Use of the CD2 signaling domain in second-generation chimeric antigen receptors

Patent metadata

Field	Value
Publication number	US-11597754-B2
Application number	US-201916460221-A
Country	US
Kind code	B2
Filing date	Jul 2, 2019
Priority date	Feb 22, 2012
Publication date	Mar 7, 2023
Grant date	Mar 7, 2023

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 expressing a CAR having an antigen binding domain, a transmembrane domain, a CD2 signaling domain, and a CD3 zeta signaling domain. The invention also includes incorporating CD2 into the CAR to alter the cytokine production of CAR-T cells in both negative and positive directions.

First claim

What is claimed is:

1. A method of treating a human with cancer, the method comprising:
administering to the human a T cell genetically engineered to express a chimeric antigen receptor (CAR), wherein the CAR comprises:
(i) an antigen binding domain, wherein the antigen binding domain targets a tumor antigen selected from the group consisting of CD19, CD20, CD22, ROR1, mesothelin, CD33, IL3Ra, c-Met, PSMA, Glycolipid F77, EGFRvIII, GD-2, NY-ESO-1 TCR, MAGE A3 TCR, and MUC1 (CA15-3), and any combination thereof,
(ii) a transmembrane domain,
(iii) a costimulatory signaling region comprising a CD2 signaling domain and a CD28 signaling domain, or a CD2 signaling domain and a 4-1BB signaling domain, wherein the CD2 signaling domain is encoded by a nucleic acid sequence comprising nucleotides 996-1346 of SEQ ID NO: 1, and
(iv) a CD3 zeta signaling domain,
thereby treating the human.

2. The method of claim 1 , wherein the T cell is an autologous T cell.

3. The method of claim 1 , wherein the tumor antigen is PSMA.

4. The method of claim 1 , wherein the antigen binding domain is a Fab or a scFv.

5. The method of claim 1 , wherein the tumor antigen is MUC1 (CA 15-3).

6. The method of claim 1 , wherein the transmembrane domain is a CD8 transmembrane domain.

7. The method of claim 1 , wherein the transmembrane domain is encoded by a nucleic acid sequence comprising nucleotides 924-995 of SEQ ID NO:1.

8. The method of claim 1 , wherein the CAR further comprises a hinge domain.

9. The method of claim 8 , wherein the hinge domain is a CD8 hinge domain.

10. The method of claim 1 , wherein the cancer is a solid tumor.

11. The method of claim 10 , wherein the solid tumor is of the breast, ovary, pancreas, or lung.

12. The method of claim 1 , wherein the cancer is a hematological cancer.

13. The method of claim 12 , wherein the hematological cancer is multiple myeloma.

14. The method of claim 1 , further comprising administering to the human a T cell ablative therapy in conjunction with the T cell genetically engineered to express the chimeric antigen receptor (CAR).

15. The method of claim 14 , wherein the T cell ablative therapy comprises administration of fludarabine and/or cyclophosphamide.

16. The method of claim 1 , wherein the administering is performed via intravenous delivery.

17. The method of claim 1 , wherein the administering is performed via intratumoral delivery.

18. A method of providing an anti-tumor immunity in a mammal in need thereof, the method comprising:
administering to the mammal an effective amount of a T cell genetically modified to express a chimeric antigen receptor (CAR),
wherein the CAR comprises:
an antigen binding domain that targets a tumor antigen selected from the group consisting of CD19, CD20, CD22, ROR1, mesothelin, CD33, IL3Ra, c-Met, PSMA, Glycolipid F77, EGFRvIII, GD-2, NY-ESO-1 TCR, MAGE A3 TCR, and MUC1 (CA15-3), and any combination thereof,
a transmembrane domain,
a costimulatory signaling region comprising a CD2 signaling domain and a CD28 signaling domain, or a CD2 signaling domain and a 4-1BB signaling domain, wherein the CD2 signaling domain is encoded by a nucleic acid sequence comprising nucleotides 996-1346 of SEQ ID NO: 1, and
a CD3 zeta signaling domain.

19. The method of claim 18 , wherein the cell is a T cell.

20. The method of claim 18 , wherein the mammal is a human.

Assignees

• Univ Pennsylvania

Inventors

• June Carl H
• Scholler John
• Posey Jr Avery D

Classifications

• A61K40/4255

  Mesothelin [MSLN] · CPC title

• A61K40/4211

  CD19 or B4 · CPC title

• A61K40/31

  Chimeric antigen receptors [CAR] · CPC title

• A61K40/11

  T-cells, e.g. tumour infiltrating lymphocytes [TIL] or regulatory T [Treg] cells; Lymphokine-activated killer [LAK] cells · CPC title

• A61K2239/21

  Transmembrane domain · CPC title