Phase I clinical trial of a recombinant canarypoxvirus (ALVAC) vaccine expressing human carcinoembryonic antigen and the B7.1 co-stimulatory molecule.
The generation of cytotoxic effector T cells requires delivery of two signals, one derived from a specific antigenic epitope and one from a costimulatory molecule. A phase I clinical trial was conducted with a non-replicating canarypoxvirus (ALVAC) constructed to express both human carcinoembryonic antigen (CEA) and the B7.1 costimulatory molecule. This was the first study in cancer patients to determine if the delivery of costimulation with a tumor vaccine was feasible and improved immune responses. Three cohorts of six patients, each with advanced CEA-expressing adenocarcinomas, were treated with increasing doses of an ALVAC-CEA-B7.1 vaccine (4.5 x 10(6), 4.5 x 10(7), and 4.5 x 10(8) plaque-forming units, PFU). Patients were vaccinated by intramuscular injection every 4 weeks for 3 months and monitored for side-effects, tumor growth and anti-CEA immune responses. ALVAC-CEA-B7.1 at doses up to 4.5 x 10(8) PFU was given without evidence of significant toxicity or autoimmune reactions. Three patients experienced clinically stable disease that correlated with increasing CEA-specific precursor T cells, as shown by in vitro interferon-gamma enzyme-linked immunoassay spot tests (ELISPOT). These three patients underwent repeated vaccination resulting in augmented CEA-specific T cell responses. This study represents the first use of costimulation to enhance antitumor vaccines in cancer patients. This approach resulted in CEA-specific immunity associated with stable diseases in three patients. This study also demonstrated that CEA-specific T cell responses could be sustained by repeated vaccinations. Although the number of patients was small, the addition of B7.1 to virus-based vaccines may improve immunological and stable diseases to vaccination against tumor-associated antigens with tolerable toxicity.
Hörig
H
H
Albert Einstein Cancer Center, Bronx, NY 10461, USA.
Lee
D S
DS
Conkright
W
W
Divito
J
J
Hasson
H
H
LaMare
M
M
Rivera
A
A
Park
D
D
Tine
J
J
Guito
K
K
Tsang
K W
KW
Schlom
J
J
Kaufman
H L
HL
D000230:Adenocarcinoma / Q000276:immunology / Q000628:therapy; D000328:Adult; D000368:Aged; D018150:Avipoxvirus / Q000235:genetics* / Q000276:immunology*; D018122:B7-1 Antigen / Q000235:genetics* / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use* / Q000633:toxicity; D002272:Carcinoembryonic Antigen / Q000235:genetics* / Q000276:immunology; D002460:Cell Line; D002478:Cells, Cultured; D015331:Cohort Studies; D003110:Colonic Neoplasms / Q000276:immunology / Q000628:therapy; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D008175:Lung Neoplasms / Q000276:immunology / Q000628:therapy; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000276:immunology / Q000628:therapy; D010455:Peptides / Q000627:therapeutic use; D010641:Phenotype; D012004:Rectal Neoplasms / Q000276:immunology / Q000628:therapy; D013274:Stomach Neoplasms / Q000276:immunology / Q000628:therapy; D013601:T-Lymphocytes / Q000276:immunology; D013997:Time Factors
D018122:B7-1 Antigen; D019496:Cancer Vaccines; D002272:Carcinoembryonic Antigen; D000939:Epitopes; D010455:Peptides; D007371:Interferon-gamma