CRISPR-Cas T Cell Gene Knockout for Solid Tumor Immunotherapy
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Solution Overview
Problem
Current adoptive cell transfer therapies for cancer using genetically engineered T cells face limitations in T cell proliferation, survival, and function, particularly in solid tumors, leading to mixed results in clinical trials, with fewer responses observed in tumors like melanoma, renal cell carcinoma, and colorectal cancer.
Innovation Solution
The methods and compositions described involve modifying T cell-expressed genes such as FAS, BID, CTLA4, PDCD1, CBLB, PTPN6, TRAC, and TRBC to enhance T cell proliferation, survival, and function by targeted knockout or knockdown using CRISPR/Cas systems, specifically altering gene expression to overcome inhibitory signaling and promote cytotoxic activity against cancer cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If T cells are genetically engineered with TCR or CAR genes to target tumor antigens, then anti-tumor specificity is improved, but T cell proliferation and survival in solid tumor environments deteriorates
Solution Approach 1:
The patent modifies T cell gene expression parameters by knocking down inhibitory genes (FAS, BID, PDCD1, CTLA4, CBLB, PTPN6) to change the cellular state and improve proliferation and survival capabilities in solid tumor environments
Solution Approach 2:
The patent extracts and removes harmful inhibitory signaling pathways from T cells by targeting and knocking down specific genes (FAS, BID, PDCD1, CTLA4, CBLB, PTPN6) that limit T cell function in solid tumors
2Object-generated harmful factors
If T cells are engineered to recognize and attack cancer cells, then cytotoxic activity is improved, but T cell survival and persistence in tumor microenvironment deteriorates
Solution Approach 1:
The patent converts harmful inhibitory signals (FAS, BID, PDCD1, CTLA4, CBLB, PTPN6) that normally limit T cell survival into beneficial effects by knocking these genes down, thereby transforming the limitation into an advantage for prolonged T cell persistence and anti-tumor durability
3Ease of manufacture
If conventional adoptive cell transfer is used without gene editing, then treatment simplicity is maintained, but anti-tumor efficacy in solid tumors deteriorates
Solution Approach 1:
The patent performs preliminary gene editing of T cells ex vivo before infusion, pre-modifying their genetic makeup to overcome solid tumor barriers. This advance preparation enables the T cells to achieve superior anti-tumor efficacy in solid tumors compared to conventional approaches without complex in vivo manipulation
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
This approach aims to improve the efficacy of genetically modified T cells by enhancing their ability to proliferate, survive, and function within the tumor environment, potentially leading to more effective anti-tumor responses, especially in solid tumors where previous therapies have shown limited success.
Implementation Method 1
modifying T cell-expressed genes such as FAS, BID, CTLA4, PDCD1, CBLB, PTPN6, TRAC, and TRBC to enhance T cell proliferation, survival, and function by targeted knockout or knockdown using CRISPR/Cas systems
Data Source
AI summary
CRISPR/CAS-related compositions and methods for treatment of cancer.