Celluris developed a novel CAR-T mechanism that is able to modulate the tumoral microenvironment and also be switched-off by the administration of both receptor epitope peptides, constituting a regulatory safety switch. Celluris contruct, named RfuCAR, comprises a bispecific in tandem receptor CAR, which includes a scFv that recognizes and ligates surface molecules on tumoral cells (tumoral target) and the extra-cellular signal receptor(ECR). The scFv motif will ligate the tumoral cell and lead them to apoptosis exactly as a regular CAR works. The ECR will ligate to the specific signal secreted in the tumoral microenvironment inhibiting the extra-cellular signal pathways. This inhibition will decrease the extra-cellular pathway activation leading to the modulation of tumoral cell proliferation. Regulation of this extra-cellular signal content in the microenvironment will modulate other cytokines activation in the tumoral environment, putativelly preventing the oversecretion of cytokines observed in cytokine release syndrome (CRS) and neurotoxicity events.

If any of the toxic CAR-T effects are detected in the patient, the RfuCAR cells action can be transiently switched-off and also tuned by the administration of different peptides that link to ECR, ECR with ligand and/or tumoral scFv epitopes. These peptides will be able to link the two RfuCAR preventing the ligation to tumoral cells and/or extra-cellular signal inhibiting or modulating RfuCAR activity. The RfuCAR cells will still be able to proliferate in the patient and get back to kill tumoral cells as soon as the administration of the peptides ceases.

RfuCAR construct and mechanism is a novel approach that aims at regulate the tumoral microenvironment not only throught the cell signaling pathway, but also to the secreted molecules from macrophages and other cells.  In vitro and in vivo models and tests are being conducted in order to corroborate the advantages of Celluris RfuCAR applications.