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T lymphocytes isolated from patients with advanced colorectal cancer are suitable for gene immunotherapy approaches
A J Sheen1, D J Sherlock, J Irlam
1Cancer Research UK Department of Medical Oncology, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, University of Manchester, UK.
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.
Insights
Gene immunotherapy shows promise for metastatic colorectal cancer. Patient T cells effectively expressed a chimeric immune receptor targeting cancer cells, demonstrating feasibility for autologous gene therapy.
Area of Science:
- Immunology
- Oncology
- Gene Therapy
Background:
- Metastatic colorectal cancer (CRC) has a poor 5-year survival rate despite current treatments.
- Gene immunotherapy is an emerging strategy to improve CRC treatment efficacy.
- Tumor-associated defects in patient T lymphocytes may hinder gene-targeted T cell therapy.
Purpose of the Study:
- To assess the feasibility of transducing T lymphocytes from advanced CRC patients with a chimeric immune receptor.
- To evaluate the functional anti-tumor activity of these gene-modified T cells against CEA-expressing CRC cells.
Main Methods:
- Primary T lymphocytes were isolated from 10 patients with advanced colorectal cancer.
- T cells were transduced using retroviral gene transfer to express a chimeric immune receptor (single-chain variable fragment specific for carcinoembryonic antigen fused to CD3zeta).
- Transduced T cells were expanded and tested for cytotoxic activity against CEA-expressing tumor cells.
Main Results:
- T lymphocytes from all 10 patients were successfully transduced and expanded without selection.
- Gene-modified T cells exhibited functional, tumor-specific cytotoxic activity against CEA-expressing colorectal cancer cells.
- Control cultures showed negligible cytotoxic activity.
Conclusions:
- Patient-derived T lymphocytes can be effectively engineered for autologous gene immunotherapy in colorectal cancer.
- This approach demonstrates the potential of using patient T cells to develop personalized anti-cancer therapies.
- Successful transduction and functional activity highlight the feasibility of this gene immunotherapy strategy for advanced CRC.
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