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Manipulating arid5b expression in immune cells to promote metabolism, survival, and function

A technology of immune cells and cells, applied in the direction of blood/immune system cells, receptors/cell surface antigens/cell surface determinants, animal cells, etc., can solve the problem of failing to prove the anti-tumor efficacy of metabolic or functional changes

Inactive Publication Date: 2021-06-01
RGT UNIV OF MINNESOTA
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Despite the potential of this approach to promote NK cell persistence, studies have failed to demonstrate metabolic or functional changes in such transgenic cells to suggest increased antitumor efficacy

Method used

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  • Manipulating arid5b expression in immune cells to promote metabolism, survival, and function
  • Manipulating arid5b expression in immune cells to promote metabolism, survival, and function
  • Manipulating arid5b expression in immune cells to promote metabolism, survival, and function

Examples

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Embodiment 1

[0079] Example 1 - ARID5B regulates metabolic programming in human adaptive NK cells

[0080] Previous work by the inventors demonstrated that natural killer (NK) cells with adaptive immunological properties expand and persist in response to human cytomegalovirus. This example explores the unique metabolic processes of these cells and demonstrates that adaptive CD3 - CD56 dim CD57 + NKG2C + Cells exhibited metabolic features of lymphocyte memory, including enhanced oxidative mitochondrial respiration, mitochondrial membrane potential, and spare respiratory capacity. Mechanistically, we identified the selective induction of short isoforms of the chromatin-modifying transcriptional regulator AT-rich interacting domain 5B (ARID5B) by DNA hypomethylation in adaptive NK cells. Knockdown of ARID5B in NK cell line (NK-92) resulted in decreased mitochondrial oxidative metabolism, ETC gene expression, survival and IFN-γ production. In contrast, overexpression of ARID5B in NK-92 ...

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Abstract

Provided herein are methods of manipulating ARID5B expression in immune cells such NK cells, T cells, and T cell and NK cell progenitors to enhance their persistence and function in vivo. Also provided herein are modified immune cells and compositions comprising such modified cells for anti-cancer, anti-viral, and other immunotherapies. In some embodiments, immune cells are genetically modified to increase ARID5B expression and, thus, improve persistence, increase in vivo anti-tumor efficacy, and increase viability and functionality of the modified cells after freezing and thawing.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to U.S. Provisional Patent Application Serial No. 62 / 670,962, filed May 14, 2018, the entire contents of which are incorporated herein by reference. [0003] Statement Regarding Federally Sponsored Research or Development [0004] This invention was made with government support under CA111412, HL122216, CA065493, and CA197292 awarded by the National Institutes of Health. The government has certain rights in this invention. Background technique [0005] Human natural killer (NK) cells are a subset of peripheral blood lymphocytes characterized by the absence of CD3 / TCR expression and by the expression of CD16 and CD56 surface antigens. Unlike T cells and B cells, NK cells do not express rearranged antigen-specific receptors. In contrast, NK effector functions (eg, cytotoxicity, cytokine release) are determined by the integration of signals received through germline-encoded receptors that...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K35/17A61K35/28A61K39/00A61P35/00C12N5/10
CPCC12N2510/00C12N5/0646C07K14/7051C07K14/4702C07K2319/03Y02A50/30A61K39/4613A61K39/464838A61K39/4611C07K14/47
Inventor 杰弗里·史蒂文·米勒弗兰克·马丁·齐霍茨基
Owner RGT UNIV OF MINNESOTA
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