Immunological evaluation of CTL precursor‐oriented vaccines for advanced lung cancer patients

Abstract

Recent clinical trials of peptide vaccine for cancer patients have rarely resulted in tumor regression. One of the reasons for this failure could be an insufficient induction of anti-tumor responses in these regimens, in which peptide-specific memory cytotoxic T lymphocytes (CTLs) were not measured prior to vaccination. We investigated in this study whether pre-vaccination measurement of peptide-specific CTLs can provide any advantages in lung cancer patients receiving peptide vaccination with regard to safety and immunological responses. Ten patients with advanced lung cancer received vaccination with peptides under a regimen of CTL precursor-oriented vaccination, in which pre-vaccination peripheral blood mononuclear cells (PBMCs) were at first screened for reactivity in vitro to each of 14 peptides, followed by in vivo administration of only the reactive peptides. Profiles of the vaccinated peptides varied markedly among the 10 patients. This regimen was generally well-tolerated, although local skin reactions, diarrhea, and colitis were observed in 8, 2, and 1 patient, respectively. Increased CTL responses against the immunized peptides and tumor cells were observed in the post-vaccination PBMCs from 4 of 8 and 3 of 10 patients tested, respectively. Peptidespecific IgG became detectable in post-vaccination sera in 4 of 10 patients tested, and these 4 patients had a long progression-free survival. Furthermore, the median survival time of 9 patients with non-small cell lung cancer was 668.0 ± ± ± ±164.2 days. These results encourage further development of CTL precursor-oriented peptide vaccination for lung cancer patients. (Cancer Sci 2003; 94: 548-556) dentification of a large number of antigenic epitopes 1-9) recognized by cytotoxic T lymphocytes (CTLs) reacting to tumor cells has opened the door to clinical trials of peptide-based immunotherapy for cancer patients. [10][11][12][13][14][15][16] Many clinical trials of peptide-based immunotherapy for malignant melanoma and other epithelial tumors have been conducted in the past decade, but major clinical responses were rarely obtained in these clinical studies, including our trial of a cyclophilin B (CypB) peptide vaccination for advanced lung cancer patients 17) and a SART3 peptide vaccination for advanced colorectal cancer patients.18) One reason for this failure to obtain tumor regression could be an insufficient induction of anti-tumor responses in these vaccine regimens, in which peptide-specific memory T cells were not measured in pre-vaccination peripheral blood mononuclear cells (PBMCs). We have speculated that vaccination based on information from pre-vaccination measurement of peptide-specific CTLs in the circulation might induce potent anti-tumor immune responses in cancer patients. This hypothesis is based on the assumption that initiation of immune-boosting of CTLs through peptide vaccination could be more effective than immune-priming of naive T cells with regard to induction of prompt and strong immunity to both the peptide and tumor cells. We ha...

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

“…This indicates that the elicitation of IgG reactive to administered peptides is not limited to the UBE2V 43-51 peptide. In addition, we found that vaccine-induced, peptide-specific IgG tended to detectable in advanced lung cancer patients with a long progression-free survival (23). Although many clinical trials of peptide-based immunotherapy have been conducted to induce CD8 ϩ T cell-mediated tumor regression, no apparent correlation has been observed between in vivo tumor regression and the induction of peptide-specific CTLs in the periphery (3,24).…”

“…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).…”

Identification of epidermal growth factor receptor-derived peptides immunogenic for HLA-A2+ cancer patients

“…We previously reported that IgG reactive against CTL epitope peptides was often detected in the prevaccination sera of cancer patients and also in the sera of HDs, and there was no obvious HLA-class I-A restriction involved (Ohkouchi et al, 2002;Kawamoto et al, 2003;Mine et al, 2003;Noguchi et al, 2003;Sato et al, 2003). Further, some CTL-directed peptides have shown the ability to elicit both cellular and humoral immune responses in vivo in phase I clinical studies, and levels of antipeptide IgG in postvaccination sera have well correlated with the overall survival of advanced cancer patients who received peptide vaccination Sato et al, 2003).…”

Characterization of tumor antigen peptide-specific T cells isolated from the neoplastic tissue of patients with gastric adenocarcinoma

“…The sequences of the GCAA peptides are reported in Table 2. All these peptides have proven the ability to induce HLA-A02-or HLA-A24-restricted and tumor-speciWc cytotoxic lymphocyte activity in the PBMCs of gastric cancer patients [27,47,51].…”