Gene therapy of patient-derived T lymphocytes to target and eradicate colorectal hepatic metastases.
AuthorsSheen, Aali J
Irlam, Joely J
Guest, Ryan D
Sherlock, David J
Hawkins, Robert E
Gilham, David E
AffiliationCancer Research United Kingdom, Department of Medical Oncology, Paterson Institute for Cancer Research, University of Manchester, United Kingdom.
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AbstractPURPOSE: The overall aim of this study was to develop a novel treatment for colorectal cancer based on the use of gene therapy. Genetic modification of T lymphocytes has been used to specifically target and kill tumor cell lines directly. To test the efficacy of this method with clinically relevant materials, this study investigated the potential of T lymphocytes derived from patients with advanced colorectal disease to target autologous primary tumor material. METHODS T lymphocytes isolated preoperatively were modified genetically with recombinant retroviruses encoding CD3zeta-based chimeric immune receptors and were tested for functional activity against freshly isolated autologous tumor cells harvested from hepatic colorectal metastases. RESULTS: Patient-derived T cells were successfully transduced, and chimeric immune receptor expression was confirmed. Carcinoembryonic antigen expression on freshly isolated colorectal tumor cells was also demonstrated by molecular and immunohistochemical techniques. T cells expressing the anticarcinoembryonic antigen receptor were specifically activated by coculture with disaggregated or intact, diced tumor, whereas control non-carcinoembryonic antigen-targeted T-cell populations failed to activate. CONCLUSIONS: These results indicate that gene-targeted primary T lymphocytes depict specific functional activity against autologous colorectal tumor cells. This evidence indicates that chimeric immune receptor-expressing T cells may be able to circumvent the mechanisms used by tumor cells to avoid immune cell activity in vivo. This study emphasizes the potential of this approach as a therapy for carcinoembryonic antigen-expressing primary colorectal tumor and its metastases.
CitationGene therapy of patient-derived T lymphocytes to target and eradicate colorectal hepatic metastases. 2003, 46 (6):793-804 Dis. Colon Rectum
JournalDiseases of the Colon and Rectum