The presence of tumor-reactive CTLs in tumor infiltrates and in the periphe
ral blood of cancer patients demonstrates an immune response against tumors
that apparently cannot control disease spread. This raises concerns as to
whether amplification of this response may be useful during disease progres
sion. Induction of tumor-reactive CTLs in healthy donors at risk, as well a
s in patients free of disease, may be therapeutically important, based on t
he hypothesis that CTLs that recognize tumors early may be more effective i
n containing their progression than CTLs that expand only when the disease
progresses. To address the feasibility of priming cytolytic activity in hea
lthy donors, we used the HER-2 peptide E75 (369-377) as an immunogen and au
tologous peripheral blood mononuclear cell-derived dendritic cells as antig
en-presenting cells. We found that of 10 healthy donors tested, two respond
ed at priming with E75 presented on autologous dendritic cells by induction
of E75-specific CTL activity. Three other responders were identified after
two additional restimulations, Of these five responders, three recognized
E75 presented on the ovarian tumor line SKOV3.A2, as demonstrated by cold-t
arget inhibition experiments. Induction of cytolytic activity at priming wa
s enhanced in responders by tumor necrosis factor-cr and interleukin 12 but
not in the nonresponders, alpha B7.1 monoclonal antibody added at priming
enhanced induction of lytic activity in only one of the four nonresponding
donors tested, suggesting that in the majority of donors, E75-precursor CTL
s were not tolerized, Because of the possibility that disease may develop i
n nonresponders, strategies to improve the immunogenicity of tumor antigens
for healthy donors may be required for development of cancer vaccines.