Immune Cell Receptor Cassette Swapping for Rapid Personalized Therapy
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Solution Overview
Problem
Current adoptive immune cell therapies are limited by a lack of suitable patient and tumor-specific immune cells, necessitating the development of therapeutically sufficient and functional antigen-specific immune cells for effective immunotherapy.
Innovation Solution
The production of immune cells involves generating a heterologous expression cassette for a placeholder T-cell receptor (TCR) in immune cells, which is then replaced with an expression construct encoding a therapeutic antigen receptor, enabling the immune cells to specifically target cancer cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If current adoptive immune cell therapies are used, then patient-specific immune cells can be generated, but the process is time-consuming and lacks scalability
Solution Approach 1:
The patent applies preliminary action by pre-establishing a standardized production platform with heterologous expression cassettes containing placeholder TCRs in immune cells before actual therapeutic use. This pre-prepared system allows rapid replacement of placeholder TCRs with patient-specific therapeutic TCRs through CRISPR-Cas9 mediated excision and transgene insertion, eliminating the need to generate immune cells from scratch for each patient and dramatically reducing production time while maintaining scalability.
Solution Approach 2:
The patent uses an intermediary approach by introducing heterologous expression cassettes with placeholder TCRs as temporary intermediaries in the immune cells. These placeholder TCRs serve as functional placeholders that enable cell production and can be subsequently replaced with patient-specific TCRs. This intermediary system decouples the production process from the final therapeutic requirement, allowing standardized manufacturing followed by rapid customization.
2Reliability
If patient-specific immune cells are generated from scratch, then therapeutic specificity is achieved, but manufacturing complexity increases
Solution Approach 1:
The patent applies segmentation by dividing the TCR generation process into distinct modular components: (1) standardized heterologous expression cassettes with placeholder TCRs that are pre-installed in immune cells, (2) CRISPR-Cas9 excision machinery for removing placeholders, and (3) transgene insertion systems for adding patient-specific TCRs. This modular segmentation allows each component to be optimized independently and simplifies the overall manufacturing process while maintaining therapeutic specificity.
Solution Approach 2:
The patent uses copying by creating standardized heterologous expression cassettes with placeholder TCRs that can be replicated across multiple immune cell lines. These placeholder cassettes serve as templates that can be efficiently replaced with patient-specific TCR sequences through precise excision and insertion, avoiding the need to redesign the entire expression system for each patient and reducing manufacturing complexity.
3Duration of action of moving object
If conventional TCR generation methods are used, then functional immune cells are produced, but the magnitude and duration of anti-tumor responses are limited
Solution Approach 1:
The patent applies parameter changes by modifying the TCR expression system through heterologous cassettes with placeholder TCRs that can be precisely replaced with patient-specific TCRs having optimized binding characteristics. This allows adjustment of TCR affinity, specificity, and expression levels to enhance anti-tumor response magnitude and duration while maintaining manufacturing efficiency through standardized production platforms.
Data Source
AI summary
This invention relates to methods for producing immune cells expressing a therapeutic antigen receptor. An immune cell is provided that comprises a heterologous expression cassette. The heterologous expression cassette comprises (a) a coding sequence for a production TCR, (b) a constitutive promoter operably linked to the coding sequence, (c) a 5′ targeting site, and optionally (d) a 3′ targeting site. An expression construct is then introduced into the immune cell at the site of the heterologous expression cassette. The expression construct comprises a coding sequence for a therapeutic antigen receptor and the therapeutic antigen receptor is then expressed in the immune cell. Methods, reagents for use in the methods and immune cells produced by the methods are provided.