Method for modulating car-induced immune cells activity
AssigneeCellectis
InventorsPhilippe Duchateau, Alexandre Juillerat, Laurent Poirot
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Abstract
The present invention relates to a method to modulate the level of activation of an engineered immune cell (such as a Chimeric Antigen Receptor T-cell) for immunotherapy. The present invention also relates to cells obtained by the present method, preferably comprising said modulable/tunable chimeric antigen receptors for use in therapeutic or prophylactic treatment.
Claims29
A method comprising:
- contacting an engineered immune cell with an external ligand,
- wherein the engineered immune cell co-expresses a Chimeric Antigen Receptor (CAR) comprising a first dimerization domain comprising FKBP or FRB, the CAR being activated in vivo and/or in vitro by the external ligand, and an engineered inhibitory membrane protein (IMP) complex, the IMP comprising at least one intracellular inhibitory signaling domain from PD1 and one second dimerization domain comprising FKBP or FRB, and
- wherein the external ligand binds to the CAR, which results in a signal transduction through the CAR;
- and
- adding rapamycin or a rapalog that binds to the first dimerization domain comprising FKBP or FRB of the CAR and to the second dimerization domain comprising FKBP or FRB of the IMP to form a non-covalently bonded macromolecular complex between said CAR and IMP.
A method for producing an engineered immune cell expressing a CAR non-covalently bound to an IMP complex, comprising
- transfecting into an immune cell at least a first polynucleotide encoding a CAR comprising a first dimerization domain comprising FKBP or FRB, and at least a second polynucleotide encoding an engineered IMP complex comprising at least one inhibitory signaling domain from PD1 and a second dimerization domain comprising FKBP or FRB that when contacted with rapamycin or a rapalog are capable of non-covalently binding to each other through the presence of the rapamycin or a rapalog, and
- wherein the IMP complex binds to the CAR through the rapamycin or a rapalog.
A CAR/IMP complex comprising at least two transmembrane chimeric polypeptides, wherein
- a first transmembrane polypeptide is a CAR comprising a first dimerization domain comprising FKBP or FRB;
- and
- a second transmembrane polypeptide is an engineered IMP complex, said IMP complex comprising at least one intracellular inhibitory signaling domain from PD1 and a second dimerization domain comprising FKBP or FRB;
- wherein the dimerization domains are capable of non-covalently binding to each other through the presence of rapamycin or a rapalog.
An engineered immune cell comprising a surface expressed CAR and an IMP, said IMP comprising at least one intracellular inhibitory signaling domain from PD1, wherein said CAR and IMP each comprises a dimerization domain comprising FKBP or FRB, both dimerization domains interacting with rapamycin or a rapalog to form a non-covalently bonded macromolecular complex between said CAR and IMP.
Dependencies are inferred from the claim text.