Modified Cell Expansion and Uses Thereof

• US 20190314411A1
• Filed: 04/17/2019
• Published: 10/17/2019
• Est. Priority Date: 04/17/2018
• Status: Active Grant

• Current Assignee: Innovative Cellular Therapeutics Co., Ltd., Innovative Cellular Therapeutics Holdings, Ltd.
• Original Assignee: Innovative Cellular Therapeutics Co., Ltd.
• Inventors: Xiao, Lei, Cao, Zhiyuan, Pu, Chengfei, Sun, He
• Granted Patent: US 10,869,888 B2
• Time in Patent Office: Days
• 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 38/191 Tumor necrosis factors [TNF], e.g. lymphotoxin [LT], i.e. TNF-beta
• CPC Class Codes: A61K 38/204 IL-6
• CPC Class Codes: A61K 38/208 IL-12
• 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 39/46447 Mucins, e.g. MUC-1
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07K 14/7051 T-cell receptor (TcR)-CD3 complex
• CPC Class Codes: C07K 14/82 Translation products from oncogenes
• CPC Class Codes: C07K 16/2803 against the immunoglobulin superfamily
• CPC Class Codes: C07K 16/2818 against CD28 or CD152
• CPC Class Codes: C07K 16/3092 against tumour-associated mucins
• CPC Class Codes: C07K 2317/622 Single chain antibody (scFv)
• CPC Class Codes: C07K 2319/03 containing a transmembrane segment
• 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: C12N 15/86 Viral vectors
• CPC Class Codes: C12N 2740/16043 viral genome or elements thereof as genetic vector

Abstract

The present disclosure relates to compositions and methods for enhancing T cell response and/or CAR cell expansion and/or maintenance in vivo and/or in vitro. For example, a method of enhancing T cell-based therapy comprises administering genetically modified T cells comprising a first chimeric antigen receptor (CAR) and a second CAR, wherein a binding domain of the first CAR binds a first antigen, and a binding domain of the second CAR binds a second antigen. The first antigen is different from the second antigen. In embodiments, the first CAR binds a surface molecule or antigen of a white blood cell.

Claims

1. A method of enhancing expansion of cells in a subject or treating the subject having cancer, the method comprising:

administering an effective amount of a composition to the subject having a form of cancer expressing a tumor antigen, the composition comprising a first population of cells comprising a first CAR binding a first antigen, and a second population of cells comprising a second CAR binding a second antigen, wherein the second antigen is a tumor antigen and is different from the first antigen.

2. The method of claim 1, wherein the cells are T cells, NK cells, or dendritic cells.

3. The method of claim 1, wherein the first antigen comprises a cell surface molecule of a white blood cell (WBC), a tumor antigen, or a solid tumor antigen.

4. The method of claim 3, wherein the WBC is a granulocyte, a monocyte, or lymphocyte.

5. The method of claim 3, wherein the WBC is a B cell.

6. The method of claim 3, wherein the cell surface molecule of the WBC is CD19, CD22, CD20, BCMA, CD5, CD7, CD2, CD16, CD56, CD30, CD14, CD68, CD11b, CD18, CD169, CD1c, CD33, CD38, CD138, or CD13.

7. The method of claim 3, wherein the cell surface molecule of the WBC is CD19, CD20, CD22, or BCMA.

8. The method of claim 3, wherein the cell surface molecule of the WBC is CD19.

9. The method of claim 1, wherein the tumor antigen is a solid tumor antigen.

10. The method of claim 9, wherein the solid tumor antigen is tMUC 1, PRLR, CLCA1, MUC12, GUCY2C, GPR35, CR1L, MUC 17, TMPRSS11B, MUC21, TMPRSS11E, CD207, SLC30A8, CFC1, SLC12A3, SSTR1, GPR27, FZD10, TSHR, SIGLEC15, SLC6A3, KISS1R, QRFPR, GPR119, CLDN6, UPK2, ADAM12, SLC45A3, ACPP, MUC21, MUC16, MS4A12, ALPP, CEA, EphA2, FAP, GPC3, IL13-Rα

2, Mesothelin, PSMA, ROR1, VEGFR-II, GD2, FR-α

, ErbB2, EpCAM, EGFRvIII, B7-H3, or EGFR.

11. The method of claim 9, wherein the solid tumor antigen comprises tumor associated MUC1.

12. The method of claim 1, wherein the CAR comprises an antigen binding domain, a transmembrane domain, a co-stimulatory domain, and a CD3 zeta domain.

13. The method of claim 12, wherein the co-stimulatory domain comprises the intracellular domain of CD27, CD28, 4-1BB, OX40, CD30, CD40, PD-1, ICOS, lymphocyte function-associated antigen-1 (LFA-1), CD2, CD7, LIGHT, NKG2C, B7-H3, a ligand that binds CD83, or a combination thereof.

14. The method of claim 1, wherein the first CAR comprises a scFv binding CD19, an intracellular domain of 4-1BB or CD28, CD3 zeta domain, and the second CAR comprises a scFv binding tMUC1, an intracellular domain of 4-1 BB or CD28, CD3 zeta domain.

15. The method of claim 1, wherein an antigen binding domain of the first CAR comprises the SEQ ID NO:

5 and an antigen binding domain of the second CAR comprises SEQ ID NO;

70.

16. The method of claim 1, wherein the second population of cells comprises a lentiviral vector encoding the second CAR and a dominant negative form of PD-1.

17. The method of claim 1, wherein the first population of cells comprises a lentiviral vector encoding the first CAR and a therapeutic agent.

18. The method of claim 17, wherein the therapeutic agent comprises a cytokine.

19. The method of claim 18, wherein the cytokine is IL6 and/or INFγ

.

20. The method of claim 18, wherein the cytokine is at least one of IL6, IL12, TNF-α

, or IFN-γ

.