Gene therapy of patient-derived T lymphocytes to target and eradicate colorectal hepatic metastases.

2.50
Hdl Handle:
http://hdl.handle.net/10541/82126
Title:
Gene therapy of patient-derived T lymphocytes to target and eradicate colorectal hepatic metastases.
Authors:
Sheen, Aali J; Irlam, Joely J; Kirillova, Natalia; Guest, Ryan D; Sherlock, David J; Hawkins, Robert E; Gilham, David E
Abstract:
PURPOSE: 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.
Affiliation:
Cancer Research United Kingdom, Department of Medical Oncology, Paterson Institute for Cancer Research, University of Manchester, United Kingdom.
Citation:
Gene therapy of patient-derived T lymphocytes to target and eradicate colorectal hepatic metastases. 2003, 46 (6):793-804 Dis. Colon Rectum
Journal:
Diseases of the Colon and Rectum
Issue Date:
Jun-2003
URI:
http://hdl.handle.net/10541/82126
DOI:
10.1097/01.DCR.0000069958.83926.5E
PubMed ID:
12794582
Type:
Article
Language:
en
ISSN:
0012-3706
Appears in Collections:
All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorSheen, Aali J-
dc.contributor.authorIrlam, Joely J-
dc.contributor.authorKirillova, Natalia-
dc.contributor.authorGuest, Ryan D-
dc.contributor.authorSherlock, David J-
dc.contributor.authorHawkins, Robert E-
dc.contributor.authorGilham, David E-
dc.date.accessioned2009-09-22T15:14:17Z-
dc.date.available2009-09-22T15:14:17Z-
dc.date.issued2003-06-
dc.identifier.citationGene therapy of patient-derived T lymphocytes to target and eradicate colorectal hepatic metastases. 2003, 46 (6):793-804 Dis. Colon Rectumen
dc.identifier.issn0012-3706-
dc.identifier.pmid12794582-
dc.identifier.doi10.1097/01.DCR.0000069958.83926.5E-
dc.identifier.urihttp://hdl.handle.net/10541/82126-
dc.description.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.en
dc.language.isoenen
dc.subjectColorectal Canceren
dc.subjectLiver Canceren
dc.subjectCultured Tumour Cellsen
dc.subject.meshCarcinoembryonic Antigen-
dc.subject.meshCoculture Techniques-
dc.subject.meshColorectal Neoplasms-
dc.subject.meshGene Targeting-
dc.subject.meshGene Therapy-
dc.subject.meshGene Transfer Techniques-
dc.subject.meshHumans-
dc.subject.meshImmunohistochemistry-
dc.subject.meshLiver Neoplasms-
dc.subject.meshLymphocyte Activation-
dc.subject.meshReceptors, Antigen, T-Cell-
dc.subject.meshRecombinant Fusion Proteins-
dc.subject.meshRetroviridae-
dc.subject.meshT-Lymphocytes-
dc.subject.meshTransduction, Genetic-
dc.subject.meshTumor Cells, Cultured-
dc.titleGene therapy of patient-derived T lymphocytes to target and eradicate colorectal hepatic metastases.en
dc.typeArticleen
dc.contributor.departmentCancer Research United Kingdom, Department of Medical Oncology, Paterson Institute for Cancer Research, University of Manchester, United Kingdom.en
dc.identifier.journalDiseases of the Colon and Rectumen

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