Third Signal CAR Receptor for Solid Tumor Killing
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Solution Overview
Problem
Current CAR-T cell therapies face challenges with high recurrence rates and low effectiveness in treating solid tumors due to immunosuppressive tumor microenvironments, and existing CAR-T cells have insufficient tumor killing and expansion abilities, leading to poor efficacy in controlling solid tumors and metastasis.
Innovation Solution
A chimeric antigen receptor (CAR) incorporating a third signal receptor, specifically scFv(X)-(Y)CD3zeta-MN, where X is a tumor-targeting antibody, Y is a costimulatory receptor, and N is an IL2Rg cytokine receptor, synergistically enhancing T cell activation, expansion, and effector functions to improve CAR-T cell performance.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If traditional CAR-T cells with only first and second signals are used, then the structure is relatively simple, but the tumor killing and expansion abilities are insufficient
Solution Approach 1:
The patent combines multiple signal domains (first signal CD3zeta, second signal costimulatory receptor, and third signal cytokine receptor) into a single chimeric antigen receptor molecule. This merging of functional domains allows the CAR-T cell to simultaneously receive antigen recognition signals, costimulatory signals, and cytokine signaling, thereby enhancing tumor killing ability while maintaining a unified receptor structure.
Solution Approach 2:
The third-generation CAR structure designed in the patent serves multiple functions: it recognizes tumor antigens through the extracellular domain, transmits activation signals through the CD3zeta domain, provides costimulatory signals through the costimulatory receptor domain, and responds to cytokine signals through the cytokine receptor domain. This multi-functionality enables a single CAR molecule to perform several critical roles in enhancing CAR-T cell efficacy.
2Reliability
If traditional CAR-T cells are used, then the treatment is relatively safe, but the recurrence rate is high and effectiveness in solid tumors is low
Solution Approach 1:
The patent incorporates a cytokine receptor domain that can bind to cytokines in advance, preparing the CAR-T cell for enhanced activation and expansion before encountering the tumor. This preliminary signaling capability allows the CAR-T cell to be pre-conditioned for more effective tumor engagement and long-term persistence, thereby reducing recurrence rates and improving solid tumor effectiveness.
Solution Approach 2:
The patent changes the signaling parameters of CAR-T cells by adding the third cytokine signal domain. This parameter change transforms the CAR-T cell from a basic two-signal system to a three-signal system, fundamentally altering the cell's activation threshold, expansion capacity, and persistence characteristics, thereby improving treatment effectiveness and reducing recurrence.
3Productivity
If CAR-T cells with enhanced activation are used, then the tumor killing ability increases, but immune side effects may increase
Solution Approach 1:
The patent applies local quality by making the CAR-T cell's signaling capabilities location-specific and context-dependent. The cytokine receptor domain is designed to respond to specific cytokine signals that are preferentially present in the tumor microenvironment, thereby enhancing tumor killing ability locally at the tumor site while maintaining better control over systemic immune activation and reducing off-target side effects.
Data Source
AI summary
The present invention provides a chimeric antigen receptor having a structure of scFv(X)-(Y)CD 3zeta-MN.X comprises a tumor targeting antibody or a ligand or receptor capable of specifically binding to a tumor. Y is an intracellular region of a costimulatory receptor selected from ICOS, CD28, CD27, HVEM, LIGHT, CD40L, 4-1BB, OX40, DR3, GITR, CD30, SLAM, CD2, and CD226; M is an intracellular region of a gamma chain family cytokine receptor, the cytokine receptor being selected from IL2Ra, IL2Rb, IL4Ra, IL7Ra, IL9Ra, IL15Ra, and IL21Ra. N is an intracellular region of IL2Rg. The present invention further provides a CAR-T cell constructed from the recombinant expression vector of said chimeric antigen receptor, a preparation method therefor and the use thereof. The CAR-T cell of the present invention significantly improves tumor killing capacity and amplification capacity.