CD147 CAR-T Receptor Design for Solid Tumor Persistence
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Solution Overview
Problem
Current therapies for liver cancer, particularly hepatocellular carcinoma (HCC), lack effectiveness and are hindered by high costs and severe side effects, while CAR-T cell therapy faces challenges in targeting solid tumors and maintaining persistence in the tumor microenvironment.
Innovation Solution
Development of chimeric antigen receptors (CARs) specifically targeting CD147, which are expressed at high levels in various cancers, including HCC, using modified single-chain variable fragments (scFvs) and vectors with inducible promoters, co-stimulatory molecules, and suicide genes to enhance therapeutic efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CAR-modified T cell therapy is used to treat liver cancer, then antitumor activity is improved, but severe toxicity and high costs occur
Solution Approach 1:
The patent applies local quality by designing CARs with tumor-specific targeting domains that recognize antigens uniquely or preferentially expressed on liver cancer cells. This specificity ensures that the immunotherapeutic effect is localized to tumor cells while sparing healthy tissues, thereby maintaining high antitumor activity while reducing systemic toxicity
Solution Approach 2:
The patent introduces safety switch mechanisms and controllable activation systems as intermediaries between the CAR-modified T cells and the target tumor cells. These intermediary systems allow for controlled delivery of cytotoxic effects only when and where needed, reducing off-target toxicity while preserving antitumor efficacy
2Reliability
If CAR-modified T cells are used to treat solid tumors, then immunotherapeutic effect is improved, but durability and persistence in tumor microenvironment deteriorates
Solution Approach 1:
The patent employs composite CAR designs that integrate multiple functional domains including costimulatory signals, survival signals, and cytokine receptors into a single chimeric receptor construct. This composite structure provides both immediate antitumor activity and long-term persistence signals, enabling CAR-T cells to maintain functionality and survive in the challenging tumor microenvironment
Solution Approach 2:
The patent implements continuous costimulatory signaling through the CAR design, where the receptor provides not only antigen recognition but also continuous survival and proliferation signals as long as the CAR-T cell remains engaged with the tumor antigen. This continuous useful action ensures durable persistence rather than transient activation followed by cell death or exhaustion
3Adaptability or versatility
If conventional immunotherapies are used for liver cancer, then treatment options are provided, but effectiveness deteriorates due to limited target availability
Solution Approach 1:
The patent develops universal CAR platforms that can target multiple different tumor-associated antigens expressed on liver cancer cells. By creating a family of CARs with different antigen-specific binding domains but shared functional backbones, the invention provides versatile treatment options that can be adapted to different patient populations and tumor types while maintaining reliable antitumor effectiveness
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 CD147-targeting CARs demonstrate specific cytotoxicity against CD147-positive tumor cells, effectively controlling tumor progression in preclinical models, including HCC, with reduced side effects and improved persistence.
Implementation Method 1
modified single-chain variable fragments (scFvs) that specifically bind CD147
Data Source
AI summary
Modified single chain variable fragments (scFv) that specifically bind CD147 are provided. Also provided are chimeric antigen receptors (CARs) including the modified CD147 scFv, nucleic acids encoding the CARs, vectors including the nucleic acids encoding the CARs, and immune cells expressing the CARs. Methods of treating a subject with cancer including administering to the subject an immune cell expressing a disclosed CD147-CAR are also provided.