The use of engineered T cells has proven to be successful in the field of cancer therapy. In vivo persistence of these genetically redirected T cells, which depends on their differentiation profile, plays a central role in the achievement of treatment efficacy. Indeed, less differentiated T cells proliferate and persist longer in vivo compared to their more differentiated counterparts, while having functional antitumor capacities. In this view, cord blood derived T cells display a more naïve phenotype compared to peripheral blood derived T cells. Hence, cord blood could be used as a source of T cells in order to generate gene-modified cancer-targeting cells able to persist in vivo, with the ability to ensure immunosurveillance in treated patients.
Cord blood derived T cells were isolated, activated and cultured with IL-2 or IL-7 and IL-15, before a retroviral transduction with a vector encoding a TCR targeting HPV16-E7/HLA-DR4. Transgenic T cell functional capacities were then evaluated by flow cytometry. The differentiation profile of cord blood derived T cells, genetically redirected or not and cultured in different conditions, were also analyzed.
The IL-7 and IL-15 culture condition resulted in the generation of gene-modified T cells maintaining a higher transgenic TCR expression over time compared with the IL-2 culture condition. Functional assays revealed that genetically redirected T cells cultured in both conditions were reactive against HLA-DR4+ BLCL pulsed with an E7-derived peptide. Both T cell products lead to comparable interferon-γ, tumor necrosis factor-α and interleukine-2 secretion. These results are consistent with the fact that no outstanding difference was detected between both culture conditions regarding transduced and untransduced T cell differentiation profile.
In conclusion, we were able to generate cord blood derived transgenic T cells which were specific for an HPV16-E7 peptide, with a higher TCR expression over time when cultured with IL-7 and IL-15. Our study supports that cord blood units could be used as a source of T cells to develop cost-reducing and easy to access adoptive cancer immunotherapy.
Clinical trial identification
Legal entity responsible for the study
UMR1098: INSERM, EFS BFC, Univ. Bourgogne Franche-Comté.
This work was supported by the Ligue Nationale Contre le Cancer, and by the MiMedi project funded by BPI France (grant No. DOS0060162/00) and the European Union through the European Regional Development Fund of the Region Bourgogne-Franche-Comte (grant No. FC0013440). C.M. has benefited from a fellowship from Nancy Regional University Hospital.
All authors have declared no conflicts of interest.