Exploitation du potentiel thérapeutique des cellules Natural Killer pour traiter les cancers
Despite the overwhelming success of chimeric antigen receptor (CAR)-modified T lymphocytes against leukemias, some limitations have been observed, such as the risk of developing CRS and the lack of efficiency in solid tumor settings. Many other cell-based immunotherapies have been explored to circumvent those caveats. Natural killer (NK) cells present many advantageous properties that could make them a very promising alternative to T cells in immunotherapies. However, NK cells have some caveats, mainly they are hard to modify using conventional tools and they are sensitive to many inhibitory signals expressed by cancer cells. We managed to greatly improve the efficiency of transduction using a novel viral glycoprotein, BaEVRless. In the process, we determined that this novel enveloppe glycoprotein did not modify the phenotype or intrinsic activity of the transduced NK cells. In a leukemia model, we also showed that the BaEVRless can be used to generate functionnal CAR-NK cells. Moreover, the NK cells can be transduced with larger lentiviral constructions bearing two simultaneous CAR-coding sequences. We also demonstrated that Clustered Regularly Interspersed Short Palindromic Repeats (CRISPR) modification of NK cells using a non-viral approach was possible. Using this approach, we generated NK cells with lower NKG2A expression, that were resistant to the inhibitory effects of HLA-E. This affect was seen in a breast cancer model and a colon cancer model. The in vitro results were confirmed in an in vivo preclinical xenogeneic model. Together, those results represent two improvements applicable to NK cell-based immunotherapies.
Transduction HLA-E NKG2A Immunotherapy NK cells Chimeric antigen receptors