US 2026/0174850 A1 · ENGINEERED T CELLS HAVING ALTERED PYRUVATE METABOLISM, METHODS FOR THEIR PRODUCTION AND USE IN THERAPY, E.G., FOR TREATMENT OF CANCER OR INFECTION

Abstract

The invention provides methods for upregulating mitochondrial and/or glycolytic metabolism in T cells by increasing the flux of pyruvate into the citric acid cycle, thereby increasing mitochondrial and/or glycolytic metabolism. In general these methods comprise stable expression of a transgene encoding either pyruvate dehydrogenase kinase enzyme and/or pyruvate dehydrogenase phosphatase enzyme in T cells. The invention further provides engineered T cells, preferably engineered human T cells produced by such methods, which optionally are further engineered, e.g., to express a targeting and/or therapeutic moiety and the use thereof and compositions containing in adoptive T cell therapies, e.g., the treatment and prevention of cancer, infection, inflammation, autoimmunity and neurodegenerative conditions.

Claims11

Dependent claims

Isolated or recombinant T cells, optionally human primary T cells, further optionally human primary CD4+ or CD8+ T cells, which are engineered to stably and/or heritably express increased amounts of pyruvate dehydrogenase kinase enzyme (PDK) and/or pyruvate dehydrogenase phosphatase (PDP) enzyme, or progeny thereof.

Isolated or recombinant T cells according to any one of the foregoing claims which are further engineered to comprise a desired targeting or therapeutic moiety, optionally wherein the desired targeting or therapeutic moiety comprises:

(a) a chimeric antigen receptor, or
(b) an exogenous T cell receptor, or
(c) a cytokine, or
(d) a cytokine receptor, or
(e) a chemokine, or
(f) a chemokine receptor,
(g) an immune checkpoint modulator, or
(h) any combination of (a) to (g).

5 more elements

A composition comprising isolated or recombinant T cells or progeny of any one of the foregoing claims which optionally:

(i) is lyophilized;
(ii) further comprises a therapeutic agent, optionally a cytokine, cytokine receptor, chemokine, chemokine receptor, immune checkpoint inhibitor agonist or antagonist;
(iii) further comprises a hormone, cytokine, cytokine antagonist, therapeutic antibody, immunostimulatory antibody or fusion protein, immunoinhibitory antibody or fusion protein, anti-inflammatory agent, checkpoint inhibitor or checkpoint inhibitor agonist or antagonist, e.g., a polypeptide which promotes or reduces the expression or activity of a stimulatory immune checkpoint molecule such as CD27, CD28, CD40, CD122, CD137, OX40, GITR or ICOS and/or a polypeptide which promotes or reduces the expression or activity of an inhibitory immune checkpoint molecule such as A2AR, A2BR, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, NOX2, PD-1, PD-L1, VISTA or SIGLEC7);
(iv) further comprises and/or the engineered T cells according to any of the prior claims are further engineered to comprise and express a gene encoding one of IL-2, IL-4, IL-5, IL-7, IL-10, IL-12p40, IL-12p70, IL-15, and interferon (IFN) gamma;
(v) further comprises and/or the engineered T cells according to any of the prior claims are further engineered to comprise and express a gene encoding one of a pro-inflammatory cytokine, e.g., IL-1a, IL-1b, IL-6, IL-13, IL-17a, tumor necrosis factor (TNF)-alpha TNF-beta, fibroblast growth factor (FGF) 2, granulocyte macrophage colony-stimulating factor (GM-CSF), soluble intercellular adhesion molecule 1 (sICAM-1), soluble vascular adhesion molecule 1 (sVCAM-1), vascular endothelial growth factor (VEGF), VEGF-C, VEGF-D, and placental growth factor (PLGF);
or
(vi) any combination of (i) to (v).

4 more elements

A method for producing isolated or recombinant T cells of any one of the foregoing claims, comprising:

A.
(i) inserting a DNA sequence which encodes either a PDP1 gene or a PDK1 into a vector,
(ii) contacting the vector with a T cell to form or produce a transduced T cell,
(iii) growing the transduced T cells,
(iv) harvesting and/or purifying the transduced cells,
(v) optionally expanding or permitting the harvested cells to proliferate in vitro;
and
(vi) further optionally freezing said cells so as to preserve their viability;
OR
B.
(i) inserting a DNA sequence which encodes either a PDP1 gene or a PDK1 into a DNA comprising a viral vector genome,
(ii) transfecting that genome into cultured mammalian cells,
(iii) culturing said cells to produce virus particles comprising said PDP1 or PDK1 gene,
(iv) harvesting and/or purifying said virus particles from the culture medium,
(v) contacting said virus particles with a T cell to form or produce a virally-transduced T cell,
(vi) growing the viral-transduced T cells,
(vii) harvesting and/or purifying the virally-transduced cells,
(viii) optionally expanding or permitting the cells to proliferate in vitro;
and
(ix) and further optionally, freezing said cells so as to preserve their viability.

17 more elements

Dependencies are inferred from the claim text.

Facts

Application

19/126,670Filed 2 Nov 2023

Priority

2 Nov 2022

Published

25 Jun 2026

Term ends

Not estimatedThe source records don’t support an estimate.

Classification23 codes

A61K 40/11
Characterised by the cell type used: t-cells, e.g. tumour infiltrating lymphocytes [TIL] or regulatory T [Treg] cells; Lymphokine-activated killer…
A61P 29/00
Non-central analgesic, antipyretic or antiinflammatory agents
A61K 40/30
Cellular immunotherapy: characterised by the recombinant expression of specific molecules in the cells of the immune system
A61K 40/32
Characterised by the recombinant expression of specific molecules in the cells of the immune system: t-cell receptors [TCR]

Engineered t cells having altered pyruvate metabolism, methods for their production and use in therapy, e.g., for treatment of cancer or infection

Life of this patent

Engineered t cells having altered pyruvate metabolism, methods for their production and use in therapy, e.g., for treatment of cancer or infection

Life of this patent

Abstract

Claims11