CISH Biallelic Knockout in CAR-T Cells for Allogeneic Engraftment

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Solution Overview

Problem

Existing CAR-T cell therapies face challenges in immunogenicity and reactivity, hindering their use in allogeneic adoptive transfer due to potential rejection and graft-versus-host disease.

Innovation Solution

Inactivation of the Cytokine Inducible SH2 Containing Protein (CISH) gene in cells using a CRISPR nuclease and RNA molecule with a guide sequence targeting specific regions of the CISH gene, enhancing cell activity, retention, and expansion for adoptive cancer immunotherapy.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If CAR-T cells are used for immunotherapy, then therapeutic activity is improved, but immunogenicity and reactivity increase causing rejection and graft-versus-host disease

Engineering Contradiction:

Improvetherapeutic activityVSAvoidimmunogenicity and reactivity

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent removes the CISH gene from CAR-T cells using CRISPR/Cas9 technology. By extracting this specific gene component, the cells achieve improved persistence and expansion capabilities without the harmful immunogenic effects that CISH normally mediates, thus resolving the contradiction between therapeutic activity and immunogenicity

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The patent converts the harmful immunogenic response into a benefit by knocking out CISH, which normally suppresses immune responses. The loss of CISH function paradoxically enhances cell persistence and anti-tumor activity while reducing harmful graft-versus-host disease, transforming a negative factor into a therapeutic advantage

Inventive Principle:

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

2Adaptability or versatility

If allogeneic CAR-T cells are introduced for universal therapy, then accessibility is improved, but host rejection and graft-versus-host disease increase

Engineering Contradiction:

Improveuniversal therapy applicabilityVSAvoidrejection and graft-versus-host disease

Core Design Contradiction:

Adaptability or versatilityVSObject-affected harmful factors

Solution Approach 1:

The patent creates universally applicable allogeneic CAR-T cells by knocking out CISH, enabling these cells to be used across multiple patients without significant immunogenic rejection. The modified cells maintain therapeutic functionality while gaining improved persistence and reduced harmful reactions, achieving broad universal applicability

Inventive Principle:

Principle #6Universality (Multi-functionality)

Solution Approach 2:

By removing CISH, the patent converts the typically harmful alloreactive responses into beneficial enhanced persistence and anti-tumor activity. The cells that would normally be rejected due to immunogenicity instead demonstrate improved survival and therapeutic efficacy in allogeneic settings

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

Improved performance of modified cells in allogeneic adoptive transfer therapy by reducing immunogenicity and reactivity, thereby increasing persistence and engraftment, and minimizing graft-versus-host disease.

Implementation Method 1

a complex of the CRISPR nuclease and the RNA molecule affects a double strand break in the allele of the CISH gene

Methodology Applied

Scientific EffectCRISPR nuclease DNA cleavage:

Data Source

PatentUS20260097121A1Biallelic Knockout of CISH

Publication Date: 2026.04.09 EMENDOBIO INC

AI summary

Compositions comprising an RNA molecule comprising a guide sequence portion having 17-50 contiguous nucleotides containing nucleotides in the sequence set forth in any one of SEQ ID NOs: 1-6838 and methods and uses thereof.