Compositions and Methods for Efficacy Enhancement of T-Cell Based Immunotherapy

Patent metadata

Field	Value
Publication number	US-2022017715-A1
Application number	US-201816625542-A
Country	US
Kind code	A1
Filing date	Jun 22, 2018
Priority date	Jun 23, 2017
Publication date	Jan 20, 2022
Grant date	—

Abstract

The present invention includes compositions and methods for enhancing T cell based immunotherapy. In certain aspects, the invention includes modified T cells and inhibitors of Dhx37 for use in enhancing T cell based immunotherapy and treating cancer.

First claim

1 . A method of enhancing T cell based immunotherapy in a subject, the method comprising administering to the subject in need thereof a genetically modified T cell wherein a gene selected from the group consisting of Dhx37, Lyn, Slc35c1, Lexm, Fam103a1 and Odc1 has been mutated in the T cell.

2 . The method of claim 1 , wherein the T cell is selected from the group consisting of a CD8+, a CD4+, a T regulatory (Treg) cell and a Chimeric Antigen Receptor (CAR)-T cell.

3 . The method of claim 1 , wherein the subject is a human.

4 . The method of claim 1 , wherein at least one additional gene has been mutated in the T cell.

5 . The method of claim 4 , wherein the at least one additional gene is selected from the group consisting of Dhx37, Lyn, Slc35c1, Lexm, Fam103a1 and Odc1.

6 . The method of claim 1 , further comprising administering an additional treatment to the subject.

7 . The method of claim 6 , wherein the additional treatment is selected from the group consisting of an immune checkpoint inhibitor, a PD-1 inhibitor, and a CTLA-4 inhibitor.

8 . A method of performing adoptive cell transfer therapy in a subject, the method comprising administering to the subject in need thereof a genetically modified T cell, wherein a gene selected from the group consisting of Dhx37, Lyn, Slc35c1, Lexm, Fam103a1 and Odc1 has been mutated in the T cell.

9 . The method of claim 8 , wherein the T cell is selected from the group consisting of a CD8+, a CD4+, a T regulatory (Treg) cell, and a CAR-T cell.

10 . The method of claim 8 , wherein the subject is a human.

11 . The method of claim 8 , wherein at least one additional gene has been mutated in the T cell.

12 . The method of claim 11 , wherein the at least one additional gene is selected from the group consisting of Dhx37, Lyn, Slc35c1, Lexm, Fam103a1 and Odc1.

13 . The method of claim 8 , further comprising administering an additional treatment to the subject.

14 . The method of claim 13 , wherein the additional treatment is selected from the group consisting of an immune checkpoint inhibitor, a PD-1 inhibitor, and a CTLA-4 inhibitor.

15 . A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a genetically modified T cell wherein a gene selected from the group consisting of Dhx37, Lyn, Slc35c1, Lexm, Fam103a1 and Odc1 has been mutated in the T cell.

16 . The method of claim 15 , wherein the T cell is selected from the group consisting of a CD8+, a CD4+, a T regulatory (Treg) cell, and a CAR-T cell.

17 . The method of claim 15 , wherein the subject is a human.

18 . The method of claim 15 , wherein at least one additional gene has been mutated in the T cell.

19 . The method of claim 18 , wherein the at least one additional gene is selected from the group consisting of Dhx37, Lyn, Slc35c1, Lexm, Fam103a1 and Odc1.

20 . The method of claim 15 , further comprising administering an additional treatment to the subject.

21 . The method of claim 20 , wherein the additional treatment is selected from the group consisting of an immune checkpoint inhibitor, a PD-1 inhibitor, and a CTLA-4 inhibitor.

22 . A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an inhibitor of Dhx37.

23 . The method of claim 22 , wherein the inhibitor is selected from the group consisting of an antibody, an siRNA, and a CRISPR system.

24 . The method of claim 23 , wherein the CRISPR system comprises a Cas9, and at least one sgRNA complementary to Dhx37.

25 . The method of claim 24 , wherein the sgRNA comprises a nucleotide sequence selected from the group consisting of SEQ ID NOs: 1-10.

26 . The method of claim 24 , wherein the sgRNA comprises a nucleotide sequence selected from the group consisting of SEQ ID NOs: 11-820.

27 . The method of claim 23 , wherein the antibody recognizes and binds to at least one amino acid sequence selected from the group consisting of SEQ ID NOs: 3022-3031.

28 . The method of claim 22 , further comprising administering an additional treatment to the subject.

29 . The method of claim 28 , wherein the additional treatment is selected from the group consisting of an immune checkpoint inhibitor, a PD-1 inhibitor, and a CTLA-4 inhibitor.

30 . The method of claim 22 , further comprising administering to the subject an inhibitor of a gene or gene product selected from the group consisting of Lyn, Slc35c1, Lexm, Fam103a1 and Odc.

31 . A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an inhibitor of a gene or gene product selected from the group consisting of Lyn, Slc35c1, Lexm, Fam103a1 and Odc.

32 . The method of claim 31 , wherein the inhibitor is selected from the group consisting of an antibody, an siRNA, and a CRISPR system.

33 . The method of claim 32 , wherein the CRISPR system comprises a Cas9, and at least one sgRNA complementary to a gene selected from the group consisting of Lyn, Slc35c1, Lexm, Fam103a1 and Odc.

34 . The method of claim 33 , wherein the sgRNA comprises a nucleotide sequence selected from the group consisting of SEQ ID NOs: 821-3020.

35 . The method of claim 31 , further comprising administering an additional treatment to the subject.

36 . The method of claim 35 , wherein the additional treatment is selected from the group consisting of an immune checkpoint inhibitor, a PD-1 inhibitor, and a CTLA-4 inhibitor.

37 . A method of generating a genetically modified T cell for use in immunotherapy, the method comprising administering to a naïve T cell a vector comprising a first sgRNA complementary to a first nucleotide sequence of a Dhx37 gene and a second sgRNA complementary to a second nucleotide sequence of the Dhx37 gene.

38 . The method of claim 37 , wherein the first sgRNA nucleotide sequence is selected from the group consisting of SEQ ID NOs: 1-10 and the second sgRNA nucleotide sequence is selected from the group consisting of SEQ ID NOs: 1-10.

39 . The method of claim 37 , wherein the first sgRNA nucleotide sequence is selected from the group consisting of SEQ ID NOs: 11-820 and the second sgRNA nucleotide sequence is selected from the group consisting of SEQ ID NOs: 11-820.

40 . A method of generating a genetically modified T cell for use in immunotherapy, the method comprising administering to a naïve T cell a vector comprising a first sgRNA complementary to a first nucleotide sequence of a gene selected from the group consisting of Lyn, Slc35c1, Lexm, Fam103a1 and Odc and a second sgRNA complementary to a second nucleotide sequence of a gene selected from the group consisting of Lyn, Slc35c1, Lexm, Fam103a1 and Odc.

41 . The method of claim 40 , wherein the first sgRNA nucleotide sequence is selected from the group consisting of SEQ ID NOs: 821-3020 and the second sgRNA nucleotide sequence is selected from the group consisting of SEQ ID NOs: 821-3020.

42 . A composition comprising a genetically modified T cell generated by the met

Assignees

• Dow Global Technologies Llc
• Dow Brasil Sudeste Ind Ltda
• Rohm & Haas
• Univ Yale

Inventors

• Chen Sidi
• Dong Matthew

Classifications

• A61K40/42

  Cancer antigens · CPC title

• A61K40/32

  T-cell receptors [TCR] · CPC title

• A61K40/11

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

• A61K2239/38

  characterised by the dose, timing or administration schedule · CPC title

• A61K2239/49

  Breast · CPC title