Enhancement of cytotoxic T-lymphocyte responses in patients with gastrointestinal malignancies following vaccination with CEA peptide?pulsed dendritic cells

Abstract

Carcinoembryonic antigen (CEA) is strongly expressed in a vast majority of gastrointestinal carcinomas. Recently, epitope peptides of CEA were identified. We have demonstrated HLA-A24-restricted peptide, CEA652[9] (TYACFVSNL), was capable of eliciting specific cytotoxic T lymphocytes (CTLs) which could lyse tumor cells expressing HLA-A24 and CEA. HLA-A24 is the most applicable MHC class I allele in the Japanese population. In this pilot study, we have used the peptide-pulsed dendritic cells (DCs) generated from peripheral blood mononuclear cells (PBMCs) supplemented with GM-CSF and IL-4 as the source of the vaccine. Eight patients with advanced CEA-expressing gastrointestinal malignancies received subcutaneous injections every 2 or 3 weeks. Immunomonitoring was performed by ELISpot (enzyme-linked immunosorbent spot) assay to measure the precursor frequency of CTLs and their capacity to elicit antitumor CTLs in vitro. Four of seven patients have developed their CTL response after vaccinations. DTH reaction was observed in one of eight patients at the DC-injected site. Skin biopsy at the injected site showed the infiltration of the lymphocytes. Furthermore, A24/CEA peptide tetramer assay revealed an increase in peptide-specific T-cell precursor frequency in vaccinated patients. No significant toxic adverse effects were observed, except for mild diarrhea in one case after three vaccinations. Three patients have shown stabilization of the disease after vaccinations. In conclusion, our results clearly demonstrated that our vaccination protocol was safe and might develop a CEA-specific CTL response in cancer patients.

Induction of antigen-specific CD4- and CD8-mediated T-cell responses by fusions of autologous dendritic cells and metastatic colorectal cancer cells

“…34 DCs pulsed with peptides were used in clinical trials for patients with CRCA or other cancers, and clinical response was found in a small number of patients. 19,[35][36][37] CEA and MUC1 are the most frequently overexpressed antigens in adenocarcinoma cells and can be detected in almost all human CRCA cells (Table II).…”

“…3,35,38,39 However, little is known about whether both antigen-specific CTLs exist in a patient with CRCA or can be induced simultaneously. In the present study, coculture of PBMCs with DC/CRCA fusion cells induced CTL against not only CEA but also MUC1.…”

Antitumor immune response of dendritic cells (DCs) expressing tumor‐associated antigens derived from induced pluripotent stem cells: In comparison to bone marrow‐derived DCs

“…Our previous Phase I clinical trial of cancer vaccine therapy using carcinoembryonic antigen peptide-pulsed DCs found the clinical effects of this therapy to be insufficient. 4 Therefore, we next used a gene-based vaccination strategy that used DCs adenovirally transduced with the entire tumor-associated antigen (TAA) gene. We demonstrated that DCs adenovirally transduced with the TAA gene are effective in inducing TAAspecific cytotoxic T lymphocytes (CTLs) and that these cells elicit potent antitumor responses, especially in gastrointestinal solid tumors.…”

Streptococcal preparation OK-432 promotes the capacity of dendritic cells (DCs) to prime carcinoembryonic antigen (CEA)-specific cytotoxic T lymphocyte responses induced with genetically modified DCs that express CEA

“…We performed a pilot study of DCs pulsed with CEA-specific peptides for patients with colorectal carcinoma. However, no clinical responses were found, although CEA-specific CTL responses were observed in a few patients (5). Therefore, we employed an alternative strategy for inducing antitumor immunity using DCs adenovirally transduced with the whole tumor-associated antigen (TAA) gene (6)(7)(8)(9)(10).…”