TY  - JOUR
AU  - Saleh, Haidy A
AU  - Mitwasi, Nicola
AU  - Ullrich, Martin
AU  - Kubeil, Manja
AU  - Toussaint, Magali
AU  - Deuther-Conrad, Winnie
AU  - Neuber, Christin
AU  - Arndt, Claudia
AU  - R Loureiro, Liliana
AU  - Kegler, Alexandra
AU  - González Soto, Karla Elizabeth
AU  - Belter, Birgit
AU  - Rössig, Claudia
AU  - Pietzsch, Jens
AU  - Frenz, Marcus
AU  - Bachmann, Michael
AU  - Feldmann, Anja
TI  - Specific and safe targeting of glioblastoma using switchable and logic-gated RevCAR T cells.
JO  - Frontiers in immunology
VL  - 14
SN  - 1664-3224
CY  - Lausanne
PB  - Frontiers Media
M1  - DKFZ-2023-00856
SP  - 1166169
PY  - 2023
AB  - 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.
KW  - CAR T cells (Other)
KW  - adaptor CAR platform (Other)
KW  - combinatorial gated targeting (Other)
KW  - glioblastoma (Other)
KW  - immunotherapy (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:37122703
C2  - pmc:PMC10145173
DO  - DOI:10.3389/fimmu.2023.1166169
UR  - https://inrepo02.dkfz.de/record/275757
ER  -