Modified T Cells With CRISPR Editing for Exhaustion Resistance
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Solution Overview
Problem
Existing CAR- and TCR-engineered T cell therapies face challenges due to T cell exhaustion and immunosuppression by the microenvironment, limiting their efficacy in treating cancer and chronic infections.
Innovation Solution
Genome-wide screening identifies genes that regulate T cell function, with CRISPR-mediated insertions and deletions downregulating transcriptional modulators like SIX2, KLF4, and histone methyltransferase components to enhance TCR- or CAR-T cell function.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If T cells are engineered to express artificial receptors (CAR/TCR), then target cell killing ability is improved, but T cell exhaustion and immunosuppression by microenvironment worsen
Solution Approach 1:
The patent changes the genetic parameters of T cells by knocking out specific genes (TOX, HAVCR2, LAG3, TIM3, PD1) that regulate T cell exhaustion and immunosuppression. This genetic parameter modification allows T cells to maintain enhanced target cell killing ability while resisting microenvironmental immunosuppression, thereby resolving the contradiction between productivity and reliability.
2Productivity
If T cell function is enhanced through genetic engineering, then immune efficacy is improved, but susceptibility to microenvironmental immunosuppression worsens
Solution Approach 1:
The patent applies preliminary anti-action by pre-modifying T cells through CRISPR/Cas9-mediated knockout of exhaustion-related genes (TOX, HAVCR2, LAG3, TIM3, PD1) before adoptive transfer. This preliminary genetic modification equips T cells with resistance to microenvironmental immunosuppression, allowing them to maintain enhanced immune efficacy despite exposure to suppressive tumor microenvironments.
3Loss of information
If genome-wide screening is performed to identify regulatory genes, then understanding of T cell function is improved, but screening complexity and time worsen
Solution Approach 1:
The patent performs preliminary action by conducting comprehensive genome-wide CRISPR screening in vitro to identify T cell regulatory genes (such as TOX, HAVCR2, LAG3, TIM3, PD1) before in vivo validation. This preliminary screening step consolidates the knowledge acquisition phase, enabling focused in vivo experiments with fewer candidate genes, thereby reducing overall screening time while maximizing information gain.
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
Enhances T cell immune function, improves tumor infiltration, and resistance to immunosuppression, leading to improved therapeutic outcomes in cancer models.
Implementation Method 1
the insertion and/or deletion in a gene locus is mediated by a CRISPR-related system. In certain exemplary embodiments, the insertion and/or deletion in a gene locus is mediated by CRISPR/Cas9.
Data Source
AI summary
The present disclosure provides gene edited modified immune cells or precursors thereof (e.g., gene edited modified T cells) comprising an exogenous T cell receptor (TCR) and/or a chimeric antigen receptor (CAR) having specificity for a target antigen, and an insertion and/or deletion in one or more endogenous gene loci, wherein the endogenous gene loci encode regulators of T cell function, thereby resulting in immune cells having enhanced function. Compositions and methods of treatment are also provided. The present invention provides methods of screening for TCR- or CAR-T cells with enhanced immune function (e.g., T cell efficacy, T cell memory, and/or T cell persistence).