Granted Patent
B2
US 12,270,050 · App. 16/060,651 · Granted Apr 8, 2025
Human T cell derived from T cell-derived induced pluripotent stem cell and methods of making and using
Inventors:
Bruce R. Blazar (Golden Valley, MN); Dharmeshkumar Patel (Falcon Heights, MN); Beau R. Webber (Coon Rapids, MN); Jakub Tolar (Minneapolis, MN)
Assignee:
REGENTS OF THE UNIVERSITY OF MINNESOTA
C12N5/0636A61K39/4611A61K39/4631A61K39/464412C12N5/0696C12N2501/115C12N2501/125C12N2501/15C12N2501/155C12N2501/165C12N2501/2302C12N2501/2303C12N2501/2307C12N2501/2315C12N2501/26C12N2501/415C12N2501/42C12N2501/51C12N2501/515C12N2501/602C12N2501/603C12N2501/604C12N2501/606C12N2501/727C12N2501/999C12N2506/11C12N2506/45C12N2510/00C12N2533/90
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Abstract
Induced pluripotent stem cells (iPSCs) derived from a T cell of a T cell subset. T cells derived from iPSCs derived from a T cell. Methods of deriving iPSCs from a T cell. Methods of deriving T cells from iPSCs including deriving a T cell of a T cell subset from an iPSC. Methods of engineering chimeric antigen receptor (CAR)-expressing or T cell receptor (TCR)-expressing iPSC. Methods of administering T cells derived using the methods disclosed. Induced pluripotent stem cell lines derived from T cells, methods of deriving induced pluripotent stem cell lines, and methods of deriving T cells from induced pluripotent stem cell lines.
Claims (28)
1. A method comprising:
isolating at least one stem memory T cell (Tsm);
expanding the Tsm in vitro;
reprogramming at least a portion of the expanded Tsms into iPSCs; and
differentiating at least a portion of the iPSCs into T cells, wherein differentiating comprises forming embryoid bodies (EBs) from the iPSCs and culturing the iPSCs in the presence of a Wnt pathway activator and a TGFβ signaling inhibitor, wherein the differentiated T cells comprise a Tsm.
2. The method of claim 1 , wherein the method comprises culturing the iPSCs undergoing differentiation in the presence of at least one of basic fibroblast growth factor (bFGF), bone morphogenetic protein (BMP)-4, a hematopoietic cytokine, stromal cells expressing a Notch ligand, media comprising a soluble Notch ligand, stem cell factor (SCF), IL-7, and FMS-like tyrosine kinase 3 ligand (Flt3L).
3. The method of claim 1 , wherein the method comprises culturing the iPSCs undergoing differentiation sequentially with:
media comprising at least one of bFGF and BMP-4;
media comprising at least one of a Wnt pathway activator and a TGFβ signaling inhibitor;
media comprising at least one hematopoietic cytokine; and
media comprising at least one of SCF, IL-7, and Flt3L.
4. The method of claim 1 , wherein the method comprises culturing the iPSCs undergoing differentiation sequentially in:
media comprising animal-product free medium (APEL) differentiation medium; and
media comprising a stromal cell expressing a Notch ligand or media comprising a soluble Notch ligand.
5. The method of claim 1 , wherein the differentiating comprises enriching the iPSCs for CD34 + cells.
6. The method of claim 1 , the method comprising stimulating the iPSCs undergoing differentiation via at least one of CD3 and CD28.
7. The method of claim 6 wherein differentiating comprises enriching the iPSCs for cells expressing CD45.
8. The method of claim 6 , the method comprising simulating the iPSCs undergoing differentiation in media comprising at least one of SCF, IL-7, Flt3L, IL-15, IL-21, IL-2, a Glycogen synthase kinase 3 (GSK3) inhibitor, and an AKT inhibitor.
9. The method of claim 1 , wherein the iPSCs comprise a chimeric antigen receptor-expressing cell.
10. The method of claim 1 , wherein differentiating at least a portion of the iPSCs into T cells comprises regulating BCL6 and PRDM1 expression.
11. The method of claim 10 , wherein regulating BCL6 and PRDM1 expression comprises inducing BCL6 upregulation and PRDM-1 down-regulation.
12. The method of claim 10 , wherein regulating BCL6 and PRDM1 expression comprises BCL6 knockdown using CRISPRs and inducible PRDM1 expression.
13. The method of claim 1 , wherein the Wnt pathway activator comprises a Wnt signaling agonist.
14. The method of claim 13 , wherein the Wnt signaling agonist comprises CHIR99021, CHIR-98014, LY2090314, BIO, IM-12, 3F8, A 1070722, CHIR99021 trihydrochloride, L803-mts, SB 216763, SB415286, TC-G 24, TWS119, or a combination thereof.
15. The method of claim 14 , wherein the Wnt signaling agonist comprises CHIR99021.
16. The method of claim 1 , wherein the TGFB signaling inhibitor comprises SB43 1542 EW-7197, LY2157299, LY2109761, SB525334, SD-208, SB505124, GW788388, RepSox, or a combination thereof.
17. The method of claim 16 , wherein the TGFβ signaling inhibitor comprises SB431542.
18. The method of claim 1 , wherein the at least one isolated Tsm expresses CD3, CD8, CD45RA, CD62L, CCR7, and CD95.
Assignments (2)
CONFIRMATORY LICENSE
Recorded Feb 10, 2020
From: UNIVERSITY OF MINNESOTA
To: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT
Reel/Frame 051867/0499 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Sep 20, 2018
From: BLAZAR, BRUCE R.; PATEL, DHARMESHKUMAR; WEBBER, BEAU R.; TOLAR, JAKUB
To: REGENTS OF THE UNIVERSITY OF MINNESOTA
Reel/Frame 046932/0144 →
Continuity (2)
Provisional Application
62264455
· Dec 8, 2015
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