Gene-Edited CAR-T Cells for Long-Term In Vivo Persistence
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Solution Overview
Problem
Current CAR-T therapies for tumor immunotherapy face challenges such as the need for chemotherapy pretreatment due to limited persistence of CAR-T cells in vivo, leading to relapse, and the requirement for repeated infusions.
Innovation Solution
Recombinant immune cells with simultaneous knockout of BCOR and ZC3H12A genes using CRISPR-Cas9 technology, enhancing persistence and functional properties through gene editing.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Object-affected harmful factors
If CAR-T cells are infused back without chemotherapy pretreatment, then patient safety is improved, but the CAR-T cells cannot effectively expand and persist in vivo
Solution Approach 1:
The invention changes the genetic parameters of CAR-T cells by knocking out specific genes (Pdcd1, Pten, and/or Trp53) to alter their biological properties. This enables the cells to persist and expand in vivo without requiring chemotherapy pretreatment, thus resolving the contradiction between patient safety and treatment effectiveness.
Solution Approach 2:
The invention creates modified CAR-T cells with enhanced persistence properties through gene knockout. These modified cells serve as improved copies of conventional CAR-T cells, maintaining the therapeutic function while gaining the ability to persist indefinitely without chemotherapy support.
2Reliability
If conventional CAR-T cells are used, then initial therapeutic effect is achieved, but the cells have limited duration in vivo leading to relapse
Solution Approach 1:
By knocking out genes such as Pdcd1, Pten, and/or Trp53, the invention fundamentally changes the persistence parameters of CAR-T cells. The modified cells exhibit extended duration in vivo, maintaining therapeutic effects long-term and preventing relapse, thus resolving the contradiction between initial efficacy and long-term durability.
3Reliability
If repeated infusion of recombinant T cells is performed, then therapeutic effect is maintained, but treatment complexity and cost increase
Solution Approach 1:
The invention creates improved CAR-T cell copies with inherent long-term persistence capabilities through genetic modification. These modified cells can maintain therapeutic effects without requiring repeated infusions, thereby simplifying the treatment protocol and reducing overall treatment complexity while maintaining reliability.
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 recombinant immune cells persist indefinitely in vivo, eliminating the need for chemotherapy pretreatment, achieving long-term treatment and prevention of tumors, and serving as carriers for therapeutic molecule delivery.
Implementation Method 1
Recombinant immune cells with simultaneous knockout of BCOR and ZC3H12A genes using CRISPR-Cas9 technology
Data Source
AI summary
The present invention provides a recombinant immune cell and the preparation method, the gene regulation system and the use thereof. By reducing or eliminating the expression and/or biological functions thereof of the BCOR gene and the ZC3H12A gene, the persistence of the recombinant immune cell is enhanced. In some embodiments, the present invention obtains CAR-T cells with knockout of double genes ZC3H12A and BCOR by gene editing, which can persist in vivo, solving the technical problem of long-term effectiveness of CAR-T treatment. In some embodiments, the gene-edited CAR-T cells persist in vivo and can continuously secrete therapeutic biological molecules, achieving the purpose of long-term effectiveness of a single administration.