Combination therapy with T-cell therapy and (S)-3-[4-(4-morpholine-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindole-2-yl]-piperidine-2,6-dione

Abstract

In immunotherapy, the present invention provides improved methods, compositions, kits, and systems for improving the efficacy of cells, such as improving the persistence, activity, and / or proliferation of cells upon administration to a target. [Solution] Provided are methods, compositions, uses, and products for combination therapies, including immunotherapy such as adoptive cell therapy, e.g., T-cell therapy, and the use of (S)-3-[4-(4-morpholine-4-ylmethylbenzyloxy)-1-oxo-1,3-dihydro-isoindole-2-yl]-piperidine-2,6-dione, or its enantiomer or mixture of enantiomers, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs thereof, as well as related methods, compositions, uses, and products, for treating subjects having diseases or disorders such as specific B-cell malignancies.

Claims

1. A pharmaceutical formulation comprising a dose of genetically engineered T cells expressing a chimeric antigen receptor (CAR) that specifically binds to CD19, for use in a method for treating B-cell malignancies, the method comprising: (a) the step of administering a dose of the genetically modified T cells to a subject having a B-cell malignancy; and (b) A step of administering an immunomodulatory compound to a subject, wherein the compound is (S)-3-[4-(4-morpholine-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindole-2-yl]-piperidine-2,6-dione, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion compound, or polymorph thereof, step Includes, The administration of the compound to the subject is initiated within 21 days after the administration of the genetically modified T cells, and The compound is administered daily at a dose of approximately 0.1 mg to approximately 1.0 mg / day for a maximum of 3 consecutive weeks during the first administration period. A rest period of at least one week in which the compound is not administered, beginning from the end of the first administration period, and A second administration period, comprising a 4-week cycle in which the compound is administered daily for 3 consecutive weeks at a dose of approximately 0.1 mg to approximately 1.0 mg / day in each 4-week cycle. This is implemented in cycling regimens that include A pharmaceutical product for use in a method.

2. A pharmaceutical product comprising an immunomodulatory compound for use in a method for treating B-cell malignancies, the method being: A step comprising administering the immunomodulatory compound to a subject having a B-cell malignancy, wherein the compound is (S)-3-[4-(4-morpholine-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindole-2-yl]-piperidine-2,6-dione, or a pharmaceutically acceptable salt thereof, solvate, hydrate, cocrystal, inclusion compound, or polymorph, Prior to the administration of the compound, the subjects were administered a dose of genetically modified T cells expressing a chimeric antigen receptor (CAR) that specifically binds to CD19. The administration of the compound to the subject is initiated within 21 days after the administration of the genetically modified T cells, and The compound is administered daily at a dose of approximately 0.1 mg to approximately 1.0 mg / day for a maximum of 3 consecutive weeks during the first administration period. A rest period of at least one week in which the compound is not administered, beginning from the end of the first administration period, and A second administration period, comprising a 4-week cycle in which the compound is administered daily for 3 consecutive weeks at a dose of approximately 0.1 mg to approximately 1.0 mg / day in each 4-week cycle. This is implemented in cycling regimens that include A pharmaceutical product for use in a method.

3. A pharmaceutical product comprising a dose of genetically engineered T cells expressing a CD19-specific chimeric antigen receptor (CAR) for the treatment of B-cell malignancies in a subject, used in combination with an immunomodulatory compound, wherein the compound is (S)-3-[4-(4-morpholine-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindole-2-yl]-piperidine-2,6-dione, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion compound, or polymorph thereof. The administration of the compound to the subject is initiated within 21 days after the administration of the genetically modified T cells, and The compound is administered daily at a dose of approximately 0.1 mg to approximately 1.0 mg / day for a maximum of 3 consecutive weeks during the first administration period. A rest period of at least one week in which the compound is not administered, beginning from the end of the first administration period, and A second administration period, comprising a 4-week cycle in which the compound is administered daily for 3 consecutive weeks at a dose of approximately 0.1 mg to approximately 1.0 mg / day in each 4-week cycle. This is implemented in cycling regimens that include A pharmaceutical product characterized by being used in such a manner.

4. The pharmaceutical product according to any one of claims 1 to 3, wherein the compound is administered in an amount of 0.3 mg to about 0.6 mg or about 0.3 mg to about 0.6 mg during the first and / or second administration period.

5. The pharmaceutical product according to any one of claims 1 to 4, wherein the first administration period begins on the same day as the administration of the genetically modified T cells.

6. The pharmaceutical product according to any one of claims 1 to 4, wherein the first administration period begins between 1 day or about 1 day and 15 days or about 15 days (including the values ​​at both ends) after administration of the genetically modified T cells.

7. The pharmaceutical product according to any one of claims 1 to 4 and 6, wherein the first administration period begins between 1 day or about 1 day and 11 days or about 11 days (including the values ​​at both ends) after administration of the genetically modified T cells.

8. The pharmaceutical product according to any one of claims 1 to 4 and 6, wherein the first administration period begins between 8 days or about 8 days and 15 days or about 15 days (including the values ​​at both ends) after administration of the genetically modified T cells.

9. The pharmaceutical product according to any one of claims 1 to 8, wherein the resting period begins on day 21 or approximately day 21 after administration of the genetically modified T cells.

10. The pharmaceutical product according to any one of claims 1 to 9, wherein a rest period is maintained until the target B cell count level recovers to the same or nearly the same level as measured before the first administration period.

11. A pharmaceutical product according to any one of claims 1 to 10, wherein the rest period is approximately one week.

12. The pharmaceutical product according to any one of claims 1 to 11, wherein the compound is administered orally during a first administration period.

13. The pharmaceutical product according to any one of claims 1 to 12, wherein the compound is a pharmaceutically acceptable salt or polymorph of (S)-3-[4-(4-morpholine-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindole-2-yl]-piperidine-2,6-dione.

14. The pharmaceutical product according to any one of claims 1 to 12, wherein the compound is (S)-3-[4-(4-morpholine-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindole-2-yl]-piperidine-2,6-dione hydrate.

15. The pharmaceutical product according to any one of claims 1 to 12, wherein the compound is a solvate of (S)-3-[4-(4-morpholine-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindole-2-yl]-piperidine-2,6-dione.

16. The pharmaceutical product according to any one of claims 1 to 12, wherein the compound is (S)-3-[4-(4-morpholine-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindole-2-yl]-piperidine-2,6-dione.

17. The pharmaceutical product according to any one of claims 1 to 16, wherein the B-cell malignant tumor is lymphoma.

18. The pharmacopoeia according to claim 17, wherein the lymphoma is non-Hodgkin lymphoma (NHL), and optionally, the NHL comprises invasive NHL, diffuse large B-cell lymphoma (DLBCL), optionally transformed painless DLBCL-NOS; EBV-positive DLBCL-NOS; T-cell / histiocyte-rich large B-cell lymphoma; primary mediastinal large B-cell lymphoma (PMBCL); follicular lymphoma (FL), optionally follicular lymphoma grade 3B (FL3B); and / or high-grade B-cell lymphoma (double / triple hit) having MYC and BCL2 and / or BCL6 rearrangements with DLBCL histology.

19. A pharmaceutical product according to any one of claims 1 to 18, wherein the chimeric antigen receptor (CAR) comprises an extracellular antigen recognition domain that specifically binds to CD19 and an intracellular signaling domain that includes an immune receptor tyrosine-based activation motif (ITAM).

20. The pharmaceutical product according to claim 19, wherein the intracellular signaling domain comprises a CD3 zeta (CD3ζ) chain, optionally a signaling domain of a human CD3 zeta chain.

21. The pharmaceutical product according to claim 19 or claim 20, wherein the CAR further comprises a co-stimulatory signaling region.

22. The pharmaceutical product according to claim 21, wherein the co-stimulatory signaling region comprises a signaling domain of CD28 or 4-1BB, optionally human CD28 or human 4-1BB.

23. The pharmaceutical product according to claim 21 or 22, wherein the CAR comprises, in order, a CD19-specific single-stranded variable fragment (scFv); a transmembrane domain; a co-stimulatory signaling region; and an intracellular signaling region.

24. The pharmaceutical product according to claim 23, wherein the CAR further comprises a spacer between the transmembrane domain and the scFv.

25. The pharmaceutically acceptable agent according to claim 24, wherein the spacer comprises or consists of all or part of an immunoglobulin hinge, optionally an IgG4 hinge, or a modified form thereof, and / or comprises about 15 amino acids or less.

26. The pharmaceutical product according to claim 24 or 25, wherein the spacer comprises the amino acid sequence shown in SEQ ID NO: 1; the amino acid sequences shown in SEQ ID NO: 2, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, or SEQ ID NO: 34; or a variant of any of the sequences having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more sequence identity thereto.

27. The pharmaceutical product according to any one of claims 23 to 26, wherein the transmembrane domain comprises the amino acid sequence shown in SEQ ID NO: 8 or SEQ ID NO:

9.

28. The pharmaceutical product according to any one of claims 21 to 27, wherein the co-stimulatory signaling region includes the amino acid sequence shown in SEQ ID NO: 12 or a variant thereof having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more sequence identity thereto.

29. The pharmaceutical product according to any one of claims 19 to 28, wherein the intracellular signaling region comprises an amino acid sequence shown in any one of SEQ ID NO: 13 to SEQ ID NO: 15, or a variant thereof having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more sequence identity therewith.

30. The pharmaceutical product according to any one of claims 23 to 29, wherein scFv comprises the CDRL1 sequence of RASQDISKYLN (SEQ ID NO: 35), the CDRL2 sequence of SRLHSGV (SEQ ID NO: 36), and / or the CDRL3 sequence of GNTLPYTFG (SEQ ID NO: 37), and / or the CDRH1 sequence of DYGVS (SEQ ID NO: 38), the CDRH2 sequence of VIWGSETTYYNSALKS (SEQ ID NO: 39), and / or the CDRH3 sequence of YAMDYWG (SEQ ID NO: 40).

31. The pharmaceutical product according to any one of claims 23 to 30, wherein scFv comprises a heavy chain variable (VH) region containing the amino acid sequence shown as SEQ ID NO: 41, and a light chain variable (VL) region containing the amino acid sequence shown as SEQ ID NO:

42.

32. The pharmaceutical product according to any one of claims 23 to 31, wherein scFv comprises the amino acid sequence shown in SEQ ID NO:

43.

33. The dosage of the genetically engineered T cells is 1×10 5 to 5×10 8 or about 1×10 5 to 5×10 8 total CAR-expressing T cells, 1×10 6 to 2.5×10 8 or about 1×10 6 to 2.5×10 8 total CAR-expressing T cells, 5×10 6 to 1×10 8 or about 5×10 6 to 1×10 8 total CAR-expressing T cells, 1×10 7 to 2.5×10 8 or about 1×10 7 to 2.5×10 8 total CAR-expressing T cells, or 5×10 7 to 1×10 8 or about 5×10 7 to 1×10 8 total CAR-expressing T cells (including the values at both ends), the pharmaceutical composition according to any one of claims 1 to 32.

34. The pharmaceutical product according to any one of claims 1 to 33, wherein the dose of the genetically modified T cells is administered parenterally, optionally intravenously.

35. The pharmaceutical product according to any one of claims 1 to 34, wherein the genetically modified T cells are of autologous origin to the subject.

36. The pharmaceutical product according to any one of claims 1 to 34, wherein the genetically modified T cells are allogeneic to the target.

37. The pharmaceutical product according to any one of claims 1 to 36, wherein, prior to the administration of the genetically modified T cells, the subject is pretreated with lymphocyte apheresis including the administration of fludarabine and / or cyclophosphamide.

38. Lymphocyte apheresis therapy involves approximately 200-400 mg / m². 2 Optionally, 300 mg / m² 2 Alternatively, approximately 300 mg / m² 2 Cyclophosphamide (including values ​​at both ends), and / or approximately 20–40 mg / m² 2 Optionally, 30 mg / m² 2 This may include daily administration of fludarabine for 2-4 days, or optionally 3 days, or lymphocyte apheresis at approximately 500 mg / m². 2 The pharmaceutical product according to claim 37, comprising the administration of cyclophosphamide.

39. The pharmaceutical product according to any one of claims 1 to 38, wherein the subject has received one prior treatment.

40. The pharmaceutical product according to any one of claims 1 to 38, wherein the subject has previously received more than 1, 2, 3, 4, 5, or 6 treatments.

41. The pharmacopoeia according to claim 39 or 40, wherein the prior treatment is the administration of a CD20-targeting agent and / or an anthracycline.

Images