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 CD81 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 vaccinatedmelanoma 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-b, 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.Costimulation actively shapes T-lymphocyte response as it can prevent the cells from entering a state of unresponsiveness or anergy. Costimulatory molecules are divided into two important families: the B7/CD28 and the tumor necrosis factors-receptor family.

T-cells “à la CAR-T(e)” – Genetically engineering T-cell response against cancer

“…1) [217] by T cells can promote cell proliferation both in vitro and in vivo. Moreover, we recently showed that the constitutive expression of 4-1BB/CD137 in engineered T cells can lead to improved cytokine secretion, proliferation and cytotoxicity in vitro an in ovo model we developed [218].…”

Nanomedicine for Cancer Immunotherapy: Tracking Cancer-Specific T-Cellsin Vivowith Gold Nanoparticles and CT Imaging

“…31 We further showed that such an approach may be enhanced at the protein level (TCR structure), [32][33][34][35] or by improving cellular function. 36,37 However, further advancement of T-cell based therapy requires methods that can overcome the challenges of clinical treatment. We propose a novel, clinically applicable methodology for non-invasive longitudinal and quantitative tumor-specific T-cell tracking, based on the combination of CT as an imaging modality and gold nanoparticles (GNPs) as labeling agents.…”

Tumor necrosis factor receptor superfamily member 9 is upregulated in the endothelium and tumor cells in melanoma brain metastasis

“…[5,6] An alternative approach uses genetically modified human T-cells to express higher TNFRSF9 levels. [7] TNFRSF9 stimulation has been suggested as a treatment for metastatic cancers. [8] However, to date there is only poor data about the distribution of TNFRSF9 in brain metastases, which still constitute one of the most deleterious clinical conditions in tumor patients.…”