IP Library › Granted Patent US 12679879
Granted Patent B2
US 12679879 · App. 17/830,218 · Granted Jul 14, 2026

NR4A-deficient cells expressing c-Jun and uses thereof

Inventors: Viola Lam (South San Francisco, CA); Rachel Christina Lynn (South San Francisco, CA)
Assignee: Lyell Immunopharma, Inc.
C07K14/7051A61K40/11A61K40/31A61K40/32A61K40/4202A61K40/4264A61K40/4269C12N5/0636A61K2239/55A61K2239/57C12N15/113C12N2310/20
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Quick Facts
Patent No.
US 12679879
App. No.
17/830,218
Granted
Jul 14, 2026
Kind
B2
Abstract

The present disclosure provides methods of promoting a persistent effector function of immune cells, comprising modifying the cells to overexpress c-Jun and reduced levels of a NR4A gene and/or protein. Also provided are modified cells, e.g., immune cell, which have been modified to overexpress c-Jun and express reduced levels of NR4A gene and/or protein. Overexpressing c-Jun and simultaneously reducing expression levels of a NR4A gene and/or protein leads to exhaustion/dysfunction resistant cells, which are apoptosis resistant and also immune checkpoint resistant, and also to the maintenance of anti-tumor function in tumor microenvironments.

Claims (59)

1 . A cell composition comprising a population of modified immune cells that have (i) a reduced expression level of a gene and/or protein of a member of a nuclear receptor subfamily 4 group A (NR4A) family and (ii) an increased expression level of a c-Jun protein, wherein the member of the NR4A family is selected from the group consisting of a NR4A member 1 (NR4A1), NR4A member 2 (NR4A2), and NR4A member 3 (NR4A3), wherein the modified immune cells are T cells.

2 . The cell composition of claim 1 , wherein the modified immune cells have a reduced expression level of the gene and/or protein of: (a) both NR4A1 and NR4A2; (b) both NR4A1 and NR4A3; (c) both NR4A2 and NR4A3; or (d) each of NR4A1, NR4A2, and NR4A3.

3 . The cell composition of claim 1 , wherein the modified immune cells comprise a chimeric antigen receptor (CAR) and/or a T cell receptor (TCR).

4 . The cell composition of claim 1 , wherein the population of modified immune cells comprises: (a) less than about 50% of effector T cells; (b) at least about 50% of naïve T (TN) cells, central memory T cells (TCM cells), stem memory T (TSCM) cells, or a combination thereof, or (c) both (a) and (b).

5 . The cell composition of claim 1 , wherein the modified immune cells have been contacted with:

(a) a gene editing tool which comprises a guide RNA comprising, consisting of, or consisting essentially of the sequence set forth in any one of SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 61, SEQ ID NO: 65, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 70, SEQ ID NO: 71, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 82, SEQ ID NO: 83, SEQ ID NO: 86, SEQ ID NO: 94, and SEQ ID NO: 96,

(b) a nucleotide sequence encoding the c-Jun protein; or

(c) both (a) and (b).

6 . The cell composition of claim 5 , wherein the nucleotide sequence encoding the c-Jun protein comprises:

(a) a nucleic acid sequence having at least 89% sequence identity to the nucleic acid sequence as set forth in SEQ ID NO: 7;

(b) a nucleic acid sequence having at least 90% sequence identity to the nucleic acid sequence as set forth in SEQ ID NO: 8;

(c) a nucleic acid sequence having at least about 30% sequence identity to the nucleic acid sequence as set forth in SEQ ID NO: 10;

(d) a nucleic acid sequence having at least 79% sequence identity to the nucleic acid sequence as set forth in SEQ ID NO: 11;

(e) a nucleic acid sequence having at least 88% sequence identity to the nucleic acid sequence as set forth in SEQ ID NO: 12;

(f) a nucleic acid sequence having at least 82% sequence identity to the nucleic acid sequence as set forth in SEQ ID NO: 13;

(g) a nucleic acid sequence having at least 90% sequence identity to the nucleic acid sequence as set forth in SEQ ID NO: 14;

(h) a nucleic acid sequence having at least 55% sequence identity to the nucleic acid sequence as set forth in SEQ ID NO: 15; or

(i) a nucleic acid sequence having at least 85% sequence identity to the nucleic acid sequence as set forth in SEQ ID NO: 16.

7 . A pharmaceutical composition comprising the cell composition of claim 1 and a pharmaceutically acceptable carrier.

8 . A cell composition comprising a cell which (a) expresses a ligand binding protein, (b) has an increased expression level of a c-Jun protein, and (b) has a reduced expression level of a gene and/or protein of a member of a nuclear receptor subfamily 4 group A (NR4A) family, wherein the cell has been modified with a gRNA comprising, consisting of, or consisting essentially of the sequence set forth in any one of set forth in any one of SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 61, SEQ ID NO: 65, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 70, SEQ ID NO: 71, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 82, SEQ ID NO: 83, SEQ ID NO: 86, SEQ ID NO: 94, and SEQ ID NO: 96, and wherein the cell is a T cell.

9 . The cell composition of claim 2 , wherein the modified immune cells have a reduced expression level of the gene and/or protein of both NR4A1 and NR4A2.

10 . The cell composition of claim 2 , wherein the modified immune cells have a reduced expression level of the gene and/or protein of both NR4A1 and NR4A3.

11 . The cell composition of claim 2 , wherein the modified immune cells have a reduced expression level of the gene and/or protein of both NR4A2 and NR4A3.

12 . The cell composition of claim 2 , wherein the modified immune cells have a reduced expression level of the gene and/or protein of each of NR4A1, NR4A2, and NR4A3.

13 . The cell composition of claim 8 , wherein the ligand binding protein comprises a chimeric antigen receptor (CAR) and/or a T cell receptor (TCR).

14 . The cell composition of claim 8 , wherein the cell has been contacted with a nucleotide sequence encoding the c-Jun protein.

15 . The cell composition of claim 14 , wherein the nucleotide sequence encoding the c-Jun protein comprises:

(a) a nucleic acid sequence having at least 89% sequence identity to the nucleic acid sequence as set forth in SEQ ID NO: 7;

(b) a nucleic acid sequence having at least 90% sequence identity to the nucleic acid sequence as set forth in SEQ ID NO: 8;

(c) a nucleic acid sequence having at least about 30% sequence identity to the nucleic acid sequence as set forth in SEQ ID NO: 10;

(d) a nucleic acid sequence having at least 79% sequence identity to the nucleic acid sequence as set forth in SEQ ID NO: 11;

(e) a nucleic acid sequence having at least 88% sequence identity to the nucleic acid sequence as set forth in SEQ ID NO: 12;

(f) a nucleic acid sequence having at least 82% sequence identity to the nucleic acid sequence as set forth in SEQ ID NO: 13;

(g) a nucleic acid sequence having at least 90% sequence identity to the nucleic acid sequence as set forth in SEQ ID NO: 14;

(h) a nucleic acid sequence having at least 55% sequence identity to the nucleic acid sequence as set forth in SEQ ID NO: 15; or

a nucleic acid sequence having at least 85% sequence identity to the nucleic acid sequence as set forth in SEQ ID NO: 16.

16 . The cell composition of claim 6 , wherein the nucleotide sequence encoding the c-Jun protein comprises:

(a) the nucleic acid sequence set forth in SEQ ID NO: 7;

(b) the nucleic acid sequence set forth in SEQ ID NO: 8;

(c) the nucleic acid sequence set forth in SEQ ID NO: 10;

(d) the nucleic acid sequence set forth in SEQ ID NO: 11;

(e) the nucleic acid sequence set forth in SEQ ID NO: 12;

(f) the nucleic acid sequence set forth in SEQ ID NO: 13;

(g) the nucleic acid sequence set forth in SEQ ID NO: 14;

(h) the nucleic acid sequence set forth in SEQ ID NO: 15; or

(i) the nucleic acid sequence set forth in SEQ ID NO: 16.

17 . The cell composition of claim 15 , wherein the nucleotide sequence encoding the c-Jun protein comprises:

(a) the nucleic acid sequence set forth in SEQ ID NO: 7;

(b) the nucleic acid sequence set forth in SEQ ID NO: 8;

(c) the nucleic acid sequence set forth in SEQ ID NO: 10;

(d) the nucleic acid sequence set forth in SEQ ID NO: 11;

(e) the nucleic acid sequence set forth in SEQ ID NO: 12;

(f) the nucleic acid sequence set forth in SEQ ID NO: 13;

(g) the nucleic acid sequence set forth in SEQ ID NO: 14;

(h) the nucleic acid sequence set forth in SEQ ID NO: 15; or

(i) the nucleic acid sequence set forth in SEQ ID NO: 16.

18 . A pharmaceutical composition comprising the cell composition of claim 8 and a pharmaceutically acceptable carrier.

19 . The cell composition of claim 5 , wherein the guide RNA consists of the sequence set forth in any one of SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 61, SEQ ID NO: 65, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 70, SEQ ID NO: 71, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 82, SEQ ID NO: 83, SEQ ID NO: 86, SEQ ID NO: 94, and SEQ ID NO: 96.

20 . The cell composition of claim 8 , wherein the guide RNA consists of the sequence set forth in any one of SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 61, SEQ ID NO: 65, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 70, SEQ ID NO: 71, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 82, SEQ ID NO: 83, SEQ ID NO: 86, SEQ ID NO: 94, and SEQ ID NO: 96.