FolR1-Specific CAR T-Cell Therapy for Resistant Cancers
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Solution Overview
Problem
Current therapeutic options for ovarian cancer, triple-negative breast cancer, gastric cancer, lung cancer, renal cancer, and pancreatic cancer are limited, with a need for alternative treatments due to relapse and resistance to chemotherapy, and these cancers exhibit high expression of the tumor-associated antigen FolR1, making it a promising target for CAR T-cell therapy.
Innovation Solution
Development of a chimeric antigen receptor (CAR) specific for FolR1, comprising a heavy chain variable region and a light chain variable region of an antibody, combined with a CD8alpha hinge and CD3ζ signaling domain, to target and kill cancer cells expressing FolR1, with enhanced killing properties compared to other variants.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If conventional CAR T-cell therapy is used for FolR1-positive cancers, then treatment specificity is improved, but killing efficiency is insufficient
Solution Approach 1:
The patent modifies the CAR structure by changing parameters such as the hinge region sequence (using CD8alpha hinge instead of conventional hinges), transmembrane domain composition, and intracellular signaling domains. These parameter changes optimize both the specificity for FolR1 and the killing efficiency of CAR T-cells against FolR1-positive cancer cells.
Solution Approach 2:
The CAR construct uses composite material principles by combining multiple functional domains: the scFv antigen-binding domain, CD8alpha hinge region, transmembrane domain, and intracellular signaling domains (CD3ζ and costimulatory domains). This composite structure integrates different functional elements to achieve both high specificity and enhanced killing efficiency.
2Productivity
If standard chemotherapy is used for ovarian cancer, then initial response is improved, but relapse and resistance occur
Solution Approach 1:
The patent replaces the mechanical/chemical mechanism of chemotherapy with a biological mechanism - adoptive cell transfer using engineered CAR T-cells. This substitution eliminates the problem of chemotherapy resistance and relapse by using the immune system's targeted cellular attack, which adapts to tumor-specific antigens like FolR1.
Solution Approach 2:
The CAR T-cell therapy enables the patient's own immune system to fight the cancer by infusing engineered T-cells that specifically recognize and attack FolR1-positive tumor cells. This self-service approach leverages the patient's immunological system rather than relying on external chemical agents that can develop resistance.
Data Source
AI summary
The present invention provides a chimeric antigen receptor (CAR) comprising: an antigen binding domain specific for folate receptor 1 (FolR1), a spacer, a transmembrane domain and an intracellular signaling domain. Moreover it was found that an antigen binding domain that comprises from the N- to the C-terminus the heavy chain variable region of an antibody (VH) comprising the amino acid sequence Seq ID No:2 a light chain variable region of an antibody (VL) comprising the amino acid sequence Seq ID No:4 shows superior killing properties compared to other variants.