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Cd123-specific chimeric antigen receptor redirected t cells and methods of their use

A technology of chimeric antigen receptors and cells, applied in the direction of receptors/cell surface antigens/cell surface determinants, antibodies, animal cells, etc., can solve problems such as recurrence

Active Publication Date: 2016-03-09
CITY OF HOPE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Although current treatment regimens for AML achieve complete responses in selected patients, many eventually relapse, highlighting the need for new treatments that can elicit more durable responses

Method used

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  • Cd123-specific chimeric antigen receptor redirected t cells and methods of their use
  • Cd123-specific chimeric antigen receptor redirected t cells and methods of their use
  • Cd123-specific chimeric antigen receptor redirected t cells and methods of their use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0104] Example 1: T cells transduced with CD123CAR exhibit potent cytolytic activity and multiple effector functions against AML in vitro

[0105] Materials and methods

[0106] Cell lines. Unless otherwise stated, all cell lines were maintained in RPMI 1640 (Irvine Scientific) supplemented with 2 mM L-glutamine, 25 mM HEPES, and 10% heat-inactivated FCS (Hyclone) (hereinafter referred to as complete medium (CM)). Peripheral blood mononuclear cells (PBMC) were transformed with Epstein-Barr virus to generate lymphoblastoid cell lines (LCL) as previously described [19]. LCL-OKT3 cells express membrane-bound OKT3 and were grown in CM supplemented with 0.4 mg / ml hygromycin [20]. K562 cells were obtained from ATCC and cultured as recommended. KG1a cells (kindly provided by Dr. Ravi Bhatia) were maintained in IMDM (Irvine Scientific) supplemented with 25 mM HEPES, 4 mM L-glutamine (Irvine Scientific) and 20% FCS. 293T cells (a kind gift from the Center for Biomedicine and Genetic...

Embodiment 2

[0149] Example 2: T cells transduced with CD123CAR delay leukemia progression in vivo

[0150] CD123CAR constructs. The 26292CAR (S228P+L235E) and 32716CAR (S228P+L235E) constructs were generated as described in Example 1 above. Two additional CD123CAR constructs containing an additional mutation (N297Q) at position 297 in the IgG4 hinge for each scFv (“26292CAR(S228P+L235E+N297Q)” and “32716CAR(S228P+L235E+N297Q)” were also generated N297Q)")( Figure 12 and 13 , mutate bold and underline).

[0151] NSG mice were transplanted with AML tumor cells (day 0) and treated with 5.0x10 6 CAR+ T cells were processed and leukemia progression was monitored by bioluminescent imaging. Such as Figure 8 Shown in , the leukemic burden progressed at day 8 compared to the treatment day for mice treated with T cells transduced with 26292CAR(S228P+L235E), indicative of the use of the CD123CAR construct with hinge region mutations at positions S228P and L235E Transduced cells have no effec...

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Abstract

A family of chimeric antigen receptors (CARs) containing a CD123 specific scFv was developed to target different epitopes on CD123. In some embodiments, such a CD123 chimeric antigen receptor (CD123CAR) gene includes an anti-CD123 scFv region fused in frame to a modified IgG4 hinge region comprising an S228P substitution, an L235E substitution, and optionally an N297Q substitution; a costimulatory signaling domain; and a T cell receptor (TCR) zeta chain signaling domain. When expressed in healthy donor T cells (CD4 / CD8), the CD123CARs redirect T cell specificity and mediated potent effector activity against CD123+ cell lines as well as primary AML patient samples. Further, T cells obtained from patients with active AML can be modified to express CD123CAR genes and are able to lyse autologous AML blasts in vitro. Finally, a single dose of 5.0 x 106 CAR123 T cells results in significantly delayed leukemic progression in mice. These results suggest that CD123CAR-transduced T cells may be used as an immunotherapy for the treatment of high risk AML.

Description

[0001] priority claim [0002] This application claims priority to US Patent Application Serial No. 13 / 844,048, filed March 15, 2013, which is incorporated by reference in its entirety, including the drawings. [0003] government interest [0004] This invention was made with Government support under NIH grants P50CA107399, P01CA030206, and M01RR0004. The government has certain rights in this invention. Background of the invention [0005] Acute myeloid leukemia (AML) is characterized by rapid proliferation of immature myeloid cells in the bone marrow, resulting in dysfunctional hematopoiesis [1]. First-line treatment of acute myeloid leukemia (AML) has remained essentially unchanged for almost 50 years, and AML remains a disease with a poor prognosis. Although standard induction induces complete remission, many patients eventually relapse and succumb to the disease [2]. Therefore, the development of new treatments for AML is of paramount importance. [0006] Allogeneic h...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N15/62C12N5/10A61K48/00A61K39/00A61P35/02
CPCA61K2039/505C07K2317/622C07K2319/00C07K14/7051A61K35/17C07K16/2866A61P35/00A61P35/02A61P43/00C12N15/85C12N5/0636C12N2510/00C07K2317/53C07K2317/24C07K2319/02C07K2319/03
Inventor S.福曼A.马迪罗斯
Owner CITY OF HOPE
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