IL-4 Fusion Protein for Adoptive T-Cell Therapy Persistence

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Solution Overview

Problem

The efficacy of adoptive T cell transfer therapy (ACT) in treating solid tumors is limited by the survival deficit of terminally exhausted CD8+ T cells, which are crucial for eliminating tumor cells but fail to respond to current therapeutics.

Innovation Solution

Fusing Interleukin-4 (IL-4) to a moiety that enhances its half-life and stability, such as albumin or an antibody fragment, to stabilize and prolong the survival of terminally exhausted CD8+ T cells, thereby boosting the efficacy of ACT.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Strength

If terminally exhausted CD8+ T cells are used to eliminate solid tumor cells, then tumor cytolytic capability is improved, but T cell survival is worsened

Engineering Contradiction:

Improvetumor cytolytic capabilityVSAvoidT cell survival

Core Design Contradiction:

StrengthVSReliability

Solution Approach 1:

The patent introduces an IL-4 fusion protein as an intermediary substance that mediates between the terminally exhausted T cells and the tumor microenvironment. This fusion protein binds to IL-4 receptors and delivers survival signals to T cells, thereby improving their persistence without compromising their cytolytic function against tumors.

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent modifies the parameters of T cell survival by changing the cytokine environment through IL-4 fusion protein administration. This alters the biochemical conditions in the tumor microenvironment, transforming it from a hostile environment that causes T cell exhaustion and death to one that supports T cell survival while maintaining cytolytic activity.

Inventive Principle:

Principle #35Parameter changes

2Ease of operation

If current therapeutic interventions are applied to exhausted T cells, then T cell activation is improved, but response efficacy is worsened

Engineering Contradiction:

ImproveT cell activationVSAvoidtherapeutic response

Core Design Contradiction:

Ease of operationVSReliability

Solution Approach 1:

Instead of attempting to reactivate terminally exhausted T cells through conventional checkpoint blockade or other activation strategies, the patent inverts the approach by directly providing survival support through IL-4 fusion protein. This acknowledges that these cells are beyond reactivation and focuses on preserving their existing cytolytic function rather than trying to restore it.

Inventive Principle:

Principle #13The other way round (Inversion)

3Duration of action of stationary object

If IL-4 is administered to prolong T cell survival, then T cell longevity is improved, but half-life of the cytokine is worsened

Engineering Contradiction:

ImproveT cell longevityVSAvoidcytokine half-life

Core Design Contradiction:

Duration of action of stationary objectVSDuration of action of moving object

Solution Approach 1:

The patent creates a composite molecule by fusing IL-4 with a long-half-life protein domain (such as IgG Fc region or albumin). This composite structure combines the biological activity of IL-4 with the extended circulation half-life of the fusion partner, thereby achieving both prolonged T cell survival signaling and sustained cytokine presence in the system.

Inventive Principle:

Principle #40Composite materials

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 fusion of IL-4 with a moiety significantly improves the survival and functionality of terminally exhausted CD8+ T cells, enhancing the therapeutic effect of ACT against solid tumors and promoting tumor regression.

Implementation Method 1

Fusing Interleukin-4 (IL-4) to a moiety that enhances its half-life and stability, such as albumin or an antibody fragment

Methodology Applied

Scientific EffectProtein fusion:

Implementation Method 2

a moiety that enhances its half-life and stability, such as albumin or an antibody fragment, to stabilize and prolong the survival

Methodology Applied

Scientific EffectHalf-life extension:

Implementation Method 3

these subsets are prone to perish due to survival deficit

Methodology Applied

Scientific EffectCytokine signaling:

Implementation Method 4

Fc-IL-4 improves the survival of terminally exhausted CD8+ T cells population both ex and in vivo

Methodology Applied

Scientific EffectApoptosis inhibition:

Implementation Method 5

Fc-IL-4 potently improves the survival and longevity of terminally exhausted CD8+ T cells by enhancing glycolysis

Methodology Applied

Scientific EffectGlycolysis:

Data Source

PatentUS20250295736A1Highly effective adoptive t cell therapy

Publication Date: 2025.09.25 ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE (EPFL)

AI summary

The present invention relates generally to the field of anti-cancer therapy and autoimmune therapy, in particular to the use of adoptive T cell transfer therapy. More specifically, the present invention relates to compositions, pharmaceutical compositions or methods using IL-4, a fragment or variant thereof, fused to a moiety, to increase the efficacy of an anti-cancer immunotherapy or an autoimmune therapy.