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T-Cell Responses to HLA-A*0201 Immunodominant Peptides Derived from -Fetoprotein in Patients with Hepatocellular Cancer

¹ Divisions of Surgical Oncology;
² Hematology/Oncology,
³ Experimental Radiation Oncology, and the
⁴ Department of Microbiology, Immunology and Molecular Genetics, University of California at Los Angeles, Los Angeles, California

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 -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 µg or 500 µg 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 IFN 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.

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