Heterodimeric inactivatable chimeric antigen receptors

A heterodimeric inactivatable chimeric antigen receptor (CAR) comprising:

• a) a first polypeptide chain comprising:
• i) an extracellular region;
• ii) a first transmembrane (TM) region;
• iii) a first co-stimulatory endodomain (ED);
• and
• iv) a first member of a dimerization pair;
• and
• b) a second polypeptide chain comprising:
• i) optionally, an extracellular region which does not comprise a target-binding region;
• ii) a second TM region;
• iii) optionally, a second co-stimulatory ED;
• iv) a second member of the dimerization pair;
• and
• v) an intracellular signaling ED,
• wherein the first and second member of the dimerization pair form a heterodimer, wherein the heterodimer formed by the first and second member of the dimerization pair is disrupted in the presence of an inhibitory molecule resulting in inhibition of CAR-mediated signaling, and wherein (1) the first member of the dimerization pair comprises a sequence selected from SEQ ID NO:
• 5, SEQ ID NO:
• 22, SEQ ID NO:
• 23, SEQ ID NO:
• 24, SEQ ID NO:
• 24 comprising residues 35-50 of SEQ ID NO:
• 22 in place of residues 51-91 of SEQ ID NO:
• 24, and SEQ ID NO:
• 30, and the second member of the dimerization pair comprises a sequence IAXXLXXIGXXF (SEQ ID NO:
• 179), wherein X is any natural amino acid and L is optionally substituted with A, or (2) the first member of the dimerization pair comprises a sequence IAXXLXXIGXXF (SEQ ID NO:
• 179), wherein X is any natural amino acid and L is optionally substituted with A, and the second member of the dimerization pair comprises a sequence selected from SEQ ID NO:
• 5, SEQ ID NO:
• 22, SEQ ID NO:
• 23, SEQ ID NO:
• 24, SEQ ID NO:
• 24 comprising residues 35-50 of SEQ ID NO:
• 22 in place of residues 51-91 of SEQ ID NO:
• 24, and SEQ ID NO:
• 30, and
• the inhibitory molecule is venetoclax, A-1331852, or A-1155463.