CRISPR-Edited T Cells for Enhanced Culture Persistence
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Solution Overview
Problem
Current CAR-T cell therapy faces challenges in improving the persistence of T cells in culture, which affects both manufacturing efficiency and clinical efficacy.
Innovation Solution
Development of a T cell bank comprising genetically edited T cells with modifications in genes related to cell self-renewal, apoptosis, and T cell exhaustion, such as TET2, FAS, and CD70, using CRISPR/Cas-mediated gene editing to enhance persistence and functionality.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If T cells are collected and engineered with CARs using CRISPR/Cas9 gene editing, then the T cells can specifically target and kill cancer cells, but the persistence of T cells in culture is reduced
Solution Approach 1:
The patent applies parameter changes by modifying the genetic composition of T cells through CRISPR/Cas9-mediated gene editing. Specifically, the invention disrupts the TET2 gene and modifies apoptosis-related genes (such as FAS) to alter cellular parameters including proliferation rate, survival signaling, and resistance to cell death. These genetic parameter changes enable T cells to maintain enhanced persistence in culture while retaining their cancer-targeting efficacy through CAR expression.
2Productivity
If T cells are engineered to enhance persistence, then manufacturing efficiency improves, but the complexity of the engineering process increases
Solution Approach 1:
The patent employs segmentation by dividing the gene editing process into distinct modular components: (1) delivery of CRISPR/Cas9 system components (Cas9 protein and guide RNAs) into T cells, (2) targeted disruption of specific genes (TET2, FAS, and other apoptosis-related genes), and (3) subsequent CAR expression. This segmented approach allows each genetic modification step to be independently optimized and controlled, managing process complexity while achieving enhanced T cell persistence and manufacturing efficiency.
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 genetically edited T cells exhibit enhanced expansion capacity, prolonged persistence in culture and animal models, reduced apoptosis, and improved CAR-T cell efficacy, potentially leading to more effective and safer therapeutic outcomes.
Implementation Method 1
The CARs may be introduced into the T cells using CRISPR/Cas9 gene editing technology
Data Source
AI summary
A T cell bank comprising genetically engineered T cells having one or more of the following features as compared to the non-engineered T cell counterparts: (a) enhanced expansion capacity in culture, (b) enhanced proliferation capacity, (c) reduced apoptosis, and (d) enhanced activation frequencies. Such genetically engineered T cells may comprise (i) a mutated gene involved in cell self-renewal; (ii) a disrupted gene involved in apoptosis; (iii) a disrupted gene involved in regulation of T cell exhaustion; or (iv) a combination of any one of (i)-(iii).