title: Enhanced antitumor activity mediated by human 4-1BB-engineered T cells.
abstract: 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.
authors.affiliation: Laboratory of Tumor Immunology and Immunotherapy, The Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat, Gan, Israel.
authors.forename: Inbal
authors.initials: I
authors.lastname: Daniel-Meshulam
authors.forename: Miryam
authors.initials: M
authors.lastname: Horovitz-Fried
authors.forename: Cyrille J
authors.initials: CJ
authors.lastname: Cohen
mesh_terms: D053330:4-1BB Ligand / Q000032:analysis; D049109:Cell Proliferation; D003602:Cytotoxicity, Immunologic; D006801:Humans; D008545:Melanoma / Q000276:immunology*; D020800:Receptor, Nerve Growth Factor / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology*; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000032:analysis / Q000502:physiology*; D014611:Vaccination
chemical_list: D053330:4-1BB Ligand; D020800:Receptor, Nerve Growth Factor; C505714:TNFRSF9 protein, human; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9
keywords: 4-1BB; T-cell engineering; T-cells; immunotherapy