1 research outputs found
Engineering antigenâspecific NK cell lines against the melanomaâassociated antigen tyrosinase via TCR gene transfer
Introduction of Chimeric Antigen Receptors to NK cells has so far been the main practical method for targeting NK cells to specific surface antigens. In contrast, T cell receptor (TCR) gene delivery can supply large populations of cytotoxic Tâlymphocytes (CTL) targeted against intracellular antigens. However, a major barrier in the development of safe CTLâTCR therapies exists, wherein the mispairing of endogenous and genetically transferred TCR subunits leads to formation of TCRs with offâtarget specificity. To overcome this and enable specific intracellular antigen targeting, we have tested the use of NK cells for TCR gene transfer to human cells. Our results show that ectopic expression of TCR α/ÎČ chains, along with CD3 subunits, enables the functional expression of an antigenâspecific TCR complex on NK cell lines NKâ92 and YTS, demonstrated by using a TCR against the HLAâA2ârestricted tyrosinaseâderived melanoma epitope, Tyr368â377. Most importantly, the introduction of a TCR complex to NK cell lines enables MHCârestricted, antigenâspecific killing of tumor cells both in vitro and in vivo. Targeting of NK cells via TCR gene delivery stands out as a novel tool in the field of adoptive immunotherapy which can also overcome the major hurdle of âmispairingâ in TCR gene therapy