Methods of conditioning patients for T cell therapy

Patent metadata

Field	Value
Publication number	US-10322146-B2
Application number	US-201715649369-A
Country	US
Kind code	B2
Filing date	Jul 13, 2017
Priority date	May 28, 2015
Publication date	Jun 18, 2019
Grant date	Jun 18, 2019

Abstract

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.

First claim

What is claimed is:

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 to about 50 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; wherein the engineered CAR T cells express a chimeric antigen receptor that comprises an scFv, and wherein the scFv is capable of binding CD19.

2. The method of claim 1 , wherein the therapeutically effective amount of the engineered CAR T cells is about 1×10 6 to about 5×10 6 engineered CAR T 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 to about 600 mg/m 2 /day and a dose of fludarabine between 30 mg/m 2 /day and 50 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; wherein the engineered CAR T cells express a chimeric antigen receptor that comprises an scFv, and wherein the scFv is capable of binding CD19.

4. The method of claim 1 , wherein the dose of fludarabine is about 30 mg/m 2 /day.

5. The method of claim 3 , wherein the dose of fludarabine is about 30 mg/m 2 /day.

6. The method of claim 3 , wherein the patient has non-Hodgkin's lymphoma.

7. The method of claim 3 , wherein the dose of fludarabine is administered daily for two days to five days.

8. The method of claim 1 , wherein the dose of fludarabine is administered daily for two days to five days.

9. The method of claim 7 , wherein the dose of fludarabine is administered daily for three days.

10. 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).

11. 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).

12. The method of claim 3 , wherein the patient has leukemia.

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 the group consisting of IL-10, IL-5, IP-10, MCP-1, PLGF, CRP, sICAM-1, and any combination thereof.

15. The method of claim 1 , wherein the dose of fludarabine is administered daily for two days.

16. The method of claim 1 , wherein the dose of fludarabine is administered daily for three days.

17. The method of claim 1 , wherein the dose of cyclophosphamide and the dose of fludarabine are administered daily on the same day.

18. The method of claim 1 , wherein the dose of cyclophosphamide is administered at least about one day before the dose of fludarabine.

19. The method of claim 1 , wherein the dose of fludarabine is administered at least about one day before the dose of cyclophosphamide.

20. The method of claim 1 , wherein the therapeutically effective amount of engineered CAR T cells is about 1×10 6 or about 2×10 6 cells/kg.

21. The method of claim 1 , wherein the therapeutically effective amount of engineered CAR T cells is about 2×10 6 cells/kg.

22. The method of claim 3 , wherein the therapeutically effective amount of engineered CAR T cells is about 1×10 6 or about 2×10 6 cells/kg.

23. The method of claim 1 , wherein the dose of cyclophosphamide is about 500 mg/m 2 /day, and wherein the dose of fludarabine is about 30 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 500mg/m 2 /day and a dose of fludarabine at about 30 mg/m 2 /day to about 50 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; wherein the engineered CAR T cells express a chimeric antigen receptor that comprises an scFv, and wherein the scFv is capable of binding CD19.

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 CART cells is about 1×10 6 or about 2×10 6 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 to about 50 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; wherein the dose of fludarabine is administered daily for about three days; wherein the engineered CAR T cells express a chimeric antigen receptor that comprises an scFv, and wherein the scFv is capable of binding CD19.

29. The method of claim 28 , wherein the therapeutically effective amount of engineered CART cells is about 1×10 6 or about 2×10 6 cells/kg.

30. The method of claim 3 , wherein the dose of cyclophosphamide is about 500 mg/m 2 /day, and wherein the dose of fludarabine is about 30 mg/m 2 /day.

Assignees

• Kite Pharma Inc
• Us Health

Inventors

• Bot Adrian
• Wiezorek Jeffrey S
• GO William
• JAIN Rajul
• Kochenderfer James N
• Rosenberg Steven A

Classifications

• A61K38/2053

  IL-8 · CPC title

• A61K38/2013

  IL-2 · CPC title

• A61K31/675 Primary

  having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61P35/02

  specific for leukemia · CPC title