AQP3-Targeting CAR-T Cells for Solid Tumor Infiltration
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Solution Overview
Problem
Current CAR-T therapies for solid tumors, including lung cancer, face limitations due to the lack of specific tumor antigens and the immunosuppressive microenvironment of solid tumors, which reduces the therapeutic efficacy and increases side effects.
Innovation Solution
The development of a CAR-T cell system that targets Aquaporin 3 (AQP3), a protein highly expressed in both lung cancer cells and stromal cells, as a novel anti-cancer target. This CAR-T cell system includes a chimeric antigen receptor (CAR) fusion protein with an extracellular recognition region specific to AQP3, a hinge region, a transmembrane region, and an intracellular stimulatory signaling domain.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional CAR-T therapy is used for solid tumors, then tumor targeting is attempted, but therapeutic efficacy is greatly limited due to lack of specific tumor antigens and immunosuppressive microenvironment
Solution Approach 1:
The patent employs a dual-target CAR-T system that simultaneously targets AQP3 (highly expressed in tumor cells) and AQP9 (expressed in stromal cells). This multi-functionality allows the CAR-T cells to recognize and attack both tumor cells and the protective stromal barrier, overcoming the limitation of single-antigen targeting in solid tumors.
Solution Approach 2:
The patent divides the tumor microenvironment into two distinct targets: AQP3 on tumor cells and AQP9 on stromal cells. By segmenting the targeting strategy into two separate antigen-antibody pairs within the dual CAR structure, the system can independently address different functional barriers (tumor cell recognition and stromal penetration) that collectively limit CAR-T efficacy in solid tumors.
2Productivity
If CAR-T cells are designed to target solid tumors, then tumor killing ability is enhanced, but infiltration into tumor tissue is greatly limited by the complicated microenvironment including CAFs and ECM
Solution Approach 1:
The patent uses AQP9 on stromal cells as an intermediary target to facilitate CAR-T cell infiltration through the tumor stroma. By incorporating AQP9 targeting into the dual CAR system, the CAR-T cells can first engage and disrupt the stromal barrier (mediated by AQP9) before reaching and killing tumor cells (via AQP3), thereby overcoming the physical obstruction posed by the tumor microenvironment.
3Adaptability or versatility
If CAR-T therapy is applied to lung cancer, then new treatment hope is provided, but target ability is reduced due to lack of significantly specific antigen for lung cancer
Solution Approach 1:
The dual-target CAR-T system provides universality by targeting two different antigens (AQP3 and AQP9) that are both highly expressed in lung cancer and its microenvironment. This multi-antigen approach ensures broad applicability to lung cancer while maintaining high specificity through the unique expression patterns of AQP3 in tumor cells and AQP9 in stromal cells.
Data Source
AI summary
Disclosed are a chimeric antigen receptor T (CAR-T) cell and a construction method thereof, and an antitumor drug. In the present application, aquaporin 3 (AQP3) is adopted as a novel anti-cancer target, and AQP3 is highly expressed in both tumor cells and tumor stromal cells and can mediate the transport of both water and glycerol, which is conducive to breakage of a physical barrier of a tumor and promotes CAR-T cells to well infiltrate into a tumor to kill the tumor. The chimeric antigen receptor (CAR) fusion protein of the present application can be used in the treatment of AQP3-positive malignant tumors, and especially, when used in the treatment of non-small cell lung cancer (NSCLC), the CAR fusion protein exhibits a significant therapeutic effect. In addition, when used in the treatment of lung cancer, the CAR fusion protein causes little damage to a normal tissue and exhibits high safety.