Compositions and methods for CAR T cell therapy
The present disclosure relates to methods of treating a patient with a cancer by administering to the patient a composition comprising CAR T cells and 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 compound, or a pharmaceutically acceptable salt thereof, wherein the compound comprises a folate linked to fluorescein isothiocyanate (FITC) by a linker;
ii) administering to the patient a chimeric antigen receptor T cell (CAR T cell) composition comprising CAR T cells comprising an anti-FITC antibody or fragment thereof; and
iii) reducing or preventing cytokine release syndrome (CRS) or cytokine storm by administering to the patient a rescue agent which is a folate,
wherein step iii) is performed after steps i) and ii), and
wherein the cancer is a folate receptor-expressing cancer;
whereupon the patient is treated for cancer.
2. The method of claim 1 , wherein the folate of the rescue agent is folic acid or leucovorin.
3. The method of claim 1 , wherein the folate linked to FITC in the compound has the formula
wherein X 1 and Y 1 are each independently selected from the group consisting of halo, R 2 , OR 2 , SR 3 , and NR 4 R 5 ;
wherein U, V, and W represent divalent moieties each independently selected from the group consisting of —(R 6a )C═, —N═, —(R 6a )C(R 7a )—, and —N(R 4a )—;
wherein Q is selected from the group consisting of C and CH and T is selected from the group consisting of S, O, N, and —C═C—;
wherein X 2 and X 3 are each independently selected from the group consisting of oxygen, sulfur, —C(Z)—, —C(Z)O—, —OC(Z)—, —N(R 4b )—, —C(Z)N(R 4b )—, —N(R 4b )C(Z)—, —OC(Z)N(R 4b )—, —N(R 4b )C(Z)O—, —N(R 4b )C(Z)N(R 5b )—, —S(O)—, —S(O) 2 —, —N(R 4a )S(O) 2 —, —C(R 6b ) (R 7b )—, —N(C≡CH)—, —N(CH 2 C≡CH)—, C 1 -C 12 alkylene, and C 1 -C 12 alkyeneoxy, where Z is oxygen or sulfur;
wherein R 1 is selected-from the group consisting of hydrogen, halo, C 1 -C 12 alkyl, and C 1 -C 12 alkoxy;
wherein R 2 , R 3 , R 4 , R 4a , R 4b , R 5 , R 5b , R 6b , and R 7b are each independently selected from the group consisting of hydrogen, halo, C 1 -C 12 alkyl, and C 1 -C 12 alkoxy, C 1 -C 12 alkanoyl, C 1 -C 12 alkenyl, C 1 -C 12 alkynyl, (C 1 -C 12 alkoxy)carbonyl, and (C 1 -C 12 alkylamino)carbonyl;
wherein R 6 and R 7 are each independently selected from the group consisting of hydrogen, halo, C 1 -C 12 alkyl, and C 1 -C 12 alkoxy; or, R 6 and R 7 are taken together to form a carbonyl group;
wherein R 6a and R 7a are each independently selected from the group consisting of hydrogen, halo, C 1 -C 12 alkyl, and C 1 -C 12 alkoxy; or, R 6a and R 7a are taken together to form a carbonyl group;
wherein p, r, s, and t are each independently either 0 or 1; and
wherein * represents a covalent bond to the rest of the compound.
4. 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.
5. The method of claim 4 , wherein the linker comprises PEG.
6. The method of claim 1 , wherein the compound, or the pharmaceutically acceptable salt thereof, is not an antibody, and does not comprise a fragment of an antibody.
7. The method of claim 1 , wherein the anti-FITC antibody or fragment thereof is a single chain fragment variable (scFv) region, wherein the CAR has a co-stimulation domain and the co-stimulation domain is CD137 (4-1BB), and wherein the CAR has an activation signaling domain and the activation signaling domain is a T cell CD3ζ chain.
8. The method of claim 1 , wherein multiple doses of the compound, or the pharmaceutically acceptable salt thereof, and/or the CAR T cell composition are administered.
9. The method of claim 1 , wherein the CAR T cells administered to the patient in the CAR T cell composition comprise from about 1 million to about 15 million of the CART cells.
10. The method of claim 1 , wherein a CRS grade is determined in the patient, and wherein the CRS grade is 1, 2, 3, or 4.
11. The method of claim 10 , wherein the rescue agent is administered after determining the CRS grade.
12. The method of claim 1 , wherein the cancer comprises a tumor.
13. The method of claim 12 , wherein tumor size is reduced in the patient.
14. The method of claim 1 , wherein the CART cell composition is administered simultaneously with the compound or pharmaceutically acceptable salt thereof.
15. The method of claim 1 , wherein the CART cell composition is administered after administering the compound or pharmaceutically acceptable salt thereof.
16. The method of claim 1 , wherein the CART cell composition is administered before administering the compound or pharmaceutically acceptable salt thereof.