A phage display selected Fab fragment with MHC class I-restricted specificity for MAGE-A1 allows for retargeting of primary human T lymphocytes

The clinical benefit of adoptive transfer of WC-restricted cytotoxic T lymp hocytes(CTL) for the treatment of cancer is hampered by the low success rat e to generate antitumor CTLs. To bypass the need for tumor-specific CTL, we developed a strategy that allows for grafting of human T lymphocytes with MHC-restricted antigen specificity using in vitro selected human Fab fragme nts fused to the Fc(epsilon )RI-gamma signaling molecule. Retroviral introd uction of a Fab-based chimeric receptor specific for MAGE-A1/HLA-A1 into pr imary human T lymphocytes resulted in binding of relevant peptide/MHC compl exes. Transduced T lymphocytes responded to native MAGE-A1/HLA-A1(POS) targ et cells by specific cytokine production and cytolysis. Therefore, peptide/ MHC-specific Fab fragments represent new alternatives to TCR to confer huma n T lymphocytes with tumor specificity, which provides a promising rational e for developing immunogene therapies.