CAR T Cell Elimination via Inducible MHC Class I Suppression

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Solution Overview

Problem

Current CAR T cell therapies face challenges in safety due to immunogenicity of suicide genes and incomplete elimination of engineered cells, particularly in actively proliferating cells and allogenic settings, where off-target effects and persistence issues arise with gene editing tools like CRISPR/Cas systems.

Innovation Solution

A pharmaceutical composition comprising autologous immune cells with an inducible gene expression system that reduces MHC class I expression using immunoevasins, allowing for controlled and efficient elimination by autologous NK cells, thereby enhancing safety and purity by eliminating unintended transduced cells like leukemic B cells.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If suicide genes are used for CAR T cell elimination, then elimination capability is provided, but immunogenicity and incomplete elimination occur

Engineering Contradiction:

Improveelimination capabilityVSAvoidimmunogenicity

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The patent extracts the MHC class I molecule from the CAR T cell surface through immunoevasin expression, removing the critical recognition marker that prevents NK cell-mediated elimination. This extraction enables complete and non-immunogenic removal of engineered cells without relying on traditional suicide genes.

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The patent introduces immunoevasins as intermediary molecules that mediate between the CAR T cell and NK cell. These immunoevasins temporarily suppress MHC class I expression, allowing NK cells to recognize and eliminate the engineered cells through a controlled mechanism that avoids direct immunogenic confrontation.

Inventive Principle:

Principle #24Intermediary (Mediator)

2Manufacturing precision

If gene editing tools like CRISPR/Cas are used to reduce MHC class I, then MHC class I expression decreases, but off-target effects and persistence issues arise

Engineering Contradiction:

ImproveMHC class I expression reductionVSAvoidoff-target effects

Core Design Contradiction:

Manufacturing precisionVSObject-affected harmful factors

Solution Approach 1:

The patent employs dynamic, reversible suppression of MHC class I expression through immunoevasin expression rather than permanent genetic editing. This dynamic approach allows precise control over when MHC class I is suppressed, eliminating off-target effects associated with CRISPR/Cas while maintaining the ability to restore normal function when needed.

Inventive Principle:

Principle #15Dynamics

Solution Approach 2:

The patent changes the expression level parameter of MHC class I molecules on the cell surface through immunoevasin-mediated suppression. This parameter change enables NK cell recognition without altering the underlying genome, avoiding off-target effects while achieving complete expression reduction.

Inventive Principle:

Principle #35Parameter changes

3Productivity

If CAR T cells are used for cancer therapy, then cancer elimination is achieved, but safety issues arise from persistence and proliferation

Engineering Contradiction:

Improvecancer elimination efficacyVSAvoidsafety

Core Design Contradiction:

ProductivityVSReliability

Solution Approach 1:

The patent incorporates immunoevasin expression as a preliminary safety mechanism within the CAR T cell before administration. This preliminary action ensures that engineered cells can be rapidly and completely eliminated by NK cells if safety issues arise, providing a built-in safety switch that prevents persistent proliferation and enhances overall therapy safety.

Inventive Principle:

Principle #10Preliminary action

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 use of immunoevasins for reducing MHC class I expression on CAR T cells leads to a more extensive and controlled elimination compared to existing methods, with rapid onset and minimal off-target effects, improving the safety and efficacy of CAR T cell therapy by ensuring complete removal of engineered cells.

Implementation Method 1

an inducible gene expression system that reduces MHC class I expression using immunoevasins

Methodology Applied

Scientific EffectMHC class I expression reduction:

Implementation Method 2

Autologous cells of a subject not presenting MHC class I on their cell surfaces anymore are recognized by autologous NK cells and eliminated

Methodology Applied

Scientific EffectNK cell-mediated elimination:

Data Source

PatentUS20230405047A1Methods and compositions for eliminating engineered immune cells

Publication Date: 2023.12.21 MILTENYI BIOTEC BV & CO KG

AI summary

The present invention provides a composition comprising A) immune cells such as T cells comprising a) an inducible gene expression system comprising I) a first nucleic acid comprising a drug-inducible promoter operably linked to a second nucleic acid, and II) said second nucleic acid encoding a polypeptide or a non-coding RNA (ncRNA) which decreases cell surface expression level of major histocompatibility complex (MHC) class I relative to cell surface expression level of MHC class I of an immune cell that does not express said polypeptide or ncRNA; and b) a third nucleic acid encoding a chimeric antigen receptor (CAR) or T cell receptor (TCR); and B) a drug that induces said drug-inducible promoter. Preferentially, said polypeptide may be a viral protein which decreases cell surface expression level of major histocompatibility complex (MHC) class I relative to cell surface expression level of MHC class I of an immune cell that does not express the viral protein.