Gene therapy of patient-derived T lymphocytes to target and eradicate colorectal hepatic metastases.
OBJECTIVE
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.
Sheen
Aali J
AJ
Cancer Research United Kingdom, Department of Medical Oncology, Paterson Institute for Cancer Research, University of Manchester, United Kingdom.
Irlam
Joely
J
Kirillova
Natalia
N
Guest
Ryan D
RD
Sherlock
David J
DJ
Hawkins
Robert E
RE
Gilham
David E
DE
D002272:Carcinoembryonic Antigen / Q000032:analysis; D018920:Coculture Techniques; D015179:Colorectal Neoplasms / Q000473:pathology*; D018390:Gene Targeting; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000276:immunology / Q000556:secondary* / Q000628:therapy*; D008213:Lymphocyte Activation; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000276:immunology; D012190:Retroviridae / Q000235:genetics; D013601:T-Lymphocytes; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured
D002272:Carcinoembryonic Antigen; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins