Granted Patent
B2
US 12,564,648 · App. 19/188,828 · Granted Mar 3, 2026
Gene editing of CAR-T cells for the treatment of T cell malignancies with chimeric antigen receptors
Assignee:
Washington University
A61K48/0066A61K40/11A61K40/22A61K40/31A61K40/418A61K40/421A61K40/4211A61K48/0008A61K48/0058A61K48/0091A61P35/02A61P37/06C12N5/0636A61K2239/31A61K2239/38A61K2239/48
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Abstract
The present disclosure provides the use of fratricide-resistant chimeric antigen receptor T (CAR-T) cells targeting antigens expressed by T cell malignancies.
Claims (45)
1 . A method for treating a CD7 positive hematologic cancer in a human subject, the method comprising administering an effective dose of human T cells, wherein the T cells:
(a) express a chimeric antigen receptor (CAR) that specifically binds CD7;
(b) comprise a first genetic modification comprising a first indel in the genomic locus of CD7, wherein the first indel occurs at a position within:
80,274,181-80,274,203;
80,274,195-80,274,217;
80,274,238-80,274,260,
80,274,239-80,274,261;
80,274,555-80,274,577;
80,274,563-80,274,585;
80,274,569-80,274,591;
80,274,571-80,274,593;
80,274,580-80,274,602; or
80,274,586-80,274,608 of chromosome 17, wherein positional numbering is according to Genome Reference Consortium Human Build 37 (GRCh37); and
(c) comprise a second genetic modification comprising a second indel in the genomic locus of T cell Receptor Alpha Chain (TRAC).
2 . The method of claim 1 , wherein the first indel occurs at a position within 80,274,563-80,274,585.
3 . The method of claim 1 , wherein the first indel occurs at a position within 80,274,569-80,274,591.
4 . The method of claim 1 , wherein the first indel occurs at a position within 80,274,571-80,274,593.
5 . The method of claim 1 , wherein the first indel occurs at a position within 80,274,580-80,274,602.
6 . The method of claim 1 , wherein the effective amount comprises at least one infusion of between about 10 5 -10 7 T cells per kilogram of body weight of the subject.
7 . The method of claim 1 , wherein the cells demonstrate reduced T cell fratricide compared to CAR-bearing T cells that are not genetically engineered to be deficient in CD7.
8 . The method of claim 1 , wherein the T cells demonstrate improved in vivo persistence and/or expansion compared to CAR-bearing T cells that are not genetically engineered to be deficient in one or more of TRAC and CD7.
9 . The method of claim 1 , wherein the T cells demonstrate improved therapeutic activity compared to CAR-bearing T cells that are not genetically engineered to be deficient in one or more of TRAC and CD7.
10 . The method of claim 1 , wherein the T cells demonstrate fewer side effects in the human subject, compared to CAR-bearing T cells that are not engineered to be deficient in one or more of TRAC and CD7, wherein the side effects comprise alloreactivity and/or graft-versus-host disease (GvHD).
11 . The method of claim 1 , wherein the CD7 positive hematologic cancer is chosen from T-cell acute lymphoblastic leukemia (T-ALL), T-cell lymphoblastic lymphoma (T-LBL), T-cell non-Hodgkin's Lymphoma (T-NHL) and acute myeloid leukemia (AML).
12 . The method of claim 11 , wherein the administration comprises infusion of the efftive amount of T cells to the subject, wherein the infusion is provided once, and the effective amount of T cells comprises between about 10 5 -10 7 T cells per kilogram of body weight of the human subject.
13 . The method of claim 12 , wherein the cells demonstrate reduced T cell fratricide compared to CAR-bearing T cells that are not genetically engineered to be deficient in CD7.
14 . The method of claim 12 , wherein the T cells demonstrate improved in vivo persistence compared to CAR-bearing T cells that are not genetically engineered to be deficient in one or more of TRAC and CD7.
15 . The method of claim 12 , wherein the T cells demonstrate improved in vivo expansion compared to CAR-bearing T cells that are not genetically engineered to be deficient in one or more of TRAC and CD7.
16 . The method of claim 12 , wherein the T cells demonstrate improved therapeutic activity compared to CAR-bearing T cells that are not genetically engineered to be deficient in one or more of TRAC and CD7.
17 . The method of claim 12 , wherein the T cells demonstrate fewer side effects in the human subject, compared to CAR-bearing T cells that are not engineered to be deficient in one or more of TRAC and CD7, wherein the side effects comprise alloreactivity or graft-versus-host disease (GvHD).
18 . The method of claim 1 , wherein the T cells are administered following chemotherapy.
19 . The method of claim 1 , wherein the T cells are accompanied by another therapy or treatment modality, wherein the other therapy or treatment modality is one or more of immunotherapy, chemotherapy and radiation therapy.
20 . The method of claim 1 , wherein the second indel in the genomic locus of TRAC occurs at a position within 23,016,517-23,016,536 of chromosome 14, wherein positional numbering is according to Genome Reference Consortium Human Build 37 (GRCh37).
21 . A method for treating a CD7 positive hematologic cancer in a human subject, the method comprising administering an effective amount of human T cells, wherein the T cells:
(a) express a chimeric antigen receptor (CAR) that specifically binds CD7;
(b) comprise a first genetic modification comprising a first indel in the genomic locus of CD7, wherein the first indel occurs within the genomic region targeted by sequences selected from SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO:14, SEQ ID NO: 15, SEQ ID NO:16, SEQ ID NO: 17, or SEQ ID NO: 18; and
(c) comprise a second genetic modification comprising a second indel in the genomic locus of T cell Recepto Alpha Chain (TRAC).
22 . The method of claim 21 , wherein the first indel occurs within the genomic region targeted by SEQ ID NO:10.
23 . The method of claim 21 , wherein the first indel occurs within the genomic region targeted by SEQ ID NO:16.
24 . The method of claim 21 , wherein the first indel occurs within the genomic region targeted by SEQ ID NO:17.
25 . The method of claim 21 , wherein the first indel occurs within the genomic region targeted by SEQ ID NO:18.
26 . The method of claim 21 , wherein endogenous T cell receptor mediated signaling is blocked in the T cells.
27 . The method of claim 21 , wherein the T cells are human T cells sourced from an allogeneic donor.
28 . The method of claim 27 , wherein the T cells comprise CD4+ T cells, CD8+ T cells, or a combination thereof.
29 . The method of claim 21 , wherein the second indel in the genomic locus of TRAC occurs within the genomic region targeted by residues 1-20 of SEQ ID NO: 19.
Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Jun 11, 2025
From: DIPERSIO, JOHN F.; COOPER, MATTHEW
To: WASHINGTON UNIVERSITY
Reel/Frame 071381/0337 →
Continuity (5)
Division
16322803
Provisional Application
62505614
· May 12, 2017
Provisional Application
62482570
· Apr 6, 2017
Provisional Application
62370485
· Aug 3, 2016
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