Specific and safe targeting of glioblastoma using switchable and logic-gated RevCAR T cells


Specific and safe targeting of glioblastoma using switchable and logic-gated RevCAR T cells

Abdelfatah Saleh Hassan, H. A.; Mitwasi, N.; Ullrich, M.; Kubeil, M.; Toussaint, M.; Deuther-Conrad, W.; Neuber, C.; Arndt, C.; Rodrigues Loureiro, L. R.; Kegler, A.; González Soto, K. E.; Belter, B.; Rössig, C.; Pietzsch, J.; Frenz, M.; Bachmann, M.; Feldmann, A.

Glioblastoma (GBM) is still an incurable tumor that is associated with high
recurrence rate and poor survival despite the current treatment regimes. With
the urgent need for novel therapeutic strategies, immunotherapies, especially
chimeric antigen receptor (CAR)-expressing T cells, represent a promising
approach for specific and effective targeting of GBM. However, CAR T cells
can be associated with serious side effects. To overcome such limitation, we
applied our switchable RevCAR system to target both the epidermal growth
factor receptor (EGFR) and the disialoganglioside GD2, which are expressed in
GBM. The RevCAR system is a modular platform that enables controllability,
improves safety, specificity and flexibility. Briefly, it consists of RevCAR T cells
having a peptide epitope as extracellular domain, and a bispecific target module
(RevTM). The RevTM acts as a switch key that recognizes the RevCAR epitope and
the tumor-associated antigen, and thereby activating the RevCAR T cells to kill
the tumor cells. However, in the absence of the RevTM, the RevCAR T cells are
switched off. In this study, we show that the novel EGFR/GD2-specific RevTMs
can selectively activate RevCAR T cells to kill GBM cells. Moreover, we show that
gated targeting of GBM is possible with our Dual-RevCAR T cells, which have
their internal activation and co-stimulatory domains separated into two
receptors. Therefore, a full activation of Dual-RevCAR T cells can only be
achieved when both receptors recognize EGFR and GD2 simultaneously via
RevTMs, leading to a significant killing of GBM cells both in vitro and in vivo.

Keywords: RevCAR; CAR T cell therapy; immunotherapy; combinatorial tumor targeting

Permalink: https://www.hzdr.de/publications/Publ-36813
Publ.-Id: 36813