Immune cell compositions and methods of use
Disclosed herein are cells that are immune cells or precursor cells thereof, which cells recombinantly express a chimeric antigen receptor (CAR), and a dominant negative form of an inhibitor of a cell-mediated immune response of the immune cell, wherein the CAR binds to a cancer antigen. Also disclosed herein are T cells that recognize and are sensitized to a cancer antigen, which T cells recombinantly express a dominant negative form of an inhibitor of a T cell-mediated immune response. Additionally provided are methods of using such cells to treat cancer in a subject in need thereof.
1. A polypeptide that is a dominant negative form of programmed death 1 (PD-1), wherein the dominant negative form (a) lacks a signaling domain, (b) comprises a CD8 transmembrane domain, and (c) comprises an extracellular domain comprising the ligand binding domain of PD-1, wherein the extracellular domain is fused to the CD8 transmembrane domain, and wherein the dominant negative form comprises amino acids 21-244 of SEQ ID NO: 43.
2. A polypeptide that is a dominant negative form of programmed death 1 (PD-1), wherein the dominant negative form (a) lacks a signaling domain, (b) comprises a CD8 transmembrane domain, and (c) comprises an extracellular domain comprising the ligand binding domain of PD-1, wherein the extracellular domain is fused to the CD8 transmembrane domain, and wherein the sequence of the dominant negative form in mature form lacking a signal peptide consists of amino acids 21-244 of SEQ ID NO: 43.
3. A nucleic acid encoding the polypeptide of claim 1 .
4. A vector comprising the nucleic acid of claim 3 .
5. A cell comprising the nucleic acid of claim 3 .
6. The cell of claim 5 , wherein the cell is a T cell.
7. A cell that is an immune cell or precursor thereof, which cell recombinantly expresses a dominant negative form of programmed death 1 (PD-1), wherein the dominant negative form (a) lacks a signaling domain, (b) comprises a CD8 transmembrane domain, and (c) comprises an extracellular domain comprising the ligand binding domain of PD-1, wherein the extracellular domain is fused to the CD8 transmembrane domain, wherein the cell is transduced with a nucleic acid encoding the dominant negative form, and wherein the encoded dominant negative form comprises the sequence of SEQ ID NO: 43.
8. A cell that is an immune cell or precursor cell thereof, which cell recombinantly expresses the polypeptide of claim 1 .
9. A cell that is an immune cell or precursor thereof, which cell recombinantly expresses the polypeptide of claim 2 .
10. The cell of claim 7 , wherein the cell is a T cell.
11. The cell of claim 8 , wherein the cell is a T cell.
12. The cell of claim 9 , wherein the cell is a T cell.
13. A pharmaceutical composition comprising a therapeutically effective amount of the T cell of claim 11 ; and a pharmaceutically acceptable carrier.
14. A pharmaceutical composition comprising a therapeutically effective amount of the T cell of claim 12 ; and a pharmaceutically acceptable carrier.
15. A nucleic acid encoding the polypeptide of claim 2 .
16. A vector comprising the nucleic acid of claim 15 .
17. A cell comprising the nucleic acid of claim 15 .
18. The cell of claim 17 , wherein the cell is a T cell.