Summary
Chimeric 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.
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.
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More information & hyperlinks
| Web resources: | https://cordis.europa.eu/project/id/101098331 |
| Start date: | 01-07-2023 |
| End date: | 30-06-2028 |
| Total budget - Public funding: | 2 498 435,00 Euro - 2 498 435,00 Euro |
Cordis data
Original description
Chimeric 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.
Status
SIGNEDCall topic
ERC-2022-ADGUpdate Date
31-07-2023
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