Peptide Vaccination for Patients With Melanoma and Other Types of Cancer Based on Pre-existing Peptide-Specific Cytotoxic T-Lymphocyte Precursors in the Periphery

Abstract

Identification of antigenic peptides expressed on cancer cells enables us to treat cancer patients with peptide-based immunotherapy. Although optimal protocols for peptide-based vaccines have not yet been elucidated, boosting the immune system could be a better approach than priming the immune system to elicit prompt and potent peptide-specific T-cell responses in cancer patients. With this possibility in mind, the authors undertook a clinical trial in which cancer patients were vaccinated with peptides (maximum 4) after confirmation of pre-existing peptide-specific cytotoxic T-lymphocyte (CTL) precursors in the periphery. Fourteen patients (seven with melanoma and seven with other types of cancer) positive for either HLA-A24 or HLA-A2 were enrolled in this study. Fourteen and 16 peptides were used to screen for HLA-A24+ and HLA-A2+ patients, respectively. The vaccination was well tolerated, and the only adverse effects were local pain and fever. Kinetic analysis revealed that peptide-reactive CTLs increased after peptide vaccination in 7 of 14 patients. Immunoglobulin G (IgG) reactive to the administered peptides was detected in 2 patients before vaccination, although it became detectable in 8 of the other 12 patients after the peptide vaccination. Stable disease for more than 6 months was observed in five patients (one with melanoma and four with other types of cancer); all of these patients showed increased levels of peptide-specific IgG. These results indicate that peptide vaccination of patients showing evidence of pre-existing peptide-specific CTL precursors can be applied in further clinical trials aimed at the treatment of melanoma and other types of cancer.

Expression Hierarchy of T Cell Epitopes from Melanoma Differentiation Antigens: Unexpected High Level Presentation of Tyrosinase-HLA-A2 Complexes Revealed by Peptide-Specific, MHC-Restricted, TCR-Like Antibodies

“…However, the existence of tumor-reactive CD8 ϩ T cells in the peripheral circulation of a patient or an experimental animal is not sufficient to cause the rejection of an established tumor. Clinical trials using peptide Ags for vaccination succeeded in routinely generating tumor-reactive CTLs in patients (5,6), but vaccination alone only sporadically induced tumor regression in patients with metastatic disease. Even in transgenic mice that were engineered to enable every T cell to express a tumor-reactive TCR, tumors still grew progressively.…”

In Vivo Evidence That Peptide Vaccination Can Induce HLA-DR-Restricted CD4+ T Cells Reactive to a Class I Tumor Peptide

“…In contrast, HLA-DRB1*0403-restricted CD4 ϩ T cell precursors against the UBE2V 43-51 peptide were detected only after the peptide vaccination. In our clinical trial, vaccination with four peptides, including the UBE2V 43-51 peptide, did not increase but rather abolished the pre-existing CTL precursors in the periphery in three HLA-A2 ϩ cancer patients (22), although the peptide vaccination induced UBE2V 43-51 peptide-specific IgG in these three patients. We have no explanation for the abolishment of peptide-specific CTL precursors in these patients, but we speculate that the concomitant induction of Th cells contributed to the increase in HLA-A2-restricted T cell response to the UBE2V peptide, at least in this particular patient.…”

“…This means that the dramatic induction of IgG reactive to administered peptides is not limited to the present case. In addition, peptide vaccination resulted in the induction of IgG reactive to several tumor peptides other than the UBE2V 43-51 peptide (22,23). This indicates that the elicitation of IgG reactive to administered peptides is not limited to the UBE2V 43-51 peptide.…”

“…We have recently conducted clinical trials in which cancer patients were vaccinated with peptides (maximum of four) to which pre-existing CTL precursors in the periphery were confirmed before vaccination (22,23). In this protocol the profiles of the vaccinated peptides varied among patients, and the UBE2V 43-51 peptide was vaccinated into three HLA-A2 ϩ cancer patients (one with thyroid cancer, one with mastocarcinoma, and one with seminoma) as one of four peptides (22). As a result, anti-UBE2V 43-51 peptide IgG was induced in all three patients after the third vaccination.…”

Identification of parathyroid hormone-related protein-derived peptides immunogenic in human histocompatibility leukocyte antigen-A24+ prostate cancer patients

“…This means that the PTHrP 102 -111 peptide was recognized by both the cellular and humoral immune systems. Although we do not yet have a clear understanding of the roles played by peptide-specific IgG in antitumour immune responses, our clinical trials revealed that a peptide vaccination frequently resulted in the induction of IgG reactive to the CTL epitope peptides which were administered Tanaka et al, 2003). In addition, the induction of IgG reactive to the vaccinated peptides was positively correlated with longer survival of advanced lung cancer patients .…”