Chimeric receptors and uses thereof in immune therapy

1. A chimeric receptor, comprising:

(a) an extracellular ligand-binding domain of an Fc receptor;

(b) a transmembrane domain;

(c) at least one co-stimulatory signaling domain, which is from a co-stimulatory protein involved in immune cell co-stimulation; and

(d) a cytoplasmic signaling domain comprising an immunoreceptor tyrosine-based activation motif (ITAM);

wherein either (c) or (d) is located at the C-terminus of the chimeric receptor; wherein (c) and (d) are different signaling domains; and wherein if (a) is an extracellular ligand-binding domain of CD16A, (d) does not comprise an ITAM domain of an Fc receptor.

2. The chimeric receptor of claim 1 , wherein (d) is located at the C-terminus of the chimeric receptor.

3. The chimeric receptor of claim 1 , further comprising (e) a hinge domain which is located at the C-terminus of (a) and the N-terminus of (b).

4. The chimeric receptor of claim 1 , wherein the chimeric receptor comprises:

(a) an extracellular ligand-binding domain of F158 FCGR3A or V158 FCGR3A variant,

(b) a hinge and transmembrane domain of CD8α,

(c) a co-stimulatory signaling domain of 4-1BB, and

(d) a cytoplasmic signaling domain of CD3ζ.

5. The chimeric receptor of claim 4 , wherein the chimeric receptor further comprises a signal peptide of CD8α.

6. The chimeric receptor of claim 4 , wherein the extracellular domain of F158 FCGR3A and V158 FCGR3A variant consist of the amino acid sequences of SEQ ID NO:70 and SEQ ID NO:57, respectively.

7. The chimeric receptor of claim 4 , wherein the hinge and transmembrane domains of CD8α consist of the amino acid sequence of SEQ ID NO: 58.

8. The chimeric receptor of claim 4 , wherein the co-stimulatory signaling domain of 4-1BB consists of the amino acid sequence of SEQ ID NO: 59.

9. The chimeric receptor of claim 4 , wherein the cytoplasmic signaling domain of CD3ζ consists of the amino acid sequence of SEQ ID NO: 60.

10. The chimeric receptor of claim 5 , wherein the signal peptide of CD8a consists of the amino acid sequence of SEQ ID NO: 61.

11. The chimeric receptor of claim 4 , which comprises the amino acid sequence of residues 22 to 436 of SEQ ID NO: 1, or residues 22 to 436 of SEQ ID NO: 31.

12. The chimeric receptor of claim 5 , which comprises the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO:31.

13. A nucleic acid comprising a nucleotide sequence encoding a chimeric receptor of claim 1 .

14. A host cell comprising the chimeric receptor of claim 1 .

15. The host cell of claim 14 , wherein the chimeric receptor comprises:

(a) an extracellular ligand-binding domain of F158 FCGR3A or V158 FCGR3A variant,

(b) a hinge and transmembrane domain of CD8a,

(c) a co-stimulatory signaling domain of 4-1BB, and

(d) a cytoplasmic signaling domain of CD3ζ.

16. The host cell of claim 14 , which is a T lymphocyte or an NK cell.

17. The host cell of claim 16 , wherein the T lymphocyte or the NK cell is activated and/or expanded ex vivo.

18. The host cell of claim 16 , wherein the T lymphocyte or NK cell is an autologous T lymphocyte or an autologous NK cell isolated from a patient having a cancer.

19. The host cell of claim 16 , wherein the T lymphocyte or NK cell is an allogenic T lymphocyte or an allogenic NK cell.

20. A pharmaceutical composition comprising the host cell of claim 14 and a pharmaceutically acceptable carrier or excipient.

21. A method for enhancing efficacy of an antibody-based immunotherapy of a cancer in a subject being treated with an anti-cancer antibody, the method comprising administering to the subject a therapeutically effective amount of T lymphocytes or NK cells that express the chimeric receptor of claim 1 .

22. The method of claim 21 , wherein the chimeric receptor comprises:

(a) an extracellular ligand-binding domain of F158 FCGR3A or V158 FCGR3A variant,

(b) a hinge and transmembrane domain of CD8a,

(c) a co-stimulatory signaling domain of 4-1BB, and

(d) a cytoplasmic signaling domain of CD3ζ.

23. The method of claim 21 , wherein the antibody has a humanized Fc portion, which bind to human CD16.

24. The method of claim 21 , wherein the antibody is selected from the group consisting of Rituximab, Trastuzumab, hu14.18K322A, Epratuzumab, Cetuximab, and Labetuzumab.

25. The method of claim 21 , wherein the T lymphocytes or NK cells are autologous T lymphocytes or autologous NK cells isolated from the subject, or wherein the T lymphocytes or NK cells are allogenic cells.

26. The method of claim 25 , wherein, prior to the administration step, the autologous T lymphocytes or autologous NK cells are activated and/or expanded ex vivo.

27. The method of claim 25 , wherein the allogeneic T lymphocytes are T lymphocytes, in which the expression of the endogenous T cell receptor has been inhibited or eliminated.

28. The method of claim 21 , wherein the chimeric receptor is introduced into the T lymphocytes or the NK cells by a method selected from the group consisting of retroviral transduction, lentiviral transduction, DNA electroporation, and RNA electroporation.

29. A method of enhancing a T lymphocyte or an NK cell antibody-dependent cell cytotoxicity (ADCC) in a subject, the method comprising administering to the subject a therapeutically effective amount of T lymphocytes or NK cells that express the chimeric receptor of claim 1 .

30. The method of claim 29 , wherein the chimeric receptor comprising:

(a) an extracellular ligand-binding domain of F158 FCGR3A or V158 FCGR3A variant,

(b) the hinge and transmembrane domain of CD8a,

(c) a co-stimulatory signaling domain of 4-1BB, and

(d) a cytoplasmic signaling domain of CD3ζ.

31. A method for preparing immune cells expressing a chimeric receptor, comprising:

(i) providing a population of immune cells;

(ii) introducing into the immune cells a nucleic acid encoding a chimeric receptor of claim 1 ; and

culturing the immune cells under conditions allowing for expression of the chimeric receptor.