TREATMENT OF CANCER USING ANTI-CD19 CHIMERIC ANTIGEN RECEPTOR

• US 20150283178A1
• Filed: 04/07/2015
• Published: 10/08/2015
• Est. Priority Date: 04/07/2014
• Status: Active Grant

• Current Assignee: Novartis Ag, Trustees Of The University Of Pennsylvania (University of Pennsylvania)
• Original Assignee: Novartis Ag, Trustees Of The University Of Pennsylvania (University of Pennsylvania)
• Inventors: June, Carl H., Porter, David L., Maus, Marcela, Wasik, Mariusz, Gill, Saar, Byrd, John, Muthusamy, Natarajan, Mannick, Joan, Glass, David, Murphy, Leon, Brogdon, Jennifer, Fraietta, Joseph, Ruella, Marco, Dubovsky, Jason, Johnson, Amy, Kenderian, Saad, Sellers, William Raj
• Granted Patent: US 10,357,514 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/5156 expressing foreign proteins
• CPC Class Codes: A61K 2039/5158 Antigen-pulsed cells, e.g. T-cells
• CPC Class Codes: A61K 2239/26 Universal/off- the- shelf cellular immunotherapy; Allogenic cells or means to avoid rejection
• CPC Class Codes: A61K 2239/31 characterized by the route of administration
• CPC Class Codes: A61K 2239/38 characterised by the dose, timing or administration schedule
• CPC Class Codes: A61K 2239/48 Blood cells, e.g. leukemia or lymphoma
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/436 the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/53 having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine melarsoprol A61K31/555 ; with four nitrogen atoms A61K31/495
• CPC Class Codes: A61K 35/17 Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes when activated by a specific antigen A61K39/00
• CPC Class Codes: A61K 39/001112 CD19 or B4
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 39/39558 against tumor tissues, cells, antigens
• CPC Class Codes: A61K 39/4611 T-cells, e.g. tumor infiltrating lymphocytes [TIL], lymphokine-activated killer cells [LAK] or regulatory T cells [Treg]
• CPC Class Codes: A61K 39/4631 Chimeric Antigen Receptors [CAR]
• CPC Class Codes: A61K 39/4636 Immune checkpoint inhibitors
• CPC Class Codes: A61K 39/464412 CD19 or B4
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 14/7051 : T-cell receptor (TcR)-CD3 complex
• CPC Class Codes: C07K 16/2803 : against the immunoglobulin superfamily
• CPC Class Codes: C07K 2317/14 : Specific host cells or culture conditions, e.g. components, pH or temperature
• CPC Class Codes: C07K 2317/24 : containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/565 : Complementarity determining region [CDR]
• CPC Class Codes: C07K 2317/622 : Single chain antibody (scFv)
• CPC Class Codes: C07K 2317/73 : Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
• CPC Class Codes: C07K 2319/03 : containing a transmembrane segment
• CPC Class Codes: C12N 2501/599 : with CD designations not provided for elsewhere
• CPC Class Codes: C12N 2501/727 : Kinases (EC 2.7.)
• CPC Class Codes: C12N 2510/00 : Genetically modified cells
• CPC Class Codes: C12N 5/0636 : T lymphocytes

Abstract

The invention provides compositions and methods for treating diseases associated with expression of CD19, e.g., by administering a recombinant T cell comprising the CD19 CAR as described herein, in combination with a kinase inhibitor, e.g., a kinase inhibitor described herein. The invention also provides kits and compositions described herein.

Claims

1. A method of treating a mammal having a disease associated with expression of CD19 comprising administering to the mammal an effective amount of a population of cells that expresses a CAR molecule that binds CD19 (a CAR19-expressing cell), in combination with one or more kinase inhibitors chosen from a Bruton'"'"'s tyrosine kinase (BTK) inhibitor, a cyclin dependent kinase 4 (CDK4) inhibitor, an mTOR inhibitor, or a mitogen activated protein kinase interacting kinase (MNK) inhibitor.

2. The method of claim 1, wherein the kinase inhibitor and the CAR19-expressing cell are administered to the mammal as a first line of therapy.

3. The method of claim 1, wherein the CAR19-expressing cell is administered to the mammal after administration of the kinase inhibitor.

4. The method of claim 1, wherein the mammal is, or is identified as being, a complete or partial responder to the BTK inhibitor, or a complete or partial responder to the CAR19-expressing cell.

5. The method of claim 1, wherein the BTK inhibitor is chosen from ibrutinib, GDC-0834, RN-486, CGI-560, CGI-1764, HM-71224, CC-292, ONO-4059, CNX-774, or LFM-A13.

6. The method of claim 1, wherein the CDK4 inhibitor is chosen from:

palbociclib, aloisine A, flavopiridol, 2-(2-chlorophenyl)-5,7-dihydroxy-8-[(3S,4R)-3-hydroxy-1-methyl-4-piperidinyl]-4-chromenone;

crizotinib (PF-02341066, P276-00, RAF265, indisulam, roscovitine, dinaciclib, BMS 387032, MLN8054, AG-024322, AT7519, AZD5438, BMS908662;

or ribociclib.

7. The method of claim 1, wherein the mTOR inhibitor is chosen from:

rapamycin, a rapamycin analog such as everolimus, temsirolimus, ridaforolimus, semapimod, AZD8055, PF04691502, SF1126, XL765, or OSI-027.

8. The method of claim 1, wherein the MNK inhibitor is chosen from:

CGP052088, CGP57380, cercosporamide, ETC-1780445-2, or 4-amino-5-(4-fluoroanilino)-pyrazolo[3,4-d]pyrimidine.

9. The method of claim 1, wherein the kinase inhibitor is ibrutinib and the ibrutinib has a dose of about 250 mg, 300 mg, 350 mg, 400 mg, 420 mg, 440 mg, 460 mg, 480 mg, 500 mg, 520 mg, 540 mg, 560 mg, 580 mg, or 600 mg daily.

10. The method of claim 1, wherein the cell expresses a CAR molecule comprising an anti-CD19 binding domain, a transmembrane domain, and an intracellular signaling domain.

11. The method of claim 10, wherein the intracellular signaling domain comprises a costimulatory domain and a primary signaling domain.

12. The method of claim 10, wherein the CAR molecule comprises an anti-CD19 binding domain comprising a light chain complementary determining region 1 (LC CDR1), a light chain complementary determining region 2 (LC CDR2), a light chain complementary determining region 3 (LC CDR3), a heavy chain complementary determining region 1 (HC CDR1), a heavy chain complementary determining region 2 (HC CDR2), and a heavy chain complementary determining region 3 (HC CDR3) of an anti-CD19 binding domain.

13. The method of claim 10, wherein the anti-CD19 binding domain comprises a murine light chain variable region of Table 7, a murine heavy chain variable region of Table 7, or both.

14. The method of claim 10, wherein the anti-CD19 binding domain comprises a LC CDR1 of SEQ ID NO:

5, a LC CDR2 of SEQ ID NO;

26, and a LC CDR3 of SEQ ID NO;

27.

15. The method of claim 10, wherein the anti-CD19 binding domain comprises a HC CDR1 of SEQ ID NO:

19, a LC CDR2 of any of SEQ ID NOS;

20-23, and a HC CDR3 of SEQ ID NO;

24.

16. The method of claim 10, wherein the anti-CD19 binding domain comprises a sequence of SEQ ID NO:

59, or a sequence with 95-99% identify thereof.

17. The method of claim 10, wherein the anti-CD19 binding domain is a humanized anti-CD19 binding domain.

18. The method of claim 17, wherein the humanized anti-CD19 binding domain comprises a sequence chosen from:

SEQ ID NO;

1, SEQ ID NO;

2, SEQ ID NO;

3, SEQ ID NO;

4, SEQ ID NO;

5, SEQ ID NO;

6, SEQ ID NO;

7, SEQ ID NO;

8, SEQ ID NO;

9, SEQ ID NO;

10, SEQ ID NO;

11 and SEQ ID NO;

12, or a sequence with 95-99% identity thereof.

19. The method of claim 18, wherein the humanized anti-CD19 binding domain is a scFv that comprises a light chain variable region attached to a heavy chain variable via a linker, wherein the linker comprises a sequence of SEQ ID NO:

53.

20. The method of claim 10, wherein the CAR molecule comprises a transmembrane domain of a protein chosen from:

the alpha, beta or zeta chain of the T-cell receptor, CD28, CD3 epsilon, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137 or CD154.

21. The method of claim 20, wherein the transmembrane domain comprises a sequence of SEQ ID NO:

15.

22. The method of claim 21, wherein the anti-CD19 binding domain is connected to the transmembrane domain by a hinge region, wherein the hinge region comprises a sequence of SEQ ID NO:

14 or SEQ ID NO;

45.

23. The method of claim 10, wherein the CAR molecule comprises a costimulatory domain, wherein the costimulatory domain comprises a sequence of SEQ ID NO:

16 or SEQ ID NO;

51.

24. The method of claim 10, wherein the CAR molecule comprises an intracellular signaling domain, wherein the intracellular signaling domain comprises a functional signaling domain of 4-1BB, a functional signaling domain of CD3 zeta, or both, or wherein the intracellular signaling domain comprises a sequence of CD27, a functional signaling domain of CD3 zeta, or both.

25. The method of claim 10, wherein the intracellular signaling domain comprises a sequence of SEQ ID NO:

16, a sequence of SEQ ID NO;

17, or both;

wherein the intracellular signaling domain comprises a sequence of SEQ ID NO;

16, a sequence of SEQ ID NO;

43, or both;

wherein the intracellular signaling domain comprises a sequence of SEQ ID NO;

51, a sequence of SEQ ID NO;

17, or both;

or wherein the intracellular signaling domain comprises a sequence of SEQ ID NO;

51, a sequence of SEQ ID NO;

43, or both.

26. The method of claim 10, wherein the CAR molecule further comprises a leader sequence, wherein the leader sequence comprises an amino acid sequence of SEQ ID NO:

13.

27. The method of claim 10, wherein CAR molecule comprises an amino acid sequence of SEQ ID NO:

58, SEQ ID NO;

31, SEQ ID NO;

32, SEQ ID NO;

33, SEQ ID NO;

34, SEQ ID NO;

35, SEQ ID NO;

36, SEQ ID NO;

37, SEQ ID NO;

38, SEQ ID NO;

39, SEQ ID NO;

40, SEQ ID NO;

41, or SEQ ID NO;

42.

28. The method of claim 1, further comprising administration of an agent which inhibits an immune inhibitory molecule chosen from:

PD1, PD-L1, CTLA4, TIM3, CEACAM (e.g., CEACAM-1, CEACAM-3 and/or CEACAM-5), LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 or TGFR beta.

29. The method of claim 1, wherein the disease associated with expression of CD19 is a cancer.

30. The method of claim 1, wherein the disease associated with expression of CD19 is a hematological cancer chosen from a leukemia or lymphoma.

31. The method of claim 29, wherein the cancer is chosen from:

chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), multiple myeloma, acute lymphoid leukemia (ALL), Hodgkin lymphoma, B-cell acute lymphoid leukemia (BALL), T-cell acute lymphoid leukemia (TALL), small lymphocytic leukemia (SLL), B cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell neoplasm, Burkitt'"'"'s lymphoma, diffuse large B cell lymphoma (DLBCL), DLBCL associated with chronic inflammation, follicular lymphoma, pediatric follicular lymphoma, hairy cell leukemia, small cell- or a large cell-follicular lymphoma, malignant lymphoproliferative conditions, MALT lymphoma (extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue), Marginal zone lymphoma, myelodysplasia and myelodysplastic syndrome, non-Hodgkin lymphoma, plasmablastic lymphoma, plasmacytoid dendritic cell neoplasm, Waldenstrom macroglobulinemia, splenic marginal zone lymphoma, splenic lymphoma/leukemia, splenic diffuse red pulp small B-cell lymphoma, hairy cell leukemia-variant, lymphoplasmacytic lymphoma, a heavy chain disease, plasma cell myeloma, solitary plasmocytoma of bone, extraosseous plasmocytoma, nodal marginal zone lymphoma, pediatric nodal marginal zone lymphoma, primary cutaneous follicle center lymphoma, lymphomatoid granulomatosis, primary mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, ALK+ large B-cell lymphoma, large B-cell lymphoma arising in HHV8-associated multicentric Castleman disease, primary effusion lymphoma, B-cell lymphoma, or unclassifiable lymphoma.

32. The method of claim 29, wherein the cancer is chosen from MCL, CLL, ALL, Hodgkin lymphoma, or multiple myeloma.

33. The method of claim 1, further comprising administration of a cytokine chosen from IL-7, IL-15, or IL-21.

34. The method of claim 1, wherein the CAR is a regulatable CAR (RCAR), wherein the RCAR comprises:

an intracellular signaling member comprising an intracellular signaling domain and a first switch domain,

an antigen binding member comprising an antigen binding domain that binds CD19 and a second switch domain; and

a transmembrane domain.

35. The method of claim 1, wherein the disease associated with expression of CD19 is a hematological cancer, and wherein remission of the hematological cancer is prolonged or relapse of the hematological cancer is delayed.

36. The method of claim 1, wherein the CAR19-expressing cell is administered in combination a second kinase inhibitor, wherein the second kinase inhibitor is other than ibrutinib, when the mammal is, or is identified as being, a non-responder or relapser to ibrutinib, wherein second kinase inhibitor is chosen from one or more of GDC-0834, RN-486, CGI-560, CGI-1764, HM-71224, CC-292, ONO-4059, CNX-774, or LFM-A13, or a combination thereof.

37. The method of claim 1, wherein the mammal is, or is identified as being, a partial responder to the kinase inhibitor, and the mammal is administered the CAR19-expressing cell, alone or in combination with the BTK inhibitor, during the period of partial response.

38. The method of claim 1, wherein the kinase inhibitor is ibrutinib and the ibrutinib is formulated for administration for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more cycles, wherein cycle length is 21 or 28 days.

39. The method of claim 1, which comprises performing a lymphocyte infusion with at least one CD19 CAR-expressing cell.

40. The method of claim 1, wherein the mammal has undergone lymphodepletion, wherein the lymphodepletion comprises administration of one or more of melphalan, cytoxan, cyclophosphamide, and fludarabine.

41. The method of claim 1, further comprising administering a low, immune enhancing dose of an mTOR inhibitor to the mammal, wherein the mTOR inhibitor is everolimus or rapamycin.

42. A method of making a CAR-expressing immune effector population of cells, comprising:

contacting the population of cells with a BTK inhibitor; and

introducing a nucleic acid encoding a CAR molecule into the population of cells under conditions such that the CAR molecule is expressed.

43. The method of claim 42, wherein the CAR molecule is a CAR molecule that binds CD19.

44. The method of claim 42, which comprises contacting the population of cells with the BTK inhibitor for 10-20, 20-30, 30-40, 40-60, or 60-120 minutes and subsequently removing most or all of the BTK inhibitor from the population of cells, wherein the BTK inhibitor is chosen from:

ibrutinib, GDC-0834, RN-486, CGI-560, CGI-1764, HM-71224, CC-292, ONO-4059, CNX-774, or LFM-A13.

45. The method of claim 42, further comprising depleting T regulatory cells from the population of cells.

46. A reaction mixture comprising a population of immune effector cells, a BTK inhibitor, and a CAR molecule or a nucleic acid encoding a CAR molecule, wherein the BTK inhibitor is chosen from ibrutinib, GDC-0834, RN-486, CGI-560, CGI-1764, HM-71224, CC-292, ONO-4059, CNX-774, or LFM-A13.

47. A composition comprising a population of cells that expresses a CAR molecule that binds CD19, and one or more kinase inhibitors, wherein the kinase inhibitor is chosen from a Bruton'"'"'s tyrosine kinase (BTK) inhibitor, a cyclin dependent kinase 4 (CDK4) inhibitor, an mTOR inhibitor, or a mitogen activated protein kinase interacting kinase (MNK) inhibitor, wherein the CAR19-expressing cell and the one or more kinase inhibitors are present in a single dose form, or as two or more dose forms.