Treatment of cancer using anti-CD19 Chimeric Antigen Receptor

Patent metadata

Field	Value
Publication number	US-10357514-B2
Application number	US-201514680860-A
Country	US
Kind code	B2
Filing date	Apr 7, 2015
Priority date	Apr 7, 2014
Publication date	Jul 23, 2019
Grant date	Jul 23, 2019

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.

First claim

What is claimed is:

1. A method of treating a mammal having a leukemia or lymphoma associated with expression of CD19, comprising:
administering to the mammal an effective amount of a population of immune effector cells, wherein the immune effector cells comprise autologous T cells, that expresses a CAR polypeptide that binds CD19 (a CAR19-expressing cell population), in combination with ibrutinib,
wherein the CAR polypeptide comprises:
(i) an extracellular anti-CD19 binding domain that comprises: a light chain complementary determining region 1 (LC CDR1) of SEQ ID NO: 25, a light chain complementary determining region 2 (LC CDR2) of SEQ ID NO: 26, a light chain complementary determining region 3 (LC CDR3) of SEQ ID NO: 27, a heavy chain complementary determining region 1 (HC CDR1) of SEQ ID NO: 19, a heavy chain complementary determining region 2 (HC CDR2) of any of SEQ ID NO: 20-23, and a heavy chain complementary determining region 3 (HC CDR3) of SEQ ID NO: 24;
(ii) an intracellular signaling domain capable of stimulating the autologous T cells comprising the CAR polypeptide, wherein the intracellular signalling domain comprises:
(a) a primary signalling domain which comprises a CD3zeta domain, or a functional fragment thereof, and
(b) a costimulatory domain comprising an intracellular signaling domain of a protein selected from the group consisting of OX40, CD27, CD28, ICOS, and 4-1BB;

(iii) a transmembrane domain disposed between the anti-CD19 binding domain and the intracellular signalling domain, wherein the transmembrane domain is 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.

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

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

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

5. The method of claim 1 , wherein the method further comprises administering 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 ibrutinib is administered at 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.

7. The method of claim 1 , 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.

8. The method of claim 1 , wherein the anti-CD19 binding domain comprises the amino acid sequence of SEQ ID NO:59, or a sequence with 95-99% identity thereto.

9. The method of claim 1 , wherein the anti-CD19 binding domain is a humanized anti-CD19 binding domain.

10. The method of claim 9 , wherein the humanized anti-CD19 binding domain comprises an amino acid 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 thereto.

11. The method of claim 10 , 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 the sequence of SEQ ID NO: 53.

12. The method of claim 1 , wherein the transmembrane domain comprises the amino acid sequence of SEQ ID NO: 15, or a sequence with 95-99% identity thereto.

13. The method of claim 12 , wherein the anti-CD19 binding domain is connected to the transmembrane domain by a hinge region, wherein the hinge region comprises the amino acid sequence of SEQ ID NO:14, or SEQ ID NO:45.

14. The method of claim 1 , wherein the intracellular signaling domain further comprises a costimulatory domain that comprises the amino acid sequence of SEQ ID NO: 16, or SEQ ID NO:51.

15. The method of claim 1 , wherein the intracellular signaling domain comprises the amino acid sequence of SEQ ID NO: 16, the amino acid sequence of SEQ ID NO:17, or both.

16. The method of claim 1 , wherein CAR polypeptide 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.

17. 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, LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, or 2B4.

18. The method of claim 1 , wherein the leukemia or lymphoma is chosen from mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), acute lymphoid leukemia (ALL), diffuse large B cell lymphoma (DLBCL), small lymphocytic leukemia (SLL), acute myelogenous leukemia (AML), or multiple myeloma (MM).

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

20. The method of claim 1 wherein remission of the hematological cancer is prolonged or relapse of the hematological cancer is delayed.

21. The method of claim 1 , wherein the CAR19-expressing cell population 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.

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

23. The method of claim 1 , wherein 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.

24. The method of claim 1 , which comprises performing a lymphocyte infusion with the CAR19-expressing cell population.

25. 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.

26. The method of claim 1 , wherein the intracellular signaling domain comprises the amino acid sequence of SEQ ID NO:16, the amino acid sequence of SEQ ID NO:43, or both.

27. The method of claim 1 , wherein the intracellular signaling domain comprises the amino acid sequence of SEQ ID NO: 51, the amino acid sequence of SEQ ID NO:17, or both.

28. The method of claim 1 , wherein the intracellular signaling domain comprises the amino acid sequence of SEQ ID NO:51, the amino acid sequence of SEQ ID NO:43, or both.

29. The method of claim 1 , wherein the leukemia or lymphoma is a relapsed or refractory leukemia or lymphoma.

30. The method of claim 1 , wherein the leukemia or lymphoma is MCL.

31. The method of

Assignees

• Univ Pennsylvania
• Novartis Ag

Inventors

• June Carl H
• Porter David L
• Maus Marcela
• Wasik Mariusz
• Gill Saar
• Fraietta Joseph
• Ruella Marco
• Byrd John
• Dubovsky Jason
• Johnson Amy
• Muthusamy Natarajan
• Kenderian Saad
• Mannick Joan
• Glass David
• Murphy Leon
• Brogdon Jennifer
• Sellers William Raj

Classifications

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title

• A61K31/519 Primary

  ortho- or peri-condensed with heterocyclic rings · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title