H. Horig et al., Phase I clinical trial of a recombinant canarypoxvirus (ALVAC) vaccine expressing human carcinoembryonic antigen and the B7.1 co-stimulatory molecule, CANCER IMMU, 49(9), 2000, pp. 504-514
The generation of cytotoxic effector T cells requires delivery of two signa
ls, one derived from a specific antigenic epitope and one from a costimulat
ory 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 tu
mor vaccine was feasible and improved immune responses. Three cohorts of si
x 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 dose
s up to 4.5 x 108 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 b
y 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 cost
imulation to enhance antitumor vaccines in cancer patients. This approach r
esulted in CEA-specific immunity associated with stable diseases in three p
atients. This study also demonstrated that CEA-specific T cell responses co
uld be sustained by repeated vaccinations. Although the number of patients
was small, the addition of B7.1 to virus-based vaccines may improve immunol
ogical and stable diseases to vaccination against tumor-associated antigens
with tolerable toxicity.