Evaluation of the therapeutic efficacy of anti-GD2 CAR-NK cells with GITRL expression in vitro and in vivo models of tumors of neuroectodermal origin

Abstract

Therapies using CAR cells are available via autologous processes, as T cells require high HLA compatibility and allogeneic therapies have a high chance of developing graft-versus-host disease. Allogeneic therapeutic processes (off-the-shelf) allow immediate availability of cells, reducing patient waiting time. The generation of NK-CAR cells is an alternative, due to its high cytotoxic capacity and fewer restrictions on HLA compatibility, enabling its use in an allogeneic context. The microenvironment of solid tumors presents physical and metabolic barriers that hinder the entry and survival of cells in the immune system. NK cells have shown excellent antitumor responses, however, optimizations in the development of NK-CAR cells are needed to obtain a persistent response. The purpose of this study is to use a 4-generation CAR (armored NK-CAR) to enhance the antitumor activity of NK-CAR cells. Cells will be modified with anti GD2 CAR followed by co-stimulation of CD28 and CD3, and secreting GITRL to suppress the action of regulatory T cells in the tumor microenvironment, reducing local immunosuppression. To test this hypothesis, the potential for expansion and cytotoxicity of NK-CAR cells will be evaluated in vitro and in vivo in a model of human glioblastoma multiforme, an aggressive neoplasm of neuroectodermal origin with high clinical incidence. Therefore, the development of off-the-shelf NK-CAR therapy has the potential to provide a unique and safer approach to modulate the tumor microenvironment with less or no systemic adverse effects. (AU)