Immunological evaluation of personalized peptide vaccination in combination with a 5-fluorouracil derivative (TS-1) for advanced gastric or colorectal carcinoma patients

Abstract

The aim of the present study was to investigate the safety and immunological responses of personalized peptide vaccination in combination with oral administration of a 5-fluorouracil derivative (TS-1) in advanced gastric or colorectal carcinoma patients. Eleven patients (four with gastric cancer and seven with colorectal cancer) who failed to improve by prior TS-1-based chemotherapies were enrolled in this study. Peptides to be administered to patients were determined based on the presence of peptide-specific cytotoxic T lymphocyte (CTL) precursors in peripheral blood mononuclear cells and peptide-specific IgG in the plasma of cancer patients. Patients were vaccinated with peptides (a maximum of four) biweekly in combination with or without three different doses of TS-1 (20, 40 and 80 mg/m(2)/day). Although grade 3 toxicity, including anemia (one patient) and neutropenia (one patient) were observed, the combination therapy was generally well tolerated. An increase in peptide-specific IgG after the sixth vaccination was observed in the vast majority of patients irrespective of the dose of TS-1 used. In contrast, an increase in peptide-specific interferon-gamma production by CTL was most evident in patients who were administered the highest dose of TS-1. Furthermore, in the patients who received 80 mg/m(2)/day TS-1, CTL-mediated cytotoxicity against cancer cells was maintained at the prevaccination level. These results indicate that administration of the standard dose (80 mg/m(2)/day) of TS-1 in combination with a personalized peptide vaccination does not necessarily impede immunological responses in cancer patients, and could actually maintain or augment them.

Figure 1

Cytotoxicity against cancer cells before and after the personalized peptide vaccination with TS‐1. Pre‐ and post (sixth)‐vaccination peripheral blood mononuclear cells (PBMC) from three patients (patients 1, 3 and 10) were stimulated repeatedly with the corresponding peptide in the presence of interleukin (IL)‐2 for 14 days, followed by the culture with IL‐2 alone for an additional 10–14 days. Thereafter, these cultured cells were used as effector cells in the cytotoxicity assay against the indicated targets. The 6‐h ⁵¹Cr‐release assay was carried out in triplicate, and the values are shown as the mean  SD.

Figure 2

Flow cytometric analysis of peripheral blood mononuclear cells (PBMC) of the vaccinated patients. PBMC of three patients pre‐ and postvaccination with or without TS‐1 were stained with fluorescein‐isothiocyanate‐conjugated anti‐CD4 and phycoerythrin (PE)‐conjugated anti‐CD25 monoclonal antibodies, and were analyzed by flow cytometry. Patients 2 and 5 received peptide vaccination with 80 and 40 mg/m²/day of TS‐1, respectively, and patient 11 received peptide vaccination without TS‐1. The number represents the positive percentage of CD4⁺ and CD25⁺ cells.