A novel approach in cancer immunotherapy: natural killer cells expressing T cell receptors

Official URL: http://risc01.sabanciuniv.edu/record=b1649211 (Table of Contents)

T cell receptor (TCR) gene therapy is developed to redirect cytotoxic T cells towards selected epitopes of tumor antigens. However, due to the heterodimeric nature of the TCR molecule, alpha and beta chains introduced by gene delivery have a risk of pairing with the endogenously expressed complementary alpha or beta chains in the T cell. This phenomenon named as “mispairing” gives rise to TCRs of unpredictable specificity and causes potentially lethal side effects. Natural killer (NK) cells were discovered 40 years ago, by their ability to recognize and kill tumor cells without the requirement of prior immunization or stimulation. Since then, NK cells have grown to be promising agents for adoptive immunotherapy of cancer. In the last decade, several NK cell based anti-cancer products have been taken to clinical trials with promising results. However, to manufacture more efficient NK cell therapy products, it is essential to develop novel strategies to increase safety, efficiency and specificity with approaches such as retargeting NK cells against specific antigens which to date has only been possible with chimeric antigen receptors (CARs). In this thesis, we propose to use NK cells for TCR gene therapy aiming to reprogram them to selectively target tumor or virus antigens in complex with major histocompatibility complex. Our results convincingly demonstrate that the introduction of a functional TCR complex to NK cells via lentiviral gene transfer dramatically enhances the efficiency to mount antigen-specific cytotoxic activity. To our knowledge, the transfer of a TCR into an NK cell has never been reported before. Our strategy does not only have the potential to open up a whole new chapter in the field of cancer immunotherapy but also provides a final and definitive solution for the mispairing problem observed in TCR gene therapy.