Abstract
This study describes a new strategy for the identification of squamous carcinoma antigens tumor-associated antigens (TAA). The antigens were discovered by comparing microarrays of squamous carcinoma vaccines highly enriched for immunotherapeutic cells with non-enriched vaccines. The vaccines were prepared by transferring sheared genomic DNA fragments (25 kb) from KLN205 cells, a squamous carcinoma cell line (DBA/2 mouse origin (H-2(d)) into LM fibroblasts (C3H/He origin, H-2(k)). The transferred tumor DNA segments integrate spontaneously into the genome of the recipient cells, replicate as the cells divide and are expressed. As only a small proportion of the transfected cell population was expected to have incorporated DNA segments that included genes specifying TAA (the vast majority specify normal cellular constituents), a novel strategy was employed to enrich the vaccine for TAA-positive cells. Microarrays were used to compare genes expressed by enriched and non-enriched vaccines. Seventy-five genes were overexpressed in cells from the enriched vaccine. One, the gene for Cytochrome P450 (family 2, subfamily e, polypeptide 1) (Cyp2e1), was overexpressed in the enriched but not the non-enriched vaccine. A vaccine for squamous carcinoma was prepared by transfer of a 357 bp fragment of the gene for Cyp2e1 into the fibroblast cell line. Robust immunity, sufficient to result in indefinite survival, was induced in tumor-bearing mice immunized with cells transfected with this gene fragment.
Highlights
The annual worldwide incidence of squamous carcinoma of the head and neck (SCCHN) is approximately 500 000
In prior reports,[29] we described the results of studies designed to enrich a cellular vaccine for squamous cell carcinoma (SCC) for cells that expressed tumor-associated antigens (TAA)
IL-2-secretion and expression of H-2Kb-determinants by modified LM fibroblasts, used as recipients of DNA from the squamous carcinoma cells Among other advantages, the use of a fibroblast cell line as the recipient of DNA from the SCC enabled the cells to be conveniently modified in advance of DNA transfer to augment their nonspecific immunogenic properties
Summary
The annual worldwide incidence of squamous carcinoma of the head and neck (SCCHN) is approximately 500 000. It is the fifth leading cause of cancer-related death. The frequency of death of patients with metastatic SCCHN has remained essentially constant for the last 30 years, in spite of more sensitive methods of detection, improved surgical/radiotherapeutic techniques and novel chemotherapeutic agents.[1] The 5-year survival is poor. The potential benefits of immunotherapy as an adjunct to conventional forms of treatment of various types of cancer including metastatic SCCHN are well established.[2,3,4,5,6] Activated cytotoxic T lymphocytes (CTL), which are capable of recognizing and destroying cancer cells, are generated in mice, and patients receiving various
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