Methods of conditioning patients for T cell therapy
The invention provides methods of increasing the efficacy of a T cell therapy in a patient in need thereof. The invention includes a method of conditioning a patient prior to a T cell therapy, wherein the conditioning involves administering a combination of cyclophosphamide and fludarabine.
1. A method of treating a patient having a tumor comprising (i) administering to the patient a dose of cyclophosphamide at about 500 mg/m 2 /day to about 600 mg/m 2 /day and a dose of fludarabine at about 30 mg/m 2 /day and (ii) administering to the patient a therapeutically effective amount of from about 1×10 6 to about 5×10 6 engineered CAR T cells/kg; wherein the dose of cyclophosphamide is administered daily for three days.
2. The method of claim 1 , wherein the therapeutically effective amount of the engineered CAR T cells is about 1×10 6 or about 2×10 6 cells/kg.
3. A method of conditioning a patient in need of a T cell therapy comprising (i) administering to the patient a dose of cyclophosphamide at about 500 mg/m 2 /day and to about 600 mg/m 2 /day and a dose of fludarabine at about 30 mg/m 2 /day; and
(ii) administering to the patient a therapeutically effective amount of engineered CAR T cells;
wherein the dose of cyclophosphamide is administered daily for three days.
4. The method of claim 3 , wherein the tumor comprises non-Hodgkin's lymphoma.
5. The method of claim 3 , wherein the dose of fludarabine is administered daily for two days to five days.
6. The method of claim 1 , wherein the dose of fludarabine is administered daily for two days to five days.
7. The method of claim 5 , wherein the dose of fludarabine is administered daily for three days.
8. The method of claim 3 , wherein the patient has diffuse large B cell lymphoma (DLBCL), primary mediastinal large B cell lymphoma (PMBCL), or follicular lymphoma (FL).
9. The method of claim 3 , wherein the administration of cyclophosphamide and/or fludarabine begins at least about five days prior to administration of the T cell therapy (day 0).
10. The method of claim 1 , wherein the engineered CART cells express a chimeric antigen receptor that comprises an scFv antibody, wherein the scFv antibody is capable of binding a tumor antigen.
11. The method of claim 3 , wherein the patient has leukemia.
12. The method of claim 10 , wherein the tumor antigen is CD19.
13. The method of claim 1 , wherein the patient after the administration of cyclophosphamide and fludarabine exhibits an increased serum concentration, compared to the serum level prior to the administration of cyclophosphamide and fludarabine, of a homeostatic cytokine selected from interleukin 7 (IL-7), interleukin 15 (IL-15), interleukin 10 (IL-10), interleukin 5 (IL-5), gamma-induced protein 10 (IP-10), interleukin 8 (IL-8), monocyte chemotactic protein 1 (MCP-1), placental growth factor (PLGF), C-reactive protein (CRP), soluble intercellular adhesion molecule 1 (sICAM-1), soluble vascular adhesion molecule 1 (sVCAM-1), and any combination thereof.
14. The method of claim 13 , wherein the homeostatic cytokine is selected from IL-10, IL-5, IP-10, MCP-1, PLGF, CRP, sICAM-1, and any combination thereof.
15. The method of claim 1 , wherein the patient is further subjected to retreatment witha dose of cyclophosphamide and a dose of fludarabine.
16. The method of claim 1 , wherein the dose of fludarabine is administered daily for two days.
17. The method of claim 1 , wherein the dose of fludarabine is administered daily for three days.
18. The method of claim 1 , wherein the dose of cyclophosphamide and the dose of fludarabine are administered daily on the same day.
19. The method of claim 1 , wherein the dose of cyclophosphamide is administered at least about one day before the dose of fludarabine.
20. The method of claim 1 , wherein the dose of fludarabine is administered at least about one day before the dose of cyclophosphamide.
21. The method of claim 1 , wherein the therapeutically effective amount of T cells is about2×10 6 engineered CAR T cells/kg.
22. The method of claim 3 , wherein the therapeutically effective amount of T cells is about 1×10 6 or about 2×10 6 engineered CAR T cells/kg.
23. The method of claim 1 , wherein the dose of cyclophosphamide is about500 mg/m 2 /day.
24. The method of claim 1 , wherein the dose of cyclophosphamide is about 550 mg/m 2 /day.
25. A method of treating a patient having a tumor comprising (i) administering to the patient a dose of cyclophosphamide at about 500 mg/m 2 /day and a dose of fludarabine at about 30 mg/m 2 /day and (ii) administering to the patient a therapeutically effective amount of engineered CAR T cells, wherein the dose of cyclophosphamide is administered daily for three days.
26. The method of claim 25 , wherein the dose of cyclophosphamide and the dose of fludarabine are administered daily on the same day.
27. The method of claim 25 , wherein the therapeutically effective amount of engineered T cells is about 1×10 6 or about 2×10 6 engineered CAR T cells/kg.
28. A method of treating a patient having a tumor comprising (i) administering to the patient a dose of cyclophosphamide at about 600 mg/m 2 /day and a dose of fludarabine at about 30 mg/m 2 /day and (ii) administering to the patient a therapeutically effective amount of engineered CAR T cells; wherein the dose of cyclophosphamide is administered daily for about three days; and
wherein the dose of fludarabine is administered daily for about three days.
29. The method of claim 28 , wherein the T cells are CART cells.
30. The method of claim 28 , wherein the therapeutically effective amount of engineered T cells is about 1×10 6 or about 2×10 6 engineered CAR T cells/kg.