Immunotherapy with metabolic enzyme expression
View Patent ↗The present invention provides, in some embodiments, methods of promoting an immune response in a subject in need thereof, comprising administering to the subject a population of immune cells that express an enzyme that facilitates immune cell function in a nutrient-poor environment. The invention also provides, in other embodiments, compositions comprising an ex vivo population of immune cells expressing an enzyme that enhances immune cell function in a nutrient-poor environment.
1. A composition comprising an ex vivo population of immune cells that express an enzyme that catalyzes the formation of aspartate from asparagine or the formation of alanine from pyruvate and glutamate.
2. The composition of claim 1 , wherein the immune cells are T cells.
3. The composition of claim 2 , wherein the immune cells are chimeric antigen receptor (CAR)-T cells.
4. The composition of claim 1 , wherein the enzyme is asparaginase.
5. The composition of claim 4 , wherein the asparaginase is a naturally-occurring asparaginase or a variant of a naturally-occurring asparaginase having at least about 80% amino acid sequence identity to a naturally-occurring asparaginase.
6. The composition of claim 4 , wherein the asparaginase comprises, consists essentially of or consists of the sequence of SEQ ID NO:1.
7. A method of promoting an immune response in a subject in need thereof, comprising administering to the subject an effective amount of a population of immune cells that express an enzyme that catalyzes the formation of aspartate from asparagine or the formation of alanine from pyruvate and glutamate.
8. A method for treating a cancer in a subject in need thereof, comprising administering to the subject an effective amount of a population of anti-cancer immune cells that express an enzyme that catalyzes the formation of aspartate from asparagine or the formation of alanine from pyruvate and glutamate.
9. The method of claim 7 , wherein the immune cells are T cells.
10. The method of claim 9 , wherein the immune cells are CAR-T cells.
11. The method of claim 7 , wherein the immune cells express asparaginase.
12. The method of claim 11 , wherein the asparaginase is a naturally-occurring asparaginase or a variant of a naturally-occurring asparaginase having at least about 80% amino acid sequence identity to a naturally-occurring asparaginase.
13. The method of claim 11 , wherein the asparaginase comprises, consists essentially of or consists of the sequence of SEQ ID NO:1.
14. The method of claim 7 , further comprising administering one or more additional therapeutic agents to the subject.
15. The method of claim 14 , wherein the one or more additional therapeutic agents comprises a checkpoint inhibitor.
16. The method of claim 15 , wherein the checkpoint inhibitor is a PD-1, PD-L1 or CTLA-4 checkpoint inhibitor.
17. A method of enhancing an immunotherapy in a subject receiving the immunotherapy, comprising administering to the subject an effective amount of a population of immune cells that express an enzyme that catalyzes the formation of aspartate from asparagine or the formation of alanine from pyruvate and glutamate.
18. The method of claim 17 , wherein the immunotherapy comprises a checkpoint inhibitor.
19. The method of claim 18 , wherein the checkpoint inhibitor is a PD-1, PD-L1 or CTLA-4 checkpoint inhibitor.
20. The method of claim 17 , wherein the immunotherapy is a CAR-T therapy.