Publikationsrepositorium - Helmholtz-Zentrum Dresden-Rossendorf

Chimeric antigen receptors (CARs) are used for redirection of T cells against tumor cells and have demonstrated remarkable therapeutic effects against some hematological cancers. The modular system termed RevCAR can overcome the dangerous side effects associated with conventional CAR T cell therapy, such as cytokine release syndrome. It is composed of RevCAR T cells and a bispecific molecule target module, termed RevTM. This system is highly safe since RevCAR T cell activity can be controlled by RevTM and immediately switched off if side effects are detected. It is also versatile, since the same RevCAR T cell can be directed to different tumor-associated antigens (TAA) simply by adding RevTMs with different specificities. However, to improve the effectiveness in the treatment of solid tumors, the immunosuppressive tumor microenvironment (TME) still needs to be addressed. For this purpose, we have developed novel RevTMs targeting immune checkpoint molecules such as PD-L1, which are often upregulated by cancer cells to escape the immune cells. We have demonstrated that our novel RevTMs can redirect RevCAR T cells to specifically kill cell lines expressing immune checkpoint molecules. In addition to this strategy, the combinatorial targeting of a TAA and an immune checkpoint is very promising strategy to overcome the immunosuppressive microenvironment of solid tumors and thus to improve the treatment outcome.