Methods of use for CAR T cells
The present disclosure relates to methods of treating a patient with a cancer by administering to the patient a composition comprising CAR T cells wherein the CAR T cells comprise a CAR and the CAR comprises an E2 anti-fluorescein antibody fragment, and administering to the patient a small molecule linked to a targeting moiety by a linker. The disclosure also relates to compositions for use in such methods.
1. A method of treating a patient for cancer, the method comprising
i) administering to the patient a first dose of a compound, or a pharmaceutically acceptable salt thereof, wherein the compound comprises a small molecule ligand linked to a targeting moiety by a linker, wherein the small molecule ligand binds to a receptor on a cancer cell; and
ii) administering to the patient at least a second dose of the compound, or a pharmaceutically acceptable salt thereof, wherein the second dose of the compound, or the pharmaceutically acceptable salt thereof, is at least about 50 percent lower in amount than the first dose of the compound, or the pharmaceutically acceptable salt thereof;
wherein the patient has been administered, prior to step (i), a dose of a CAR (chimeric antigen receptor) T cell composition comprising CAR T cells, wherein the CAR T cells comprise a CAR directed to the targeting moiety, wherein the CAR comprises an E2 anti-fluorescein antibody fragment, and wherein the CAR T cells comprise a polypeptide having at least about 80% identity to SEQ ID NO: 2.
2. The method of claim 1 , wherein the second dose of the compound, or the pharmaceutically acceptable salt thereof, is at least about 60 percent lower in amount than the first dose of the compound, or the pharmaceutically acceptable salt thereof.
3. The method of claim 1 , wherein the second dose of the compound, or the pharmaceutically acceptable salt thereof, is at least about 70 percent lower in amount than the first dose of the compound, or the pharmaceutically acceptable salt thereof.
4. The method of claim 1 , wherein the second dose of the compound, or the pharmaceutically acceptable salt thereof, is at least about 80 percent lower in amount than the first dose of the compound, or the pharmaceutically acceptable salt thereof.
5. The method of claim 1 , wherein the second dose of the compound, or the pharmaceutically acceptable salt thereof, is at least about 90 percent lower in amount than the first dose of the compound, or the pharmaceutically acceptable salt thereof.
6. The method of claim 1 , wherein the second dose of the compound, or the pharmaceutically acceptable salt thereof, is at least about 95 percent lower in amount than the first dose of the compound, or the pharmaceutically acceptable salt thereof.
7. The method of claim 1 , wherein the CAR T cells comprise a polypeptide comprising the sequence of SEQ ID NO: 2.
8. The method of claim 1 , wherein the dose of the CAR T cells in the CAR T cell composition administered to the patient is at least about 1 million cells.
9. The method of claim 8 , wherein the dose of the CAR T cells in the CAR T cell composition administered to the patient is about 10 million of the CAR T cells.
10. The method of claim 8 , wherein the dose of the CAR T cells in the CAR T cell composition administered to the patient is about 20 million of the CAR T cells.
11. The method of claim 8 , wherein the dose of the CAR T cells in the CAR T cell composition administered to the patient is about 30 million of the CAR T cells.
12. The method of claim 1 , wherein cytokine release syndrome is not severe or is prevented in the patient.
13. The method of claim 1 , wherein body weight loss in the patient is mild or prevented.
14. The method of claim 13 , wherein body weight loss in the patient is less than about 20%.
15. The method of claim 1 , wherein the cancer comprises a tumor, wherein the tumor size is reduced, and wherein off-target toxicity does not occur or is reduced.
16. The method of claim 15 , wherein a complete response for the tumor is obtained.
17. The method of claim 1 , wherein the method does not comprise administering a rescue agent to the patient.
18. The method of claim 1 , wherein the first dose of the compound, or the pharmaceutically acceptable salt thereof, is about 100 nmoles/kg to about 1,000 nmoles/kg of the body weight of the patient.
19. The method of claim 18 , wherein the first dose of the compound, or the pharmaceutically acceptable salt thereof, is about 500 nmoles/kg of the body weight of the patient.
20. The method of claim 18 , wherein the second dose of the compound, or the pharmaceutically acceptable salt thereof, is about 0.5 nmoles/kg to about 500 nmoles/kg of the body weight of the patient.
21. The method of claim 18 , wherein the second dose of the compound, or the pharmaceutically acceptable salt thereof, is about 5 nmoles/kg to about 40 nmoles/kg of the body weight of the patient.
22. The method of claim 18 , wherein the second dose of the compound, or the pharmaceutically acceptable salt thereof, is about 40 nmoles/kg to about 150 nmoles/kg of the body weight of the patient.
23. The method of claim 18 , wherein the second dose of the compound, or the pharmaceutically acceptable salt thereof, is about 100 nmoles/kg of the body weight of the patient.
24. The method of claim 20 , further comprising administering a third dose of the compound, or the pharmaceutically acceptable salt thereof, wherein the third dose of the compound, or the pharmaceutically acceptable salt thereof, is the same as the second dose of the compound, or the pharmaceutically acceptable salt thereof.
25. The method of claim 24 , further comprising administering a fourth dose of the compound, or the pharmaceutically acceptable salt thereof, wherein the fourth dose of the compound, or the pharmaceutically acceptable salt thereof, is the same as the third dose of the compound, or the pharmaceutically acceptable salt thereof.
26. The method of claim 1 , wherein the at least one dose of the compound, or the pharmaceutically acceptable salt thereof, administered after the first dose of the compound, or the pharmaceutically acceptable salt thereof, is administered once weekly.
27. The method of claim 1 , wherein the targeting moiety binds to an E2 anti-fluorescein antibody fragment.
28. The method of claim 27 , wherein the targeting moiety is fluorescein, fluorescein isothiocyanate (FITC), or NHS-fluorescein.
29. The method of claim 27 , wherein the targeting moiety is fluorescein, or a pharmaceutically acceptable salt thereof.
30. The method of claim 1 , wherein the small molecule ligand is selected from the group consisting of a folate, 2-[3-(1,3-dicarboxylpropyl)ureido]pentanedioic acid (DUPA), a neurokinin 1 receptor (NK-1R) ligand, and a carbonic anhydrase IX (CAIX) ligand.
31. The method of claim 1 , wherein the compound is
32. The method of claim 1 , wherein the compound is
33. The method of claim 1 , wherein the linker comprises polyethylene glycol (PEG), polyproline, a hydrophilic amino acid, a sugar, an unnatural peptidoglycan, a polyvinylpyrrolidone, pluronic F-127, or a combination thereof.
34. The method of claim 1 , wherein the cancer is a folate receptor-expressing cancer.
35. The method of claim 1 , wherein the CAR T cell composition comprises CD8 and CD4 CAR T cells, and wherein the CD8:CD4 ratio of the CAR T cells is about 1:1.
36. The method of claim 1 , wherein the CART cells comprise a polypeptide having at least about 90% identity to SEQ ID NO: 2.
37. The method of claim 1 , wherein the CART cells comprise a polypeptide having at least about 95% identity to SEQ ID NO: 2.
38. The method of claim 1 , wherein the CART cells comprise a polypeptide having at least about 99% identity to SEQ ID NO: 2.
39. A method of treating a patient for cancer, the method comprising
i) administering to the patient a first dose of a compound, or a pharmaceutically acceptable salt thereof, wherein the compound comprises a folate linked to a targeting moiety by a linker, wherein the targeting moiety is fluorescein, fluorescein isothiocyanate (FITC), or NHS-fluorescein, wherein the folate binds to a folate receptor on a cancer cell; and
ii) administering to the patient at least a second dose of the compound, or a pharmaceutically acceptable salt thereof, wherein the second dose of the compound, or the pharmaceutically acceptable salt thereof, is at least about 50 percent lower in amount than the first dose of the compound, or the pharmaceutically acceptable salt thereof;
wherein the patient has been administered, prior to step (i), a dose of a CAR (chimeric antigen receptor) T cell composition comprising CAR T cells, wherein the CAR comprises an E2 anti-fluorescein antibody fragment, and wherein the CAR T cells comprise a polypeptide having at least about 80% identity to SEQ ID NO: 2.
40. The method of claim 39 , wherein the targeting moiety is fluorescein.
41. The method of claim 39 , wherein the CART cells comprise a polypeptide having at least about 90% identity to SEQ ID NO: 2.
42. The method of claim 39 , wherein the CAR T cells comprise a polypeptide having at least about 95% identity to SEQ ID NO: 2.
43. The method of claim 39 , wherein the CART cells comprise a polypeptide having at least about 99% identity to SEQ ID NO: 2.
44. The method of claim 39 , wherein the CAR T cells comprise the polypeptide set forth in SEQ ID NO: 2.