Trehalase-Engineered T Cells for Glucose-Deprived Solid Tumors

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Solution Overview

Problem

Solid tumors create a hostile microenvironment with low glucose levels, limiting the effectiveness of adoptive T cell transfer therapy (ACT) due to suppressed glycolytic metabolism in T cells, which hampers their ability to recognize and eliminate cancer cells.

Innovation Solution

Engineer human T cells to express a heterologous nucleic acid sequence encoding for an insect trehalase enzyme and trehalose transporter protein, enabling them to utilize trehalose as a carbon source in the glycolytic pathway, thereby bypassing glucose deprivation.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If T cells are administered for adoptive cell transfer therapy, then anti-cancer immunity is enhanced, but glucose deprivation in solid tumors suppresses T cell metabolic function and cytotoxic activity

Engineering Contradiction:

ImproveT cell cytotoxic activityVSAvoidglucose deprivation

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent changes the metabolic parameters of T cells by introducing alternative metabolic pathways. Specifically, it modifies T cell metabolism to utilize non-glucose carbon sources (such as glutamine, fatty acids, and ketone bodies) and to switch between metabolic modes (aerobic glycolysis, oxidative phosphorylation, fatty acid oxidation) depending on the microenvironment, thereby maintaining cytotoxic activity under glucose-deprived conditions

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent introduces metabolic intermediaries and alternative substrates that mediate energy production in T cells when glucose is unavailable. This includes utilizing glutamine as an alternative carbon source, employing ketone bodies as metabolic intermediaries, and using fatty acid oxidation pathways to generate energy and metabolic precursors, thus bypassing the need for extracellular glucose

Inventive Principle:

Principle #24Intermediary (Mediator)

2Productivity

If T cells undergo metabolic rewiring to support expansion and cytotoxic function, then anti-tumor potency is improved, but tumor microenvironment glucose depletion restricts T cell glycolytic metabolism

Engineering Contradiction:

ImproveT cell expansion and cytotoxic functionVSAvoidextracellular glucose availability

Core Design Contradiction:

ProductivityVSQuantity of substance

Solution Approach 1:

The patent employs dynamic metabolic adaptability in T cells, allowing them to flexibly switch between different metabolic pathways based on environmental conditions. T cells can transition from aerobic glycolysis in nutrient-rich conditions to oxidative phosphorylation, fatty acid oxidation, or glutamine metabolism in glucose-deprived tumor microenvironments, maintaining both expansion and cytotoxic function through metabolic plasticity

Inventive Principle:

Principle #15Dynamics

Solution Approach 2:

The patent changes metabolic parameters by introducing alternative carbon sources and modifying metabolic flux. This includes upregulating glutamine transporters and metabolic enzymes, enhancing fatty acid oxidation capacity, and adjusting the balance between anabolic and catabolic pathways to support T cell proliferation and effector functions without relying solely on extracellular glucose

Inventive Principle:

Principle #35Parameter changes

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

The engineered T cells can maintain metabolic function and cytotoxic activity even in low-glucose environments, enhancing the efficacy of ACT against solid tumors.

Implementation Method 1

Methodology Applied

Scientific EffectHydrolysis: Hydrolysis

Data Source

PatentUS20260021180A1Improving adoptive cell transfer therapy (ACT) treatment

Publication Date: 2026.01.22 YISSUM RESEARCH DEVELOPMENT COMPANY OF THE HEBREW UNIVERSITY OF JERUSALEM LTD

AI summary

Cells comprising a heterologous nucleic acid sequence that encodes for a trehalase enzyme and optionally a heterologous nucleic acid sequence that encodes for a trehalose transporter protein are provided. Pharmaceutical compositions comprising the cells, methods of adoptive cell transfer comprising administering the cells and methods of determining suitability of a subject for the performance of the methods are also provided. A pharmaceutical composition comprising pharmaceutical grade trehalose is also provided, as is a kit comprising both compositions of the invention.