Genetic modification of T cells for immunotherapy

Abstract

Adoptive transfer of antigen-specific T cells is a promising approach for preventing progressive viral infections in immunosuppressed hosts. By contrast, effective T-cell therapy of malignant disease has proven to be much more difficult to achieve. This, in part, reflects the difficulty of isolating high avidity T cells specific for tumor-associated antigens, many of which are self-antigens that have induced some level of tolerance in the host. Even when tumor-reactive T cells can be isolated, the ability of these cells to survive in vivo and traffic to tumor sites is often impaired. Additionally, most tumors employ multiple mechanisms to escape T-cell recognition, including interference in antigen presentation, secretion of inhibitory factors and recruitment of regulatory or immunosuppressive cells. The genetic modification of T cells prior to transfer provides a potential means to overcome many of these obstacles and enhance the efficacy of T-cell therapy. This review article discusses the rationale for genetic modification of T cells, the critical steps involved in gene transfer, and potential advantages and disadvantages of strategies that are now being examined to engineer improved effector T cells for the treatment of human infectious and malignant disease.

Keywords::

• adoptive immunotherapy
• cancer
• gene therapy
• T lymphocytes

Acknowledgements

This work was supported by National Institutes of Health grants R01CA114536 (SRR and CB), R01AI053193 (SRR), CA18029 (SRR), U01HL66947 (SRR and CB), M01RR00037 (SRR), and the SG Komen for the Cure grant PDF0503982 (SRR).

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