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A Phase I/II Trial Testing Immunization of Hepatocellular Carcinoma Patients with Dendritic Cells Pulsed with Four -Fetoprotein Peptides

Authors' Affiliations: ¹ Department of Medicine, Surgery and Immunology, and ² Biostatistics Facility, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, and Division of ³ Surgical Oncology, ⁴ Hematology/Oncology, and ⁵ Experimental Radiation Oncology, ⁶ Department of Microbiology, Immunology, and Molecular Genetics, University of California at Los Angeles, Los Angeles, California

Requests for reprints: Lisa H. Butterfield, University of Pittsburgh, Hillman Cancer Center, Research Pavilion, Room 1.32, 5117 Centre Avenue, Pittsburgh, PA 15213. Phone: 412-623-1418; Fax: 412-623-1415; E-mail: butterfieldl{at}upmc.edu.

-Fetoprotein (AFP) is a self protein expressed by fetal liver at high levels, but is transcriptionally repressed at birth. AFP is up-regulated in hepatocellular carcinomas, and patients with active disease could have plasma levels as high as 1 mg/mL. We previously identified four immunodominant HLA-A*0201-restricted peptides [hAFP_137-145 (PLFQVPEPV), hAFP_158-166 (FMNKFIYEI), hAFP_325-334 (GLSPNLNRFL), and hAFP_542-550 (GVALQTMKQ)] derived from human AFP that could stimulate specific T cell responses in healthy donor peripheral blood lymphocytes in vitro. We conducted a phase I/II clinical trial in which HLA-A*0201 patients with AFP-positive hepatocellular carcinoma were immunized with three biweekly intradermal vaccinations of the four AFP peptides pulsed onto autologous dendritic cells (DC). DCs were prepared from adherent peripheral blood mononuclear cells cultured with granulocyte-macrophage colony-stimulating factor and interleukin-4 for 7 days. Sixteen subjects were enrolled and 10 were treated. Peripheral blood lymphocytes were isolated from these patients before, during, and after AFP peptide/DC immunization and were tested ex vivo with MHC tetramer and IFN ELISPOT analysis. Six of 10 subjects expanded statistically significant levels of AFP-specific T cells postvaccine to at least one peptide by MHC tetramer. Also, 6 of 10 subjects increased IFN producing AFP-specific T cell responses to at least one of the peptides postvaccination, by ELISPOT. We conclude that the human T cell repertoire is capable of responding to the AFP self antigen after the administration of AFP peptide-pulsed DC even in an environment of high circulating levels of this oncofetal antigen.

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				Y. Liu, S. Daley, V. N. Evdokimova, D. D. Zdobinski, D. M. Potter, and L. H. Butterfield Hierarchy of {alpha} Fetoprotein (AFP)-Specific T Cell Responses in Subjects with AFP-Positive Hepatocellular Cancer J. Immunol., July 1, 2006; 177(1): 712 - 721. [Abstract] [Full Text] [PDF]