Methods for treatment of cancer

• US 8,906,682 B2
• Filed: 07/10/2013
• Issued: 12/09/2014
• Est. Priority Date: 12/09/2010
• Status: Active Grant

• Current Assignee: Trustees Of The University Of Pennsylvania (University of Pennsylvania)
• Original Assignee: Trustees Of The University Of Pennsylvania (University of Pennsylvania)
• Inventors: June, Carl H., Levine, Bruce L., Porter, David L., Kalos, Michael D., Milone, Michael C.
• Primary Examiner(s): BURKHART, MICHAEL D
• Application Number:
  US13/938,947
• Publication Number:
  US 20130309258A1
• Time in Patent Office: 517 Days
• Field of Search: None
• US Class Current: 435/372.3
• 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 2039/5256 expressing foreign proteins
• CPC Class Codes: A61K 2039/585 wherein the target is cancer
• 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 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 38/177 Receptors; Cell surface antigens; Cell surface determinants
• CPC Class Codes: A61K 38/1774 Immunoglobulin superfamily (e.g. CD2, CD4, CD8, ICAM molecules, B7 molecules, Fc-receptors, MHC-molecules)
• CPC Class Codes: A61K 39/001112 CD19 or B4
• 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 39/464412 CD19 or B4
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 48/005 characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/04 : Immunostimulants
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 14/075 : Adenoviridae
• CPC Class Codes: C07K 14/525 : Tumour necrosis factor [TNF]
• CPC Class Codes: C07K 14/7051 : T-cell receptor (TcR)-CD3 complex
• CPC Class Codes: C07K 14/70517 : CD8
• CPC Class Codes: C07K 14/70521 : CD28, CD152
• CPC Class Codes: C07K 14/70578 : NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95 NGF-receptor C07K14/71, TNF-receptor C07K14/7151
• CPC Class Codes: C07K 14/70596 : Molecules with a "CD"-designation not provided for elsewhere
• CPC Class Codes: C07K 16/2803 : against the immunoglobulin superfamily
• CPC Class Codes: C07K 16/2896 : against molecules with a "CD"-designation, not provided for elsewhere
• CPC Class Codes: C07K 16/30 : from tumour cells
• CPC Class Codes: C07K 16/3061 : Blood cells
• CPC Class Codes: C07K 2317/53 : Hinge
• CPC Class Codes: C07K 2317/622 : Single chain antibody (scFv)
• CPC Class Codes: C07K 2317/76 : Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/80 : remaining in the (producing) cell, i.e. intracellular antibodies or intrabodies
• CPC Class Codes: C07K 2319/00 : Fusion polypeptide
• CPC Class Codes: C07K 2319/02 : containing a signal sequence
• CPC Class Codes: C07K 2319/03 : containing a transmembrane segment
• CPC Class Codes: C07K 2319/30 : Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
• CPC Class Codes: C07K 2319/33 : fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies
• CPC Class Codes: C07K 2319/74 : containing a fusion for binding to a cell surface receptor
• CPC Class Codes: C12N 15/85 : for animal cells
• CPC Class Codes: C12N 15/861 : Adenoviral vectors
• CPC Class Codes: C12N 2501/51 : B7 molecules, e.g. CD80, CD86, CD28 (ligand), CD152 (ligand)
• CPC Class Codes: C12N 2501/515 : CD3, T-cell receptor complex
• CPC Class Codes: C12N 2510/00 : Genetically modified cells
• CPC Class Codes: C12N 2740/15034 : Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
• CPC Class Codes: C12N 2740/15043 : viral genome or elements thereof as genetic vector
• CPC Class Codes: C12N 2740/15071 : Demonstrated in vivo effect
• CPC Class Codes: C12N 5/0636 : T lymphocytes
• CPC Class Codes: C12N 7/00 : Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof preparing medicinal viral antigen or antibody compositions, e.g. virus vaccines, A61K39/00

Abstract

The present invention provides compositions and methods for treating cancer in a human. The invention includes relates to administering a genetically modified T cell to express a CAR wherein the CAR comprises an antigen binding domain, a transmembrane domain, a costimulatory signaling region, and a CD3 zeta signaling domain.

Claims

1. A method of treating leukemia in a human patient, the method comprising administering to the human patient a pharmaceutical composition comprising an anti-tumor effective amount of a population of human T cells, wherein the T cells comprise a nucleic acid sequence that encodes a chimeric antigen receptor (CAR), wherein the CAR comprises a CD19 antigen binding domain comprising the amino acid sequence of SEQ ID NO:

20, a CD8α

hinge domain, a CD8α

transmembrane domain, a 4-1 BB costimulatory signaling region, and a CD3 zeta signaling domain comprising the amino acid sequence of SEQ ID NO;

24, wherein the T cells are T cells of the human patient having leukemia.

2. The method of claim 1, wherein the anti-tumor effective amount of T cells is 10⁴ to 10⁹ cells per kg body weight of the human patient.

3. The method of claim 1, wherein the anti-tumor effective amount of T cells is 10⁵ to 10⁶ cells per kg body weight of the human patient.

4. The method of claim 1, wherein the CD8α

transmembrane domain comprises the amino acid sequence of SEQ ID NO;

22.

5. The method of claim 1, wherein the CD8α

hinge domain comprises the amino acid sequence of SEQ ID NO;

21.

6. The method of claim 1, wherein the 4-1BB costimulatory signaling region comprises the amino acid sequence of SEQ ID NO:

23.

7. The method of claim 1, wherein the CD19 binding domain is encoded by a nucleic acid sequence comprising SEQ ID NO:

14.

8. The method of claim 4, wherein the CD8α

transmembrane domain is encoded by a nucleic acid sequence comprising SEQ ID NO;

16.

9. The method of claim 5, wherein the CD8α

hinge domain is encoded by a nucleic acid sequence comprising SEQ ID NO;

15.

10. The method of claim 6, wherein the 4-1BB costimulatory signaling region is encoded by a nucleic acid sequence comprising SEQ ID NO:

17.

11. The method of claim 1, wherein the CD3 zeta signaling domain is encoded by a nucleic acid sequence comprising SEQ ID NO:

18.

12. The method of claim 1, wherein the T cells replicate in vivo in the human patient.

13. The method of claim 1, wherein the T cells form memory T cells in the human patient.

14. The method of claim 1, wherein the T cells are administered intravenously to the human patient.

15. The method of claim 1, wherein the T cells persist in the human patient.

16. The method of claim 15, wherein the T cells persist in the human patient for a period selected from the group consisting of at least three months, at least four months, at last five months, at least six months and at least seven months after administration.

17. The method of claim 15, wherein the T cells persist in the human patient for at least eight months after administration.

18. The method of claim 15, wherein the T cells persist in the human patient for at least nine months after administration.

19. The method of claim 15, wherein the T cells persist in the human patient for at least ten months after administration.

20. The method of claim 15, wherein the T cells persist in the human patient for at least eleven months after administration.

21. The method of claim 15, wherein the T cells persist in the human patient for at least twelve months after administration.

22. The method of claim 15, wherein the T cells persist in the human patient for at least two years after administration.

23. The method of claim 15, wherein the T cells persist in the human patient for at least three years after administration.

30. The method of claim 1, wherein the leukemia is chronic myelogenous leukemia (CML).

24. A method of treating leukemia in a human patient, the method comprising administering to the human patient a pharmaceutical composition comprising an anti-tumor effective amount of a population of human T cells, wherein the T cells comprise a nucleic acid sequence that encodes a chimeric antigen receptor (CAR), wherein the CAR comprises a CD19 antigen binding domain comprising the amino acid sequence of SEQ ID NO:

20, a CD8α

hinge domain comprising the amino acid sequence of SEQ ID NO;

21, a CD8α

transmembrane domain comprising the amino acid sequence of SEQ ID NO;

22, a 4-1 BB costimulatory signaling region comprising the amino acid sequence of SEQ ID NO;

23, and a CD3 zeta signaling domain comprising the amino acid sequence of SEQ ID NO;

24, wherein the T cells are T cells of the human patient having leukemia.

25. The method of claim 24, wherein the CD19 antigen binding domain of the CAR is encoded by a nucleic acid sequence comprising SEQ ID NO:

14, the CD8α

hinge domain of the CAR is encoded by a nucleic acid sequence comprising SEQ ID NO;

15, the CD8α

transmembrane domain of the CAR is encoded by a nucleic acid sequence comprising SEQ ID NO;

16, the 4-1BB costimulatory signaling region of the CAR is encoded by a nucleic acid sequence comprising SEQ ID NO;

17, and the CD3 zeta signaling domain of the CAR is encoded by a nucleic acid sequence comprising SEQ ID NO;

18.

26. A method of treating chronic lymphocytic leukemia (CLL) in a human patient, the method comprising administering to the human patient a pharmaceutical composition comprising an anti-tumor effective amount of a population of human T cells, wherein the T cells comprise a nucleic acid sequence that encodes a chimeric antigen receptor (CAR), wherein the CAR comprises a CD19 antigen binding domain comprising the amino acid sequence of SEQ ID NO:

20, a CD8α

hinge domain comprising the amino acid sequence of SEQ ID NO;

21, a CD8α

transmembrane domain comprising the amino acid sequence of SEQ ID NO;

22, a 4-1 BB costimulatory signaling region comprising the amino acid sequence of SEQ ID NO;

23, and a CD3 zeta signaling domain comprising the amino acid sequence of SEQ ID NO;

24, wherein the T cells are T cells of the human patient having CLL.

27. The method of claim 26, wherein the CD19 antigen binding domain of the CAR is encoded by a nucleic acid sequence comprising SEQ ID NO:

14, the CD8α

hinge domain of the CAR is encoded by a nucleic acid sequence comprising SEQ ID NO;

15, the CD8α

transmembrane domain of the CAR is encoded by a nucleic acid sequence comprising SEQ ID NO;

16, the 4-1BB costimulatory signaling region of the CAR is encoded by a nucleic acid sequence comprising SEQ ID NO;

17, and the CD3 zeta signaling domain of the CAR is encoded by a nucleic acid sequence comprising SEQ ID NO;

18.

28. A method of treating acute lymphocytic leukemia (ALL) in a human patient, the method comprising administering to the human patient a pharmaceutical composition comprising an anti-tumor effective amount of a population of human T cells, wherein the T cells comprise a nucleic acid sequence that encodes a chimeric antigen receptor (CAR), wherein the CAR comprises a CD19 antigen binding domain comprising the amino acid sequence of SEQ ID NO:

20, a CD8α

hinge domain comprising the amino acid sequence of SEQ ID NO;

21, a CD8α

transmembrane domain comprising the amino acid sequence of SEQ ID NO;

22, a 4-1 BB costimulatory signaling region comprising the amino acid sequence of SEQ ID NO;

23, and a CD3 zeta signaling domain comprising the amino acid sequence of SEQ ID NO;

24, wherein the T cells are T cells of the human patient having ALL.

29. The method of claim 28, wherein the CD19 antigen binding domain of the CAR is encoded by a nucleic acid sequence comprising SEQ ID NO:

14, the CD8α

hinge domain of the CAR is encoded by a nucleic acid sequence comprising SEQ ID NO;

15, the CD8α

transmembrane domain of the CAR is encoded by a nucleic acid sequence comprising SEQ ID NO;

16, the 4-1BB costimulatory signaling region of the CAR is encoded by a nucleic acid sequence comprising SEQ ID NO;

17, and the CD3 zeta signaling domain of the CAR is encoded by a nucleic acid sequence comprising SEQ ID NO;

18.