Chimeric NK receptor and methods for treating cancer
The present invention relates to chimeric immune receptor molecules for reducing or eliminating tumors. The chimeric receptors are composed a C-type lectin-like natural killer cell receptor, or a protein associated therewith, fused to an immune signaling receptor containing an immunoreceptor tyrosine-based activation motif. Methods for using the chimeric receptors are further provided.
1. A method of treating a subject comprising an autoimmune or inflammatory disease or a transplant recipient which comprises administering to a subject in need thereof an effective amount of recombinant T cells which express a nucleic acid construct comprising: a first nucleic acid sequence encoding a promoter operably linked to a second nucleic acid sequence encoding a chimeric receptor polypeptide, said second nucleic acid sequence comprising a nucleic acid encoding a C-type lectin-like type II natural killer cell receptor polypeptide fused to a nucleic acid encoding an immune signaling receptor polypeptide comprising SEQ ID NO:1, wherein the encoded chimeric receptor polypeptide is expressed on the surface of said T cell, and said C-type lectin type II natural killer receptor polypeptide comprised therein binds a ligand and activates said immune signaling receptor polypeptide comprising SEQ ID NO: 1.
2. The method of claim 1 wherein the T cell further comprises a suicide gene.
3. The method of claim 1 wherein the nucleic acid encoding said C-type lectin-like NK cell type II receptor in said nucleic acid construct is at the C-terminus of the encoded chimeric receptor polypeptide and the nucleic acid which encodes the immune signaling receptor polypeptide is at the N-terminus of the encoded chimeric receptor polypeptide.
4. The method of claim 1 wherein the C-type lectin-like NK cell type II receptor in said nucleic acid construct is selected from Dectin-1, Mast cell function-associated antigen, HNKR-P1A, LLT1, CD69, CD69 homolog, CD72, CD94, KLRF1, Oxidized LDL receptor, CLEC-1, CLEC-2, NKG2D, NKG2C, NKG2A, NKG2E, and Myeloid DAP12-associating lectin.
5. The method of claim 1 wherein the C-type lectin-like NK cell type II receptor encoded by said nucleic acid construct comprises human NKG2D.
6. The method of claim 1 wherein the C-type lectin-like NK cell type II receptor encoded by said nucleic acid construct comprises a human NKG2D polypeptide having the sequence set forth in SEQ ID NO:2 or is human NKG2C having the sequence set forth in SEQ ID NO:3.
7. The method of claim 5 , wherein the nucleic acid construct further comprises a nucleic acid encoding DAP10 or DAP12.
8. The method of claim 6 , wherein the nucleic acid construct further comprises a nucleic acid encoding DAP10 or DAP12.
9. The method of claim 1 wherein the immune signaling receptor encoded by said nucleic acid construct is CD3-zeta having the sequence set forth in SEQ ID NO:6, or is human Fc epsilon receptor-gamma chain having the sequence set forth in SEQ ID NO:7 or it comprises the cytoplasmic domain or a splicing variant thereof.
10. The method of claim 1 wherein the chimeric receptor polypeptide encoded by said nucleic acid construct comprises a fusion of NKG2D and CD3-zeta.
11. The method of claim 1 , wherein the T cells comprise primary human T cells.
12. The method of claim 4 , wherein the T cells comprise primary human T cells.
13. The method of claim 5 , wherein the T cells comprise primary human T cells.
14. The method of claim 6 , wherein the T cells comprise primary human T cells.
15. The method of claim 7 , wherein the T cells comprise primary human T cells.
16. The method of claim 8 , wherein the T cells comprise primary human T cells.
17. The method of claim 9 , wherein the T cells comprise primary human T cells.
18. The method of claim 10 , wherein the T cells comprise primary human T cells.
19. The method of claim 1 , wherein said T cells comprise T regulatory or T suppressor cells.