000343551 001__ 343551
000343551 005__ 20230827173429.0
000343551 0247_ $$2CORDIS$$aG:(EU-Grant)101098331$$d101098331
000343551 0247_ $$2CORDIS$$aG:(EU-Call)ERC-2022-ADG$$dERC-2022-ADG
000343551 0247_ $$2originalID$$acorda_____he::101098331
000343551 035__ $$aG:(EU-Grant)101098331
000343551 150__ $$aTargeting of glycosylation pathways to empower CAR-T therapy of solid tumors.$$y2023-07-01 - 2028-06-30
000343551 372__ $$aERC-2022-ADG$$s2023-07-01$$t2028-06-30
000343551 450__ $$aGlycoCAR$$wd$$y2023-07-01 - 2028-06-30
000343551 5101_ $$0I:(DE-588b)5098525-5$$2CORDIS$$aEuropean Union
000343551 680__ $$aChimeric Antigen Receptor (CAR) T cell therapy uniquely can provide life-long protection against tumor re-emergence upon clearance of even advanced-stage leukemia. However, for the more frequent solid tumor types (carcinomas, lymphomas), clearance of advanced-stage tumors, and especially the subsequent long-term protection, is only rarely achieved. The main reason for this is the multi-pathway immunosuppressive environment that these tumors evolve to overcome the selective pressure imposed by the patient’s immune system. This both hampers the initial attack by CAR-Ts, and often leads to low numbers of long-term persisting CAR-T cells, which tend to be in a state of functional exhaustion. Most attempts at overcoming this, target particular CAR-T cell proteins involved in individual pathways of immunosuppression. However, it is clear from early-stage clinical trials with such engineered CAR-T cells that multiple pathways will need to be tackled at the same time. Inspired by this challenge, I have chosen a radically different path: we are targeting the CAR-T cell glycocalyx, i.e. the assembly of glycosylated structures that forms the outer layer of the cell. The unique property of glycosylation pathways is that they often modulate a large range of cell surface receptor biology at the same time.
Excitingly, this new research line has now generated the first highly promising results with the discovery of a single CAR-T glycogene inactivation that results in robust clearance of a benchmark highly immunosuppressive carcinoma rechallenge, in mice that were CAR-T cured from their primary tumor months earlier. Encouraged by these exciting results that demonstrate strong long-term functional persistence of these glyco-engineered CAR-T cells, we have defined a programme to build on this finding and to explore a candidate set of further glycosylation engineering concepts in CAR-T cells, to further improve CAR-T therapy of solid tumors.
000343551 909CO $$ooai:juser.fz-juelich.de:1012911$$pauthority:GRANT$$pauthority
000343551 909CO $$ooai:juser.fz-juelich.de:1012911
000343551 980__ $$aG
000343551 980__ $$aCORDIS
000343551 980__ $$aAUTHORITY