GM-CSF Receptor CAR-T Cells Suppressing Secretion

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Solution Overview

Problem

Current ligand-type CARs for adoptive immunotherapy lack clinical effectiveness due to undesirable immune responses and limited development of receptor-specific cytotoxic activity, particularly in targeting tumor cells expressing the GM-CSF receptor.

Innovation Solution

Development of genetically modified cells expressing a GM-CSF receptor-specific chimeric antigen receptor (GMR.CAR) that simultaneously incorporates a polynucleotide encoding the GMR.CAR and a polynucleotide inducing RNAi against GM-CSF, to enhance cytotoxic activity and reduce GM-CSF secretion.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If a ligand-type CAR is used to target GM-CSF receptor on tumor cells, then cytotoxic activity against tumor cells is improved, but GM-CSF secretion by the modified cells increases causing undesirable immune responses

Engineering Contradiction:

Improvecytotoxic activityVSAvoidGM-CSF secretion

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The patent converts the harmful effect of GM-CSF secretion into a beneficial outcome by using RNA interference to suppress GM-CSF expression. The same GM-CSF receptor targeting that causes harmful secretion is harnessed to deliver cytotoxic activity, while the harmful secretion is simultaneously suppressed through complementary DNA sequences that induce RNAi, transforming a detrimental side effect into a controlled therapeutic mechanism

Inventive Principle:

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

Solution Approach 2:

The patent applies preliminary anti-action by incorporating RNA interference mechanisms that preemptively suppress GM-CSF secretion before it can cause harmful immune responses. The complementary DNA sequences are designed to interfere with GM-CSF mRNA translation in advance, preventing the accumulation and secretion of harmful GM-CSF protein while maintaining the desired cytotoxic activity against tumor cells

Inventive Principle:

Principle #9Preliminary anti-action

2Reliability

If conventional antibody-type CAR is used, then target binding ability is achieved, but undesirable immune responses occur due to mouse-derived scFv

Engineering Contradiction:

Improvetarget binding abilityVSAvoidimmune response

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent changes the fundamental parameter of the binding domain from mouse-derived scFv to a ligand-based approach using GM-CSF receptor targeting. This parameter change transforms the system from an antibody-based CAR that triggers immune responses to a ligand-type CAR that achieves target binding through native ligand-receptor interactions, thereby eliminating the harmful immune responses associated with xenogeneic antibodies

Inventive Principle:

Principle #35Parameter changes

3Object-affected harmful factors

If ligand-type CAR is developed to reduce immune responses, then safety is improved, but clinical effectiveness is limited due to insufficient cytotoxic activity

Engineering Contradiction:

Improveimmune responseVSAvoidcytotoxic activity

Core Design Contradiction:

Object-affected harmful factorsVSReliability

Solution Approach 1:

The patent merges two previously separate functions into a single integrated system: the GM-CSF receptor targeting function and the GM-CSF suppression function. By combining ligand-type CAR targeting with RNA interference-mediated GM-CSF suppression in the same modified cells, the patent achieves both safety (reduced immune responses) and effectiveness (maintained cytotoxic activity) that were previously limited when used separately

Inventive Principle:

Principle #5Merging (Combining)

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 GMR.CAR-T cells demonstrate improved cytotoxic activity against tumor cells by suppressing GM-CSF secretion, effectively targeting cells expressing the GM-CSF receptor, such as juvenile myelomonocytic leukemia and acute myelogenous leukemia cells, with enhanced therapeutic potential.

Implementation Method 1

a polynucleotide that induces RNAi to human GM-CSF

Methodology Applied

Scientific EffectRNA interference (RNAi):

Data Source

PatentUS10683355B2Genetically-modified cells and method for producing same

Publication Date: 2020.06.16 SHINSHU UNIVERSITY

AI summary

Production of a chimeric antigen receptor (CAR) expressing cell having excellent target cytotoxicity. Provided is a genetically modified cell comprising, introduced thereinto, a polynucleotide encoding a chimeric antigen receptor (CAR) protein having a target binding domain that specifically binds to a human granulocyte-macrophage colony stimulating factor (GM-CSF) receptor, a transmembrane domain and an intracellular signaling domain.