TCR transgenes and transgene cassettes for TCR gene therapy: status in 2008

Abstract

The genetic introduction of T cell receptor genes into T cells has been developed over the past decade as a strategy to induce defined antigen-specific T cell immunity. With the potential value of TCR gene therapy well-established in murine models and the feasibility of infusion of TCR-modified autologous T cells shown in a first phase I trial, the next key step will be to transform TCR gene transfer from an experimental technique into a robust clinical strategy. In this review, we discuss the different properties of the TCR transgene and transgene cassette that can strongly affect both the efficacy and the safety of TCR gene transfer.

Fig. 1

Choice of vector and design of TCR transgene cassette determine TCR expression. Human PBL were transduced with the retroviral vectors MX and MP71 encoding the codon-optimized and murinized MART-1 specific 1D3 TCR either in an α-IRES-β configuration (MX), or in a β-P2A-α (MP71) configuration. Percentage of MART-1-tetramer⁺CD8⁺ T cells of total CD8⁺ T cells is indicated

Fig. 2

Theoretical relationship between the available TCR repertoire and the inherent antigen selectivity of TCR in different TCR selection systems. While the exact relationship between inherent antigen selectivity and the breadth of the available repertoire for the different systems is unknown, as a general rule it is likely that the ability to recognize a broader variety of antigens is associated with a lower inherent antigen selectivity