Granted Patent
B2
US 12,721,891 · App. 19/084,311 · Granted Sep 1, 2026
Molecular engineering to enhance CAR-T mediated tumor immunotherapy
Inventors:
Hai-Hui Xue (Nutely, NJ); Yi Zhang (Wallingford, PA); David Perlin (New York, NY); Xin Zhao (Clifton, NJ); Wei Hu (Union City, NJ)
Assignee:
HACKENSACK MERIDIAN HEALTH, INC.
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Abstract
The present disclosure provides a chimeric antigen receptor (CAR) immunotherapy for treating a hematologic cancer comprising (a) genetically modifying a population of immune effector cells comprising T cell receptors (TCRs) to stably express at least one CAR, wherein the ectodomain of the CAR specifically binds a cancer antigen; (b) expanding the population of CAR-containing immune effector cells in the presence of one or more cytokines in vitro to achieve a therapeutic dose, wherein the population of CAR-containing immune effector cells exhibits a nonexhausted memory T cell phenotype; and (c) infusing eligible subjects with the CAR-containing immune effector memory T cell phenotype population of cells as needed until the hematologic cancer in the body is destroyed. The intracellular signal transduction domain of the CAR includes 4-1BB, a CD3ζ T cell activation chain and a genetically engineered TLE3, which can be ectopically expressed. The immune effector cell population engineered to express the CAR comprising the engineered TLE3 construct by lentiviral transduction is a CD3+ T cell population or an NK cell. Expression of the engineered TLE3 construct in stimulated CAR-containing immune effector cells in vitro and in vivo xenograft preclinical models promotes activation of genes that promote anti-tumor activity and also represses genes involved in excessive effector function, exhaustion or both.
Claims (35)
1 . A chimeric antigen receptor (CAR) immunotherapy for treating a hematologic cancer comprising:
(a) genetically modifying a population of immune effector cells comprising T cell receptors (TCRs) to stably express at least one chimeric antigen receptor (CAR), wherein the ectodomain of the CAR specifically binds a cancer antigen, and wherein the CAR comprises an extracellular antigen recognition domain, a spacer/hinge region and transmembrane domain, and an intracellular signal transduction domain, wherein the intracellular signal transduction domain of the CAR comprises 4-1BB; a CD3ζ T cell activation chain; and a truncated transducer-like enhancer 3 (TLE3) molecule;
(b) expanding the population of CAR-containing immune effector cells in the presence of one or more cytokines in vitro to achieve a therapeutic dose, wherein the population of CAR-containing immune effector cells expresses a non-exhausted memory T cell phenotype; and
(c) infusing eligible subjects with the CAR-containing immune effector memory T cell phenotype population of cells as needed until all cancer in the body is destroyed.
2 . The CAR-immunotherapy according to claim 1 , wherein the hematologic cancer is a leukemia, a lymphoma or a myeloma.
3 . The CAR immunotherapy according to claim 1 , wherein
the truncated TLE3 molecule is a C-terminus truncated TLE3 (TLE3ΔWDR) protein.
4 . The CAR immunotherapy according to claim 3 , wherein the CAR is linked to the engineered truncated TLE molecule via P2A peptide, which allows simultaneous translation of both proteins in the same immune effector cell.
5 . The CAR immunotherapy according to claim 1 , wherein
a) the target antigen of the CAR is CD19;
b) the target antigen of the CAR is CD20;
c) the target antigen of the CAR is CD22;
d) the target antigen of the CAR is NKG2D-1;
e) the target antigen of the CAR is CD33;
f) the target antigen of the CAR is BCMA, or
g) the target antigen of the CAR is CD123.
6 . The CAR immunotherapy according to claim 5 , wherein the CAR containing population of immune effector cells recognizes two or more tumor associated antigens simultaneously.
7 . The CAR immunotherapy according to claim 1 wherein:
a) the immune effector cell population is engineered to express the CAR comprising the truncated TLE3 molecule by lentiviral transduction;
b) the immune effector cell population is a CD3+ T cell population; and
c) the T cell population comprises CD4+ T cells, CD8+ T cells, or both.
8 . The CAR immunotherapy according to claim 1 , wherein
a) source of the immune effector cell is peripheral blood or umbilical cord blood;
b) the population of immune effector cells is autologous to the subject; or
c) the population of immune effector cells is allogeneic to the subject.
9 . The CAR immunotherapy according to claim 1 , wherein when the engineered TLE3 molecule is a C-terminus truncated TLE3 (TLE3ΔWDR) protein, compared to a no-TLE3 CAR immune effector control,
a. expression of the TLE3ΔWDR construct in CAR-containing immune effector cells enhances CAR-immune effector cell function despite chronic antigen stimulation; and/or
b. expression of the TLE3ΔWDR construct in stimulated CAR-containing immune effector cells promotes activation of genes that promote anti-tumor activity and also represses genes involved in excessive effector function, exhaustion or both; and/or
c. expression of the TLE3ΔWDR construct in stimulated CAR-containing immune effector cells reduces expression of at least one inhibitory receptor comprising PD-1, CTLA-4, LAG3, TIGIT, or a combination thereof; and/or
d. expression of the CAR-TLE3ΔWDR construct in stimulated CAR-containing immune effector cells induces transcriptomic changes comprising differential expression of genes that enhance the anti-tumor response comprising proliferation of the CAR-containing immune effector cells; enhances persistence of the CAR-containing immune effector cells and maintains immune homeostasis despite chronic antigen stimulation; and/or
e. expression of the CAR-TLE3ΔWDR construct in stimulated CAR-containing immune effector cells reprograms the immune effector cells to acquire stem-like, memory cell characteristics, central memory cell characteristics, effector memory cell characteristics, or a combination thereof including production of IFN and TNF, expression of TCF-1, TOX, or both, and/or
f. expression of the TLE3ΔWDR construct in CAR-containing immune effector cells enhances CAR-immune effector cell function after rechallenge with the cancer.
10 . The CAR immunotherapy according to claim 9 , wherein the activation of genes that promote anti-tumor activity comprise the activation of TLE3, AEBP1, ARRB1, EPAS1, MYLB1, TCEA3, ZNF629, E2F2, SMARCA2, ITGAX, FGFR1, PAGFRB, COL6A2, PIK3R6, or a combination thereof.
11 . The CAR immunotherapy according to claim 9 , wherein the repression of genes involved in excessive effector function, exhaustion, or both comprise repression of BCL2L11, BMF, NEK6, PIM3, SRGN, ETS2, TBX21, ID2, PLAGL2, NUS1, ACSL6, PAM, or a combination thereof.
12 . The CAR immunotherapy according to claim 4 , wherein ectopic expression of the truncated TLE3 molecule is effective to selectively antagonize normal TLE3 activity.
Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Apr 9, 2025
From: XUE, HAI-HUI; ZHANG, YI; PERLIN, DAVID; ZHAO, XIN; HU, WEI
To: HACKENSACK MERIDIAN HEALTH, INC.
Reel/Frame 070789/0986 →
Continuity (3)
Provisional Application
63765909
· Mar 3, 2025
Provisional Application
63707903
· Oct 16, 2024
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