-galactosidase expression in tumor samples. PBL tested before and after virus delivery contained both E1 sequences indicating that they did not result from replication-competent adenovirus (RCA) E1 sequences present in the inoculum. In addition, only on the day of the injection was Ad.RSVbetagal also detected in E1-positive PBL, indicating that virus replication in blood was very unlikely.
Griscelli
F
F
Department of Biology, Institut Gustave Roussy, Villejuif, France.
Opolon
P
P
Saulnier
P
P
Mami-Chouaib
F
F
Gautier
E
E
Echchakir
H
H
Angevin
E
E
Le Chevalier
T
T
Bataille
V
V
Squiban
P
P
Tursz
T
T
Escudier
B
B
D000256:Adenoviridae / Q000235:genetics*; D000328:Adult; D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung / Q000276:immunology / Q000628:therapy*; D005260:Female; D015870:Gene Expression; D015316:Genetic Therapy / Q000009:adverse effects* / Q000379:methods; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D007167:Immunotherapy / Q000379:methods*; D015552:Injections, Intralesional; D007376:Interleukin-2 / Q000235:genetics; D008175:Lung Neoplasms / Q000276:immunology / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction / Q000379:methods; D012333:RNA, Messenger / Q000032:analysis; D014161:Transduction, Genetic / Q000379:methods; D017201:Virus Shedding; D001616:beta-Galactosidase / Q000235:genetics
D007376:Interleukin-2; D012333:RNA, Messenger; D001616:beta-Galactosidase