Impact of preexisting and induced humoral and cellular immune responses in an adenovirus-based gene therapy phase I clinical trial for localized mesothelioma.
Little is known about the immune responses induced by recombinant adenoviral (Ad) vectors in humans. The humoral and cellular immune responses were therefore analyzed in 21 patients with localized malignancy (mesothelioma), who received intrapleurally high doses of a replication-defective Ad5 vector carrying a suicide gene. Eight of 21 patients had pretreatment titers of neutralizing antibodies (NAb) to Ad at > or =1:100. Peripheral blood mononuclear cells (PBMCs) proliferated in response to adenoviral 5 structural proteins before treatment in 17 of 21 patients. Preexisting humoral and cellular immunity did not preclude gene transfer. Vector instillation induced high titers of nonneutralizing and neutralizing anti-Ad antibody (4- to 341-fold increase in 18 of 20 patients) in a dose-dependent manner. Three patients generated antibodies to the transgene, herpes simplex virus thymidine kinase. Ad5-specific proliferation of PBMCs increased significantly (>3-fold) after vector administration in 12 of 21 patients in a dose-dependent manner. Thus, replication-defective Ad5 administered intrapleurally induced significant humoral and cellular immune responses that induced no obvious adverse clinical sequelae.
Department of Surgery, University of Pennsylvania Medical Center, Philadelphia 19104-6070, USA.
K L
KL
Molnar-Kimber
D H
DH
Sterman
M
M
Chang
E H
EH
Kang
M
M
ElBash
M
M
Lanuti
A
A
Elshami
K
K
Gelfand
J M
JM
Wilson
L R
LR
Kaiser
S M
SM
Albelda
D000256:Adenoviridae / Q000276:immunology*; D000328:Adult; D000368:Aged; D000906:Antibodies / Q000097:blood; D002455:Cell Division / Q000235:genetics; D005260:Female; D015870:Gene Expression / Q000235:genetics; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D007700:Kinetics; D008297:Male; D008654:Mesothelioma / Q000235:genetics* / Q000628:therapy; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology; D014407:Tumor Cells, Cultured
D000906:Antibodies