Longitudinal follow-up of cellular and humoral immunity induced by recombinant adenovirus-mediated gene therapy in cancer patients.
Replication-defective adenoviruses are arousing growing interest as both gene therapy and vaccine vectors. In a phase I clinical trial designed to evaluate the feasibility and tolerance of recombinant adenovirus (rAd)mediated gene transfer, we previously demonstrated that a single intratumoral injection of 10(9) PFU of rAd encoding the beta-galactosidase protein (Ad-beta-Gal) induced strong short-term (1-3 months) humoral, helper (Th1 type) and cytotoxic T cell responses specific for the transgene product in patients with advanced lung cancer. The purpose of the present study was to evaluate the persistence of long-lasting immunity to the transgene protein and in parallel, to assess patient immunocompetence revealed by responses to recall antigens (tetanus toxoid, purified protein derivative), viral pathogens (Epstein-Barr virus, influenza virus), and allogeneic antigens in mixed lymphocytic reactions. The beta-Gal-specific proliferative response declined rapidly in patients with progressive disease, as did responses to the other antigens. In contrast, a long-lasting proliferative response to beta-gal was maintained in an immunocompetent patient in complete remission 2 years after an injection of 108 PFU of Ad-beta-Gal. Anti-beta-Gal humoral (IgG and IgA) responses persisted notably, as did responses to TT and poliomyelytic antigens. While T cell effector cytotoxic responses specific for the viral peptides plummeted, the frequency of anti-beta-Gal CTL precursors remained particularly high, thus attesting to major immunization. Despite the impact of both advanced disease and chemotherapy on immunocompetence, we show the long-term persistence of immunity to the transgene protein vectorized by rAd.
Molinier-Frenkel
V
V
Département de Biologie Clinique, Institut Gustave Roussy, 94805 Villejuif, France.
Le Boulaire
C
C
Le Gal
F A
FA
Gahéry-Segard
H
H
Tursz
T
T
Guillet
J G
JG
Farace
F
F
D000256:Adenoviridae / Q000235:genetics*; D000917:Antibody Formation; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002455:Cell Division / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D005500:Follow-Up Studies; D015316:Genetic Therapy / Q000379:methods*; D004854:Herpesvirus 4, Human / Q000276:immunology; D006801:Humans; D007111:Immunity, Cellular; D007070:Immunoglobulin A / Q000097:blood; D007074:Immunoglobulin G / Q000097:blood; D008137:Longitudinal Studies; D008175:Lung Neoplasms / Q000276:immunology* / Q000628:therapy*; D009504:Neutrophils / Q000276:immunology / Q000821:virology; D009975:Orthomyxoviridae / Q000276:immunology; D011051:Poliomyelitis / Q000276:immunology; D012016:Reference Values; D013745:Tetanus Toxoid / Q000276:immunology; D001616:beta-Galactosidase / Q000235:genetics / Q000494:pharmacology
D007070:Immunoglobulin A; D007074:Immunoglobulin G; D013745:Tetanus Toxoid; D001616:beta-Galactosidase