Enhanced antitumor activity mediated by human 4‐1BB‐engineered T cells

4‐1BB (CD137) is a costimulatory molecule transiently expressed on the T‐cell surface after TCR engagement, whereas its ligand 4‐1BBL can be found on professional antigen‐presenting cells, but more importantly, also on tumor cells. As the role of the 4‐1BB/4‐1BBL pathway has emerged central to CD8⁺ T‐cell responses and survival, we sought to test its relevance in the context of genetically modified human T cells. To that end, T cells purified from healthy donors and from vaccinated‐melanoma patients were transduced to express high levels of constitutive 4‐1BB. 4‐1BB‐transduced T cells were cocultured with melanoma tumor lines and exhibited enhanced cytokine secretion, upregulation of activation markers as well as increased cytotoxicity in a chick‐chorioallantoic membrane model of human melanoma tumors. In addition, these cells expanded and proliferated at a higher rate, expressed heightened levels of the antiapoptotic molecule Bcl_XL and were also relatively insensitive to immunosuppression mediated by transforming growth factor‐β, compared to control cells. We also show that 4‐1BBL expression on the target cell is essential to 4‐1BB‐mediated functional improvement. Overall, we conclude that the modification of human T cells with 4‐1BB yields enhanced antitumor function which may have important applications in therapies based on the genetic modification of patient lymphocytes.