Drug-Resistant Treg Engineering for Steroid-Tolerant Persistence

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Solution Overview

Problem

Existing regulatory T cells (Tregs) used in immunotherapy have short persistence in vivo, which is exacerbated by standard of care treatments like steroids and calcineurin inhibitors, inhibiting their function and survival.

Innovation Solution

Genetically modify Tregs to be resistant to steroids and calcineurin inhibitors by introducing specific genetic modifications, such as indels in the NR3C1 gene locus and calcineurin inhibitor resistance genes, using CRISPR-Cas systems, to enhance their persistence and function.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If standard of care treatments (steroids and calcineurin inhibitors) are used for GVHD prophylaxis, then immune suppression is achieved, but Treg persistence and function are inhibited

Engineering Contradiction:

Improveimmunosuppression efficacyVSAvoidTreg persistence

Core Design Contradiction:

ReliabilityVSDuration of action of moving object

Solution Approach 1:

The patent modifies the Treg cells by introducing genetic alterations that change their sensitivity parameters to steroids and calcineurin inhibitors. Specifically, the Tregs are engineered to have reduced responsiveness to these drugs through modifications in steroid receptor signaling pathways and calcineurin inhibitor target sites, allowing them to maintain persistence and function despite standard GVHD prophylaxis treatment

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent converts the harmful effect of steroids and calcineurin inhibitors on Treg persistence into a beneficial outcome by engineering Tregs that are resistant to these drugs. The very drugs that normally inhibit Treg function are transformed into conditions that selective resistant Tregs can withstand, allowing them to persist and function in the presence of standard GVHD prophylaxis

Inventive Principle:

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

2Reliability

If Tregs are used for immunotherapy, then immune tolerance is promoted, but their in vivo persistence is short

Engineering Contradiction:

Improveimmune toleranceVSAvoidTreg persistence in vivo

Core Design Contradiction:

ReliabilityVSDuration of action of stationary object

Solution Approach 1:

The patent introduces genetic modifications to Treg cells that alter key parameters controlling their survival and persistence. These modifications include engineering enhanced expression of survival factors, modifying metabolic pathways to improve resilience, and altering receptor signaling to enhance homeostatic maintenance, thereby extending their in vivo persistence while maintaining immune tolerance function

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS20260108610A1Drug-Resistant Immune Cells and Methods of Use Thereof

Publication Date: 2026.04.23 REGENTS OF THE UNIVERSITY OF MINNESOTA

AI summary

The present disclosure provides modified cells including pluripotent stem cells, hematopoietic precursor cells, and hematopoietic cells (e.g., modified Tregs) that are steroid and/or calcineurin inhibitor-resistant. The present disclosure provides methods for generating steroid and/or calcineurin inhibitor-resistant modified cells including pluripotent stem cells, hematopoietic precursor cells, and hematopoietic cells. Also provided herein are compositions and methods of treatment.