CAR-T Proliferation Enhancer STAT5 STAT3 Signaling

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Solution Overview

Problem

Current universal CAR-T cell therapies face limitations due to allogeneic transplantation rejection and a cytokine-poor environment, which hampers the survival and proliferation of genetically engineered immune cells, leading to reduced therapeutic efficacy in cancer treatment.

Innovation Solution

A proliferation enhancer comprising cytokine receptor intracellular domains that initiate STAT5 and/or STAT3 signaling pathways, combined with a transmembrane and extracellular domain structure promoting homodimerization, is expressed on CAR-T cells to enhance their survival and proliferation capabilities, and a chimeric single chain molecule is used to inhibit NK cell-mediated killing.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Productivity

If universal CAR-T cells are used for allogeneic transplantation, then standardized production and timeliness are improved, but proliferation ability and survival rate deteriorate due to rejection and low cytokine environment

Engineering Contradiction:

Improvestandardized production efficiencyVSAvoidcell survival and proliferation ability

Core Design Contradiction:

ProductivityVSReliability

Solution Approach 1:

The patent introduces a constitutively active cytokine receptor (C7R) that autonomously activates STAT5 and STAT3 signaling pathways without requiring external cytokines. This self-service mechanism allows universal CAR-T cells to proliferate and survive in the cytokine-poor tumor microenvironment, directly addressing the reliability issue while maintaining standardized production capabilities

Inventive Principle:

Principle #25Self-service

Solution Approach 2:

The invention modifies the signaling pathway activation parameters by creating a constitutively active receptor that continuously activates STAT5/STAT3 pathways. This parameter change enables the cells to maintain proliferation capacity independent of external cytokine concentration, resolving the contradiction between standardized production and cellular reliability

Inventive Principle:

Principle #35Parameter changes

2Productivity

If CD34 extracellular domain is used in constitutively active cytokine receptor, then T cell proliferation is promoted, but expression efficiency and stability of CAR molecules deteriorate

Engineering Contradiction:

ImproveT cell proliferation capabilityVSAvoidCAR molecule expression efficiency and stability

Core Design Contradiction:

ProductivityVSManufacturing precision

Solution Approach 1:

The patent extracts only the essential functional domains needed for constitutive activation (intracellular signaling domains of IL-7Rα and IL-21Rα combined with a shortened extracellular domain) rather than using the full-length CD34 extracellular domain. This extraction maintains T cell proliferation promotion while eliminating the negative impact on CAR expression efficiency and stability

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The invention applies local quality by selectively combining specific domains: the intracellular domains providing constitutive activation capability are retained, while the extracellular domain is optimized to a shorter version that doesn't interfere with CAR expression. This localized optimization resolves the contradiction between proliferation promotion and manufacturing precision

Inventive Principle:

Principle #3Local quality

3Object-affected harmful factors

If class I MHC molecules are removed from donor T cells, then antigen presentation is eliminated to evade host recognition, but NK cell-mediated killing is initiated

Engineering Contradiction:

Improvehost rejection avoidanceVSAvoidNK cell killing susceptibility

Core Design Contradiction:

Object-affected harmful factorsVSObject-generated harmful factors

Solution Approach 1:

The patent converts the harmful effect of MHC removal (NK cell susceptibility) into a benefit by introducing constitutive STAT5/STAT3 activation through C7R. This signaling activation upregulates surface markers and enhances cell fitness that compensates for MHC removal, allowing the cells to evade host T cell recognition while resisting NK cell killing through enhanced survival signals

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

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 approach significantly improves the proliferation and survival of CAR-T cells in cytokine-free environments and enhances their anti-tumor activity while reducing allogeneic rejection, thereby increasing the therapeutic effectiveness of universal CAR-T cell therapy.

Implementation Method 1

one or more cytokine receptor intracellular domains capable of initiating a cellular STAT5 and/or STAT3 signaling pathway

Methodology Applied

Scientific EffectSTAT5 and STAT3 signaling pathway activation:

Implementation Method 2

the transmembrane domain and the extracellular domain comprise a structure that promotes the homodimerization of the proliferation enhancer

Methodology Applied

Scientific EffectHomodimerization:

Data Source

PatentUS20240117007A1Proliferation enhancer and use thereof

Publication Date: 2024.04.11 CURE GENETICS CO LTD

AI summary

The present invention relates to a proliferation enhancer. The enhancer comprises a protein molecule capable of initiating the cellular STATS and/or STAT3 signaling pathway and comprising the intracellular domain, the transmembrane domain and the extracellular domain. The present invention further relates to a lymphocyte expressing the proliferation enhancer and the use thereof as an immunotherapy drug.