RevCAR-expressing immune effector cells for targeting of Fn14-positive glioblastoma

In more recent studies we have established the unique adaptor chimeric antigen receptor (CAR) platform RevCAR which uses as extracellular CAR domain a peptide epitope instead of an antibody domain. RevCAR adaptors (termed RevCAR target modules, RevTMs) are bispecific antibodies. The reversible ON/OFF switch of the RevCAR system improves the safety compared to conventional CARs. Here we describe for the first time its use for retargeting of both T- and NK-92 cells. In addition, we describe the development and preclinical validation of a novel RevTM for targeting of the fibroblast growth factor-inducible 14 (Fn14) surface receptor which is overexpressed on Glioblastoma (GBM) cells and therefore a promising target for the treatment of GBM. The novel RevTM efficiently redirects RevCAR modified T- and NK92 cells and leads to the killing of GBM cells both in vitro and in vivo. Tumor cell killing is associated with increased IL-2, TNF-α and/or IFN-γ secretion. Hence, these findings give an insight into the complementary potential of both RevCAR T and NK-92 systems as a safe and specific immunotherapeutic approach against GBM.