Establishment of a platform for generating NK-CAR cells with greater therapeutic effectiveness in vitro and in vivo

Abstract

In recent decades, immunotherapy has been increasingly used to treat Cancer and T cells genetically modified with a Chimeric Antigen Receptor (CAR) has shown great clinical results for Leukemias and Lymphomas. However, some adverse effects associated to CAR-T cells have been described, such as neurotoxicity, cytokine release syndrome, graft versus host disease and the destruction of normal cells expressing the target CAR antigen, showing the importance of alternative strategies for Cancer treatment. Studies with Natural Killer cells (NK) expressing CAR have shown promising results, but limitations still exist, such as reduced cell proliferation in vitro and in vivo and reduced expression of CAR vector. The hypothesis of this project is that the development of CAR specific for NK cells will generate CAR-NK cells with greater capacity for proliferation, activation, cytokine secretion and cytolytic activity, resulting in greater therapeutic efficacy. Thus, in order to define the best condition for transduction, culture and expansion, primary and lineage NK cells will be transduced with lentiviral vectors containing different receptors, co-receptors and cytokines involved to activation of NK cells. Then, the NK-CAR cells will be characterized, and their function and therapeutic effectiveness will be evaluated in vitro and in vivo. (AU)