Human mesothelin chimeric antigen receptors and uses thereof

An immune effector cell comprising a nucleic acid molecule comprising a nucleic acid sequence encoding a chimeric antigen receptor (CAR) wherein the CAR comprises:

• i) a human anti-mesothelin binding domain comprising:
• (a) a light chain variable region comprising:
• a light chain complementary determining region 1 (LC CDR1) comprising the amino acid sequence of SEQ ID NO:
• 209;
• a light chain complementary determining region 2 (LC CDR2) comprising the amino acid sequence of SEQ ID NO:
• 233;
• and a light chain complementary-determining region 3 (LC CL)R3) comprising the amino acid sequence of SEQ ID NO:
• 257;
• and
• (b) a heavy chain variable region comprising:
• a heavy chain complementary determining region 1 (HC CDR1) comprising the amino acid sequence of SEQ ID NO:
• 144;
• a heavy chain complementary determining region 2 (HC CDR2) comprising the amino acid sequence of SEQ ID NO:
• 162;
• and a heavy chain complementary determining region 3 (HC CDR3) comprising the amino acid sequence of SEQ. ID NO:
• 185;
• ii) a transmembrane domain selected from the transmembrane domain of a protein selected from the group consisting of the alpha, beta or zeta chain of the T-cell receptor, CD28, CD3 epsilon, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137 and CD154;
• iii) a costimulatory domain;
• and
• iv) an intracellular signaling domain comprising the amino acid sequence of SEQ ID NO:
• 10;
• wherein the isolated nucleic acid molecule does not comprise a nucleic acid sequence encoding an inducible promoter;
• wherein the CAR is not a regulatable CAR;
• and
• wherein the immune effector cell expresses a protein comprising a first polypeptide comprising an extracellular portion of PD1, PD-L1, CEACAM, LAG3, CTLA4, VISTA, CD160, BMA, LAIR1, TIM3, 2B4 or TIGIT and a second polypeptide comprising a costimulatory domain and/or a primary signaling domain.