Chimeric antigen receptors targeting B-cell maturation antigen and uses thereof

1. A chimeric antigen receptor (CAR), comprising an extracellular antigen-binding domain that binds to B cell maturation antigen (BCMA), a transmembrane domain, and an intracellular domain, wherein the extracellular antigen-binding domain comprises:

(a) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO:1, and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 of the light chain variable region sequence set forth in SEQ ID NO:2;

(b) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO:5, and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 of the light chain variable region sequence set forth in SEQ ID NO:6;

(c) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO:9, and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 of the light chain variable region sequence set forth in SEQ ID NO:10;

(d) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO:13, and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 of the light chain variable region sequence set forth in SEQ ID NO:14;

(e) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO:17, and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 of the light chain variable region sequence set forth in SEQ ID NO:18;

(f) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO:21, and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 of the light chain variable region sequence set forth in SEQ ID NO:22;

(g) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO:25, and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 of the light chain variable region sequence set forth in SEQ ID NO:26;

(h) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO:29, and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 of the light chain variable region sequence set forth in SEQ ID NO:30;

(i) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO:33, and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 of the light chain variable region sequence set forth in SEQ ID NO:34;

(j) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO:37, and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 of the light chain variable region sequence set forth in SEQ ID NO:38;

(k) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO:41, and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 of the light chain variable region sequence set forth in SEQ ID NO:42;

(l) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO:45, and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 of the light chain variable region sequence set forth in SEQ ID NO:46;

(m) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO:49, and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 of the light chain variable region sequence set forth in SEQ ID NO:50;

(n) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO:53, and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 of the light chain variable region sequence set forth in SEQ ID NO:54;

(o) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO:57, and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 of the light chain variable region sequence set forth in SEQ ID NO:58;

(p) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO:61, and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 of the light chain variable region sequence set forth in SEQ ID NO:62; or

(q) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO:65, and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 of the light chain variable region sequence set forth in SEQ ID NO:66.

2. A chimeric antigen receptor (CAR), comprising an extracellular antigen-binding domain that binds to B cell maturation antigen (BCMA), a transmembrane domain, and an intracellular domain, wherein the extracellular antigen-binding domain comprises:

(a) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 89, 90, and 91, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 92, 93, and 94, respectively;

(b) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 95, 96, and 97, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 98, 99, and 100, respectively;

(c) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 101, 102, and 103, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 104, 105, and 106, respectively;

(d) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 107, 108, and 109, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 110, 111, and 112, respectively;

(e) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 113, 114, and 115, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 116, 117, and 118, respectively;

(f) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 119, 120, and 121, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 122, 123, and 124, respectively;

(g) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 125, 126, and 127, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 128, 129, and 130, respectively;

(h) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 131, 132, and 133, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 134, 135, and 136, respectively;

(i) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 137, 138, and 139, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 140, 141, and 142, respectively;

(j) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 143, 144, and 145, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 146, 147, and 148, respectively;

(k) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 149, 150, and 151, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 152, 153, and 154, respectively;

(l) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 155, 156, and 157, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 158, 159, and 160, respectively;

(m) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 161, 162, and 163, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 164, 165, and 166, respectively;

(n) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 167, 168, and 169, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 170, 171, and 172, respectively

(o) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 173, 174, and 175, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 176, 177, and 178, respectively;

(p) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 179, 180, and 181, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 182, 183, and 184, respectively; or

(q) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 185, 186, and 187, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 188, 189, and 190, respectively.

3. The CAR of claim 1 , wherein:

(a) the heavy chain variable region comprises an amino acid sequence that has at least about 90% sequence identity to the sequence set forth in SEQ ID NO:1, and the light chain variable region comprises an amino acid sequence that has at least about 90% sequence identity to the sequence set forth in SEQ ID NO:2;

(b) the heavy chain variable region comprises an amino acid sequence that has at least about 90% sequence identity to the sequence set forth in SEQ ID NO:5, and the light chain variable region comprises an amino acid sequence that has at least about 90% sequence identity to the sequence set forth in SEQ ID NO:6;

(c) the heavy chain variable region comprises an amino acid sequence that has at least about 90% sequence identity to the sequence set forth in SEQ ID NO:9, and the light chain variable region comprises an amino acid sequence that has at least about 90% sequence identity to the sequence set forth in SEQ ID NO:10;

(d) the heavy chain variable region comprises an amino acid sequence that has at least about 90% sequence identity to the sequence set forth in SEQ ID NO:13, and the light chain variable region comprises an amino acid sequence that has at least about 90% sequence identity to the sequence set forth in SEQ ID NO:14;

(e) the heavy chain variable region comprises an amino acid sequence that has at least about 90% sequence identity to the sequence set forth in SEQ ID NO:17, and the light chain variable region comprises an amino acid sequence that has at least about 90% sequence identity to the sequence set forth in SEQ ID NO:18;

(f) the heavy chain variable region comprises an amino acid sequence that has at least about 90% sequence identity to the sequence set forth in SEQ ID NO:21, and the light chain variable region comprises an amino acid sequence that has at least about 90% sequence identity to the sequence set forth in SEQ ID NO:22;

(g) the heavy chain variable region comprises an amino acid sequence that has at least about 90% sequence identity to the sequence set forth in SEQ ID NO:25, and the light chain variable region comprises an amino acid sequence that has at least about 90% sequence identity to the sequence set forth in SEQ ID NO:26;

(h) the heavy chain variable region comprises an amino acid sequence that has at least about 90% sequence identity to the sequence set forth in SEQ ID NO:29, and the light chain variable region comprises an amino acid sequence that has at least about 90% sequence identity to the sequence set forth in SEQ ID NO:30;

(i) the heavy chain variable region comprises an amino acid sequence that has at least about 90% sequence identity to the sequence set forth in SEQ ID NO:33, and the light chain variable region comprises an amino acid sequence that has at least about 90% sequence identity to the sequence set forth in SEQ ID NO:34;

(j) the heavy chain variable region comprises an amino acid sequence that has at least about 90% sequence identity to the sequence set forth in SEQ ID NO:37, and the light chain variable region comprises an amino acid sequence that has at least about 90% sequence identity to the sequence set forth in SEQ ID NO:38;

(k) the heavy chain variable region comprises an amino acid sequence that has at least about 90% sequence identity to the sequence set forth in SEQ ID NO:41, and the light chain variable region comprises an amino acid sequence that has at least about 90% sequence identity to the sequence set forth in SEQ ID NO:42;

(l) the heavy chain variable region comprises an amino acid sequence that has at least about 90% sequence identity to the sequence set forth in SEQ ID NO:45, and the light chain variable region comprises an amino acid sequence that has at least about 90% sequence identity to the sequence set forth in SEQ ID NO:46;

(m) the heavy chain variable region comprises an amino acid sequence that has at least about 90% sequence identity to the sequence set forth in SEQ ID NO:49, and the light chain variable region comprises an amino acid sequence that has at least about 90% sequence identity to the sequence set forth in SEQ ID NO:50;

(n) the heavy chain variable region comprises an amino acid sequence that has at least about 90% sequence identity to the sequence set forth in SEQ ID NO:53, and the light chain variable region comprises an amino acid sequence that has at least about 90% sequence identity to the sequence set forth in SEQ ID NO:54

(o) the heavy chain variable region comprises an amino acid sequence that has at least about 90% sequence identity to the sequence set forth in SEQ ID NO:57, and the light chain variable region comprises an amino acid sequence that has at least about 90% sequence identity to the sequence set forth in SEQ ID NO:58;

(p) the heavy chain variable region comprises an amino acid sequence that has at least about 90% sequence identity to the sequence set forth in SEQ ID NO:61, and the light chain variable region comprises an amino acid sequence that has at least about 90% sequence identity to the sequence set forth in SEQ ID NO:62; or

(q) the heavy chain variable region comprises an amino acid sequence that has at least about 90% sequence identity to the sequence set forth in SEQ ID NO:65, and the light chain variable region comprises an amino acid sequence that has at least about 90% sequence identity to the sequence set forth in SEQ ID NO:66.

4. The CAR of claim 3 , wherein:

(a) the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:1, and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO:2;

(b) the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:5, and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO:6;

(c) the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:9, and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO:10;

(d) the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:13, and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO:14;

(e) the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:17, and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO:18;

(f) the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:21, and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO:22;

(g) the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:25, and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO:26;

(h) the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:29, and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO:30;

(i) the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:33, and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO:34;

(j) the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:37, and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO:38;

(k) the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:41, and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO:42;

(l) the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:45, and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO:46;

(m) the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:49, and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO:50;

(n) the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:53, and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO:54;

(o) the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:57, and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO:58;

(p) the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:61, and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO:62; or

(q) the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:65, and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO:66.

5. The CAR of claim 2 , wherein the heavy chain variable region comprises a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 119, 120, and 121, respectively; and the light chain variable region comprises a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 122, 123, and 124, respectively.

6. The CAR of claim 2 , wherein the heavy chain variable region comprises a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 167, 168, and 169, respectively; and the light chain variable region comprises a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 170, 171, and 172, respectively.

7. The CAR of claim 2 , wherein the heavy chain variable region comprises a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 173, 174, and 175, respectively; and the light chain variable region comprises a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 176, 177, and 178, respectively.

8. The CAR of claim 2 , wherein the heavy chain variable region comprises a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 179, 180, and 181, respectively; and the light chain variable region comprises a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 182, 183, and 184, respectively.

9. The CAR of claim 2 , wherein the heavy chain variable region comprises a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 185, 186, and 187, respectively; and the light chain variable region comprises a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 188, 189, and 190, respectively.

10. The CAR of claim 4 , wherein the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:21, and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO:22.

11. The CAR of claim 4 , wherein the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 53, and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 54.

12. The CAR of claim 4 , wherein the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:57, and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO:58.

13. The CAR of claim 4 , wherein the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 61, and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 62.

14. The CAR of claim 4 , wherein the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 65, and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 66.

15. The CAR of claim 1 , wherein the extracellular antigen-binding domain comprises a linker positioned between the heavy chain variable region and the light chain variable region.

16. The CAR of claim 1 , wherein the extracellular antigen-binding domain is a single-chain variable fragment (scFv).

17. The CAR of claim 2 , wherein the extracellular antigen-binding domain comprises a linker positioned between the heavy chain variable region and the light chain variable region.

18. The CAR of claim 2 , wherein the extracellular antigen-binding domain is a single-chain variable fragment (scFv).

19. The CAR of claim 4 , wherein the extracellular antigen-binding domain comprises a linker positioned between the heavy chain variable region and the light chain variable region.

20. The CAR of claim 4 , wherein the extracellular antigen-binding domain is a single-chain variable fragment (scFv).

21. The CAR of claim 16 , wherein the extracellular antigen-binding domain is a human scFv.

22. The CAR of claim 1 , wherein the extracellular antigen-binding domain comprises the amino acid sequence set forth in SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, SEQ ID NO: 79, SEQ ID NO: 80, SEQ ID NO: 81, SEQ ID NO: 82, SEQ ID NO: 83, SEQ ID NO: 84, SEQ ID NO: 85, SEQ ID NO: 86, SEQ ID NO: 87, or SEQ ID NO: 88.

23. The CAR of claim 22 , wherein the extracellular antigen-binding domain comprises the amino acid sequence set forth in SEQ ID NO:77.

24. The CAR of claim 22 , wherein the extracellular antigen-binding domain comprises the amino acid sequence set forth in SEQ ID NO:85.

25. The CAR of claim 22 , wherein the extracellular antigen-binding domain comprises the amino acid sequence set forth in SEQ ID NO:86.

26. The CAR of claim 22 , wherein the extracellular antigen-binding domain comprises the amino acid sequence set forth in SEQ ID NO:87.

27. The CAR of claim 22 , wherein the extracellular antigen-binding domain comprises the amino acid sequence set forth in SEQ ID NO:88.

28. The CAR of claim 1 , wherein the BCMA comprises the amino acid sequence set forth in SEQ ID NO:71.

29. The CAR of claim 2 , wherein the BCMA comprises the amino acid sequence set forth in SEQ ID NO:71.

30. The CAR of claim 4 , wherein the BCMA comprises the amino acid sequence set forth in SEQ ID NO:71.

31. The CAR of claim 1 , wherein the extracellular antigen-binding domain binds to a non-linear epitope of BCMA.

32. The CAR of claim 1 , wherein the extracellular antigen-binding domain of the CAR binds to B cell maturation antigen (BCMA) with a binding affinity (K D ) of from about 1×10 −9 M to about 1×10 −8 M.

33. The CAR of claim 1 , wherein the transmembrane domain comprises a CD8 polypeptide, a CD28 polypeptide, a CD3t polypeptide, a CD4 polypeptide, a 4-1BB polypeptide, an OX40 polypeptide, an ICOS polypeptide, a CTLA-4 polypeptide, a PD-1 polypeptide, a LAG-3 polypeptide, a 2B4 polypeptide, a BTLA polypeptide, a synthetic peptide, or a combination thereof.

34. The CAR of claim 33 , wherein the transmembrane domain comprises a CD8 polypeptide.

35. The CAR of claim 33 , wherein the transmembrane domain comprises a CD28 polypeptide.

36. The CAR of claim 1 , wherein the intracellular domain comprises a CD3t polypeptide.

37. The CAR of claim 36 , wherein the intracellular domain comprises at least one signaling region that is a co-stimulatory signaling region.

38. The CAR of claim 37 , wherein the co-stimulatory signaling region comprises a CD28 polypeptide, a 4-1BB polypeptide, an OX40 polypeptide, an ICOS polypeptide, a DAP-10 polypeptide, or a combination thereof.

39. The CAR of claim 38 , wherein the co-stimulatory signaling region comprises a CD28 polypeptide.

40. The CAR of claim 38 , wherein the co-stimulatory signaling region comprises a 4-1BB polypeptide.

41. The CAR of claim 40 , wherein the transmembrane domain comprises a CD28 polypeptide.

42. The CAR of claim 2 , wherein the intracellular domain comprises a CD3ζ polypeptide and at least one signaling region that is a co-stimulatory signaling region.

43. The CAR of claim 42 , wherein the co-stimulatory signaling region comprises a 4-1BB polypeptide.

44. The CAR of claim 43 , wherein the transmembrane domain comprises a CD28 polypeptide.

45. The CAR of claim 4 , wherein the intracellular domain comprises a CD3ζ polypeptide and at least one signaling region that is a co-stimulatory signaling region.

46. The CAR of claim 45 , wherein the co-stimulatory signaling region comprises a 4-1BB polypeptide.

47. The CAR of claim 46 , wherein the transmembrane domain comprises a CD28 polypeptide.

48. An immunoresponsive cell comprising the CAR of claim 1 .

49. An immunoresponsive cell comprising the CAR of claim 2 .

50. An immunoresponsive cell comprising the CAR of claim 4 .

51. The immunoresponsive cell of claim 48 , wherein the immunoresponsive cell is selected from the group consisting of a T cell, a Natural Killer (NK) cell, a human embryonic stem cell, a lymphoid progenitor cell, a T cell-precursor cell, and a stem cell from which a lymphoid cell may be differentiated.

52. A T cell comprising the CAR of claim 1 .

53. A T cell comprising the CAR of claim 2 .

54. A T cell comprising the CAR of claim 4 .

55. A pharmaceutical composition comprising an effective amount of the immunoresponsive cell of claim 48 and a pharmaceutically acceptable excipient.

56. A pharmaceutical composition comprising an effective amount of the immunoresponsive cell of claim 49 and a pharmaceutically acceptable excipient.

57. A pharmaceutical composition comprising an effective amount of the immunoresponsive cell of claim 50 and a pharmaceutically acceptable excipient.