The influence of granulocyte macrophage colony-stimulating factor and prior chemotherapy on the immunological response to a vaccine (ALVAC-CEA B7.1) in patients with metastatic carcinoma
M. Von Mehren et al., The influence of granulocyte macrophage colony-stimulating factor and prior chemotherapy on the immunological response to a vaccine (ALVAC-CEA B7.1) in patients with metastatic carcinoma, CLIN CANC R, 7(5), 2001, pp. 1181-1191
Granulocyte macrophage colony-stimulating factor (GM-CSF) has been shown to
be an effective vaccine adjuvant because it enhances antigen processing an
d presentation by dendritic cells, ALVAC-CEA B7.1 is a canarypox virus enco
ding the gene for the tumor-associated antigen carcinoembryonic antigen (CE
A) and for a T-cell costimulatory molecule, B7.1, After an initial dose esc
alation phase, this study evaluated vaccination with 4.5 x 10(8) plaque-for
ming units ALVAC-CEA B7.1 alone (n = 30) or with GM-CSF (n = 30) in patient
s with advanced CEA-expressing tumors to determine whether the addition of
the adjuvant GM-CSF enhances induction of CEA-specific T-cells, Patients we
re vaccinated with vaccine intradermally every other week for 8 weeks. GM-C
SF was given s.c. for 5 days beginning 2 days before vaccination. Patients
with stable or responding disease after four immunizations received monthly
boost injections alone or with GM-CSF, Biopsies of vaccine sites were obta
ined 48 h after vaccination to evaluate leukocytic infiltration and CEA exp
ression. Induction of peripheral blood CPA-specific T-cell precursors was a
ssessed in HLA-AZ positive patients by an ELISPOT assay looking for the pro
duction of IFN-gamma, Therapy was well tolerated, All of the patients had e
vidence of leukocytic infiltration and CEA expression in vaccine biopsy sit
es. In the patients receiving GM-CSF, leukocytic infiltrates were greater i
n cell number but were less likely to have a predominant lymphocytic infilt
rate compared with patients receiving vaccine in the absence of the cytokin
e adjuvant, After four vaccinations, CEA-specific T-cell precursors were st
atistically increased in HLA-A2 positive patients who received vaccine alon
e. However, the GM-CSF plus vaccine cohort of HLA-AZ positive did not demon
strate a statistically significant increase in their CEA-specific T-cell pr
ecursor frequencies compared with baseline results. The number of prior che
motherapy regimens was negatively correlated with the generation of a T-cel
l response, whereas there was a positive correlation between the number of
months from the last chemotherapy regimen and the T-cell response, ALVAC-CE
A B7.1 is safe in patients with advanced, recurrent adenocarcinomas that ex
press CEA, is associated with the induction of a CEA-specific T-cell respon
se in patients treated with vaccine alone but not with vaccine and GM-CSF,
and can lead to disease stabilization for up to 13 months.