Phase I trial of recombinant adenovirus gene transfer in lung cancer. Longitudinal study of the immune responses to transgene and viral products.
Animal studies indicate that the use of replication-deficient adenovirus for human gene therapy is limited by host antivector immune responses that result in transient recombinant protein expression and blocking of gene transfer when rechallenged. Therefore, we have examined immune responses to an adenoviral vector and to the beta-galactosidase protein in four patients with lung cancer given a single intratumor injection of 10(9) plaque-forming units of recombinant adenovirus. The beta-galactosidase protein was expressed in day-8 tumor biopsies from all patients at variable levels. Recombinant virus DNA was detected by PCR in day-30 and day-60 tumor biopsies from all patients except patient 1. A high level of neutralizing antiadenovirus antibodies was detected in patient 1 before Ad-beta-gal injection whereas it was low (patient 3) or undetectable in the other two patients. All patients developed potent CD4 type 1 helper T cell (Th1) responses to adenoviral particles which increased gradually over time after injection. Antiadenovirus cytotoxic T lymphocyte responses were consistently boosted in the two patients examined (patients 3 and 4). Sustained production of anti-beta-galactosidase IgG was observed in all patients except patient 1. Consistent with anti-beta-gal antibody production, all patients except patient 1 developed intense, dose-dependent Th1 responses to soluble beta-galactosidase which increased over time. Strong beta-galactosidase-specific cytotoxic T lymphocyte responses were detected in patients 2, 3, and 4. Our results clearly show that despite the intensity of antiadenovirus responses, transgene protein expression was sufficient to induce strong and prolonged immunity in three patients. Recombinant adenovirus injected directly into the tumor is a highly efficient vector for immunizing patients against the transgene protein.
Gahéry-Ségard
H
H
Laboratoire d'Immunologie des Pathologies Infectieuses et Tumorales, INSERM Unité 445, Université R. Descartes, Hôpital Cochin, Paris, France.
Molinier-Frenkel
V
V
Le Boulaire
C
C
Saulnier
P
P
Opolon
P
P
Lengagne
R
R
Gautier
E
E
Le Cesne
A
A
Zitvogel
L
L
Venet
A
A
Schatz
C
C
Courtney
M
M
Le Chevalier
T
T
Tursz
T
T
Guillet
J G
JG
Farace
F
F
D000256:Adenoviridae / Q000235:genetics; D000914:Antibodies, Viral / Q000096:biosynthesis; D003602:Cytotoxicity, Immunologic; D004279:DNA, Viral / Q000032:analysis; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D008175:Lung Neoplasms / Q000628:therapy*; D008213:Lymphocyte Activation; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D013997:Time Factors; D001616:beta-Galactosidase / Q000235:genetics
D000914:Antibodies, Viral; D004279:DNA, Viral; D007376:Interleukin-2; D007371:Interferon-gamma; D001616:beta-Galactosidase