MSLN CAR-iNKT Cells for Solid Tumor Infiltration in Cholangiocarcinoma
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Solution Overview
Problem
Current treatments for cholangiocarcinoma, a type of liver cancer, are inadequate, with existing methods failing to meet clinical requirements for efficacy and safety, and chimeric antigen receptor (CAR)-modified T cells face challenges in infiltrating solid tumors due to the hypoxic and acidic tumor microenvironment.
Innovation Solution
Genetically modify invariant natural killer T (iNKT) cells with chimeric antigen receptors (CARs) that target mesothelin (MSLN) antigens, incorporating specific scFvs, co-stimulatory molecules like CD28 and CD3ζ, to enhance tumor cell binding and killing, using optimized CAR sequences for improved efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CAR-modified T cells are used to treat cholangiocarcinoma, then tumor cell killing capability is improved, but infiltration ability into solid tumors deteriorates due to hypoxic and acidic microenvironment
Solution Approach 1:
The patent changes the cell type from conventional T cells to iNKT cells, which have different functional characteristics including better ability to infiltrate solid tumors and respond to hypoxic and acidic microenvironments. This parameter change in cell identity resolves the contradiction by maintaining killing capability while improving infiltration ability.
2Reliability
If existing treatment methods are used for cholangiocarcinoma, then treatment safety is maintained, but treatment efficacy deteriorates due to poor clinical outcomes and low five-year survival rate
Solution Approach 1:
The patent uses iNKT cells as intermediary agents that bridge innate and adaptive immunity. These cells serve as mediators between the immune system and tumor cells, enabling effective anti-tumor response while maintaining safety. The iNKT cells recognize tumor-associated antigens and activate immune responses without causing severe side effects.
3Measurement precision
If MSLN-targeted CAR is introduced into iNKT cells, then specificity against cholangiocarcinoma is improved, but complexity of genetic modification increases
Solution Approach 1:
The CAR structure is segmented into distinct functional domains: scFv for antigen recognition, hinge region for flexibility, transmembrane domain for membrane anchoring, and intracellular signaling domains (CD28 and CD3ζ) for activation. This segmentation allows systematic construction and optimization while managing complexity through modular design.
Data Source
AI summary
The present application provides a MSLN-containing chimeric antigen receptor, iNKT cells transduced by the chimeric antigen receptor and use of the chimeric antigen receptor and the INKT cells in treatment of liver cancer, particularly cholangiocarcinoma. The present application utilizes the characteristic that iNKT cells can home and colonize the liver, and selects a proper MSLN antibody sequence, thereby realizing high tumor killing efficiency and CAR-iNKT cell proliferation speed; the Anti-MSLN CAR-INKT cell can effectively infiltrate into the liver tumor part, greatly improve the curative effect, reduce the recurrence and alleviate the toxic and side effects.