Gene transfer of MHC-restricted receptors

Adoptive therapy with allogeneic or tumor-specific T-cells has shown substantial clinical effects for several human tumors, but the widespread application of this strategy remains a daunting task. The antigen specificity of T-lymphocytes is solely determined by the T-cell receptor (TCR) alpha and beta chains. Consequently, genetic transfer of TCR chains may form an alternative and potentially appealing strategy to impose a desirable tumor-antigen specificity onto cytotoxic or helper T-cell populations. In this strategy, autologous or donor-derived T-cell populations are equipped with a TCR of defined reactivity in short-term ex vivo cultures, and re-infusion of the redirected cells is used to supply T-cell reactivity against defined tumor-specific antigens. We have previously described the genetic introduction of T-cell receptor genes into peripheral T-cells in mouse model systems. Here we discuss the requirements for the successful genetic modification of murine T-lymphocytes and the subsequent use of such genetically modified cells in in vivo models.