title: T lymphocytes isolated from patients with advanced colorectal cancer are suitable for gene immunotherapy approaches.
abstract: Despite improvements in treatment, the 5-year survival for metastatic colorectal cancer remains poor. Novel approaches such as gene immunotherapy are being investigated to improve treatment. Retroviral gene transfer methods have been shown to transduce primary human T lymphocytes effectively resulting in the expression of therapeutic genes. However, a number of defects have been identified in T lymphocytes isolated from patients bearing tumour, which may have critical implications for the development of gene-targeted T cells as an anticancer therapy. To address this issue, primary T lymphocytes were isolated from patients with advanced colorectal cancer and tested for their ability to be transduced and to express subsequently a chimeric immune receptor consisting of a single-chain antibody fragment antigen-binding moiety specific for carcinoembryonic antigen (CEA) fused to the T cell receptor (TCR) CD3zeta chain. In 10 out of 10 patients, T lymphocytes were transduced, expanded in the absence of selection and tested for functional activity against CEA-expressing tumour cells. In each case, functional-specific cytotoxic activity was observed. Negligible activity was found in control cultures. This study highlights the feasibility of patient-derived T lymphocytes as a source of immune cells for autologous gene immunotherapy approaches.
authors.affiliation: Cancer Research UK Department of Medical Oncology, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, University of Manchester, UK.
authors.forename: A J
authors.initials: AJ
authors.lastname: Sheen
authors.forename: D J
authors.initials: DJ
authors.lastname: Sherlock
authors.forename: J
authors.initials: J
authors.lastname: Irlam
authors.forename: R E
authors.initials: RE
authors.lastname: Hawkins
authors.forename: D E
authors.initials: DE
authors.lastname: Gilham
mesh_terms: D000328:Adult; D000368:Aged; D002272:Carcinoembryonic Antigen / Q000032:analysis; D018920:Coculture Techniques; D015179:Colorectal Neoplasms / Q000276:immunology / Q000628:therapy*; D015316:Genetic Therapy; D006801:Humans; D016219:Immunotherapy, Adoptive; D007376:Interleukin-2 / Q000627:therapeutic use; D008875:Middle Aged; D012190:Retroviridae / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured
chemical_list: D002272:Carcinoembryonic Antigen; D007376:Interleukin-2