Methods and compositions for the activation of gamma-delta T-cells
The present invention relates generally to methods and compositions for gene therapy and immunotherapy that activate gamma delta T-cells, and in particular, can be used in the treatment of various cancers and infectious diseases.
1. A method of activating a GD T cell comprising:
contacting a target cell with a bisphosphonate drug; and
infecting, in the presence of the GD T cell, the target cell with a viral delivery system that encodes at least one genetic element comprising a small RNA capable of inhibiting production of FDP S,
wherein the GD T cell is activated.
2. The method of claim 1 , further comprising killing of the target cell by the activated GD T cell.
3. The method of claim 1 , wherein the target cell is a cancer cell.
4. The method of claim 3 , wherein the cancer cell is derived from a carcinoma, a leukemia, a lymphoma, a sarcoma, a myeloma, a mesothelioma, a mixed type, or mixtures thereof.
5. The method of claim 1 , wherein activating the GD T cell comprises increasing tumor necrosis factor TNF-α expression by the GD T cell.
6. The method of claim 1 , wherein the small RNA is a microRNA or a shRNA.
7. The method of claim 6 , wherein the shRNA comprises a sequence having at least 80% identity with SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, or SEQ ID NO: 4.
8. The method of claim 7 , wherein the shRNA comprises SEQ ID NO: 1, SEQ ID NO:
2, SEQ ID NO: 3, or SEQ ID NO: 4.
9. The method of claim 6 , wherein the microRNA comprises a sequence having at least 80% identity with SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, or SEQ ID NO: 10.
10. The method of claim 9 , wherein the microRNA comprises SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, or SEQ ID NO: 10.
11. The method of claim 1 , wherein the bisphosphonate drug comprises zoledronic acid.
12. The method of claim 1 , wherein the contacting step and the infecting step occur simultaneously.
13. The method of claim 1 , wherein the contacting step and the infecting step occur sequentially.
14. A method of activating a lymphocyte cell comprising:
contacting a target cell with a bisphosphonate drug; and
infecting, in the presence of the lymphocyte cell, the target cell with a viral delivery system that encodes at least one genetic element comprising a small RNA capable of inhibiting production of an enzyme of the mevalonate pathway,
wherein the lymphocyte cell is activated.
15. The method of claim 14 , further comprising killing of the target cell by the activated lymphocyte.
16. The method of claim 14 , wherein the enzyme of the mevalonate pathway is FDPS.
17. The method of claim 14 , wherein the lymphocyte is a GD T cell.
18. The method of claim 17 , wherein activating the lymphocyte comprise increasing TNF-α expression by the GD T cell.
19. The method of claim 14 , wherein the target cell is a cancer cell.
20. The method of claim 19 , wherein the cancer cell is derived from a carcinoma, a leukemia, a lymphoma, a sarcoma, a myeloma, a mesothelioma, a mixed type, or mixtures thereof.