T-cell responses to HLA-A*0201 immunodominant peptides derived from alpha-fetoprotein in patients with hepatocellular cancer.

PURPOSE An existing immunological paradigm is that high concentrations of soluble protein contribute to the maintenance of peripheral tolerance/ignorance to self protein. We tested this hypothesis in a clinical immunotherapy trial using class I-restricted peptide epitopes derived from alpha-fetoprotein (AFP). AFP is a self protein expressed by fetal liver at high levels, but transcriptionally repressed at birth. AFP is de-repressed in a majority of hepatocellular carcinomas (HCCs) and patients with active disease can have plasma levels in the mg/ml range. We previously identified four immunodominant HLA-A*0201-restricted peptides derived from human AFP that could stimulate specific T-cell responses in normal volunteer peripheral blood lymphocytes cultures. We wished to test the hypothesis that AFP peptide-reactive T cells could be expanded in vivo in HCC patients immunized with these four AFP peptides. EXPERIMENTAL DESIGN We undertook a pilot Phase I clinical trial in which HLA-A*0201 patients with AFP-positive HCC were immunized with three biweekly intradermal vaccinations of the four AFP peptides (100 microg or 500 microg each) emulsified in incomplete Freund's adjuvant. RESULTS All of the patients (n=6) generated T-cell responses to most or all of the peptides as measured by direct IFNgamma enzyme-linked immunospot (ELISPOT) and MHC class I tetramer assays. CONCLUSIONS We conclude that the human T-cell repertoire is capable of recognizing AFP in the context of MHC class I even in an environment of high circulating levels of this oncofetal protein.