CRISPR-Edited CAR T Cells to Prevent CD70-Linked Exhaustion
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Solution Overview
Problem
Existing CAR T-cell therapies face challenges such as premature exhaustion and reduced efficiency in targeting and killing cancer cells, particularly due to the expression of endogenous CD70 protein.
Innovation Solution
Engineered immune cells, such as T cells, are modified using CRISPR/Cas9 gene editing to disrupt the CD70 gene and introduce a CAR, along with disruptions in TRAC and β2M genes, enhancing T cell function and cancer cell killing efficiency.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If endogenous CD70 protein is expressed in CAR T cells, then T cell receptor signaling and immune function are maintained, but premature T cell exhaustion occurs and cancer cell killing efficiency is reduced
Solution Approach 1:
The patent removes the harmful endogenous CD70 protein expression from T cells while preserving CAR-mediated cancer cell killing function. This is achieved through CRISPR/Cas9-mediated gene editing to knockout the CD70 gene, eliminating the self-targeting mechanism that causes fratricide and premature exhaustion, thereby improving cancer cell killing efficiency without compromising T cell function sustainability through the introduced CAR
2Productivity
If CRISPR/Cas9 gene editing is used to disrupt CD70 gene, then T cell exhaustion is prevented and cytotoxicity is enhanced, but manufacturing complexity increases
Solution Approach 1:
The patent replaces traditional mechanical or chemical gene disruption methods with CRISPR/Cas9 genome editing technology. This molecular biology approach uses guide RNA to direct Cas9 nuclease to specific DNA sequences, enabling precise and efficient disruption of the CD70 gene with higher specificity and lower off-target effects compared to conventional methods, thereby enhancing T cell cytotoxicity while managing manufacturing complexity through a more precise editing mechanism
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 T cell function, including prevention of premature exhaustion, enhanced expansion, increased cytotoxicity, and cytokine secretion, leading to more effective cancer cell targeting and killing.
Implementation Method 1
the cells are engineered to include CARs on their surface. The CARs may be introduced into the T cells using CRISPR/Cas9 gene editing technology
Implementation Method 2
When these allogeneic CAR T cells are injected into a patient, the receptors enable the T cells to kill cancer cells
Data Source
AI summary
Provided herein, in some embodiments, are methods and compositions (e.g., cell compositions) for the treatment of cancer.