PTPN2-Knockout T Cells for Solid Tumor Persistence and Cytotoxicity

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Solution Overview

Problem

CAR T-cell therapy has limited success in treating solid tumors due to T cell exhaustion, decreased cytokine secretion, and over-expression of exhaustion markers like PD1, LAGS, and TIM3, which is hypothesized to be regulated by PTPN2 phosphatase.

Innovation Solution

Genetically engineered T cells with CRISPR/Cas9-mediated disruption of the PTPN2 gene, optionally combined with edits to TRAC, β2M, and CD70 genes, to enhance anti-tumor activity and cytokine secretion.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If PTPN2 is not disrupted, then T cell activation and anti-tumor activity are maintained at baseline levels, but T cell exhaustion occurs leading to decreased cytokine secretion and proliferation

Engineering Contradiction:

Improveanti-tumor activityVSAvoidT cell persistence

Core Design Contradiction:

ReliabilityVSDuration of action of moving object

Solution Approach 1:

The patent extracts and removes the PTPN2 gene from the T cell genome using CRISPR/Cas9 gene editing technology. By specifically targeting and eliminating this negative regulator, the invention removes the constraint that limits T cell activation and persistence, thereby resolving the contradiction between maintaining anti-tumor activity and preventing T cell exhaustion

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The patent changes the genetic parameter of T cells by disrupting the PTPN2 gene, which fundamentally alters the cellular phenotype. This genetic modification transforms T cells from an exhausted state with limited persistence to an activated state with enhanced durability and sustained anti-tumor activity

Inventive Principle:

Principle #35Parameter changes

2Productivity

If PTPN2 is disrupted to enhance T cell activation, then cytokine secretion and anti-tumor activity improve, but exhaustion markers like PD1, LAGS, and TIM3 may be affected

Engineering Contradiction:

Improvecytokine secretionVSAvoidexhaustion marker expression

Core Design Contradiction:

ProductivityVSReliability

Solution Approach 1:

The patent converts the harmful effect of PTPN2-mediated negative regulation into a beneficial outcome. By removing PTPN2, the invention transforms the T cell response from an exhausted, low-productivity state to an activated, high-cytokine secretion state, while the apparent increase in exhaustion markers reflects enhanced activation rather than dysfunction

Inventive Principle:

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

3Reliability

If CRISPR/Cas9 is used to edit PTPN2, then T cell functionality is improved, but gene editing complexity and manufacturing challenges increase

Engineering Contradiction:

ImproveT cell functionalityVSAvoidgene editing process

Core Design Contradiction:

ReliabilityVSEase of manufacture

Solution Approach 1:

The patent employs the CRISPR/Cas9 system's inherent self-guiding capability where the guide RNA automatically directs the Cas9 nuclease to the specific PTPN2 genomic location. This self-service mechanism simplifies the manufacturing process by eliminating the need for complex protein-based targeting methods, as the system autonomously finds and edits the intended gene sequence

Inventive Principle:

Principle #25Self-service

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 engineered T cells exhibit improved cytotoxicity, enhanced cytokine production, increased CAR copy numbers, and elevated expression of LAGS and TIM3, leading to superior tumor killing and persistence.

Implementation Method 1

Genetically engineered T cells with CRISPR/Cas9-mediated disruption of the PTPN2 gene

Methodology Applied

Scientific EffectCRISPR/Cas9 gene editing:

Data Source

PatentUS12553030B2Genetically engineered T cells with PTPN2 knockout have improved functionality and anti-tumor activity

Publication Date: 2026.02.17 CRISPR THERAPEUTICS AG

AI summary

A population of genetically engineered T cells, comprising a disrupted protein tyrosine phosphatase non-receptor type 2 (PTPN2) gene and optionally a disrupted TRAC gene, a disrupted β2M gene, and/or a disrupted CD70 gene. Also provided herein are methods for making such genetically engineered T cells and therapeutic uses thereof.