Carcinoembryonic Antigen Peptide-Pulsed Dendritic Cells in Patients with Metastatic Cancer

Abstract

Because of high mortality rate of metastatic cancers and significant toxicity of chemotherapy and radiotherapy, new treatment approaches such as immunotherapy warrant evaluation. The basis for modern approaches to immunotherapy is the observation that many tumors possess antigens that can be recognized by antigen-specific T cells leading to tumor rejection. The recognition of tumor-associated antigens is generally MHC class I-restricted1 and has been localized to eight to ten amino acid peptide fragments. These fragments bind in the groove of the MHC complex where they are presented to T lymphocytes that express receptors specific for the particular peptide. Among the described tumor antigens is carcinoembryonic antigen (CEA), expressed on most gastrointestinal adenocarcinomas, 50% of breast cancers, and 70% of non–small-cell lung cancers.2 The immunogenicity of CEA in man has been established in studies where patients have been immunized with recombinant, human CEA along with GM-CSF3, vaccinia vectors containing the gene for CEA4, and anti-idiotype specific for CEA.5 Peptide fragments of CEA have been found to be epitopes for T-cell lines generated from patients previously vaccinated with vaccinia-CEA. The most potent peptide in this study, designated CAP-1, is an HLA-A2 restricted CTL epitope.4 Because naive precursors of cytotoxic T cells specific for tumor antigens are present in very low numbers, methods for stimulating the T cells are necessary. Approaches have included viral vectors, administration of antigen with adjuvants and gene-transduced tumor cells. A more recent development has been the emerging understanding of the critical role that antigen-presenting cells, such as dendritic cells (DC), play in inducing T and B-cell responses in vivo. Numerous studies have demonstrated that DC loaded with tumor antigen can induce T-cell responses in vitro and in vivo murine models without significant toxicity. We and others have developed methods for generating a sufficient number of DC in vitro for use in immunotherapy studies.6-9 Furthermore, we have demonstrated that these DC loaded with CEA and other peptides are capable of inducing CEA specific T-cell responses in vitro.10 Therefore, we hypothesize that DC loaded with tumor-associated peptides such as the CEA peptide CAP-1 will be safe and induce CAP-1 specific Tcell responses in vivo in humans with metastatic cancers. Our objectives are: a) to determine the safety and dose-limiting toxicity of intravenous and intradermal injections of autologous, DC pulsed with an HLA-A2 restricted CEA peptide; b) to evaluate cellular immune response to the CEA peptide.