CAR-GM-T Cell Vector for Solid Tumor Infiltration
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Solution Overview
Problem
Current CAR-T therapies show limited efficacy against solid tumors due to challenges such as tumor microenvironment suppression, poor infiltration, and immune evasion, which hinder the effectiveness of CAR-T cells in targeting and eliminating cancer cells.
Innovation Solution
A novel CAR expression vector is developed that includes a polynucleotide encoding a chimeric antigen receptor (CAR) linked with a self-cleaving peptide P2A to a granulocyte-macrophage colony-stimulating factor (GM-CSF) polynucleotide, enhancing CAR-T cell infiltration and immune modulation capabilities, specifically targeting tumor-specific antigens like Her2, B7-H3, and MUC16, and secreting GM-CSF, IFN-γ, and IL-2 to activate dendritic cells and trigger antigen-specific immune responses.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional CAR-T structure is used, then T cell activation is achieved, but infiltration into solid tumors is poor
Solution Approach 1:
The patent combines CAR structure with GM-CSF expression domain to create a dual-function CAR-T cell system. The CAR component provides tumor antigen recognition and T cell activation, while the GM-CSF component enhances infiltration into solid tumors and modulates the tumor microenvironment, thereby resolving the contradiction between reliable activation and effective infiltration.
Solution Approach 2:
The modified CAR-T cell is designed to perform multiple functions simultaneously: tumor antigen recognition, T cell activation, cytokine secretion (GM-CSF, IFN-γ, IL-2), and enhanced infiltration into solid tumors. This multi-functionality allows the single cell type to address both activation reliability and infiltration effectiveness.
2Productivity
If second-generation CAR structure is used, then proliferation capacity is enhanced, but killing activity against solid tumors is insufficient
Solution Approach 1:
The patent merges second-generation CAR structure with additional co-stimulatory domains and GM-CSF expression capability. This combination enhances both proliferation capacity (through multiple co-stimulatory signals) and killing activity (through GM-CSF-mediated immune modulation and direct cytotoxicity), resolving the insufficiency of killing activity despite improved proliferation.
Solution Approach 2:
The intracellular signaling domain is constructed as a composite structure incorporating multiple co-stimulatory molecules (CD3ζ, 4-1BB, and GM-CSF) in tandem. This composite signaling architecture synergistically enhances both proliferation and killing capabilities, addressing the limitation of second-generation CAR structures.
3Productivity
If third-generation CAR structure is used, then co-stimulatory domains are increased, but side effects increase without significant killing enhancement
Solution Approach 1:
The patent applies local quality by strategically placing co-stimulatory domains at specific locations within the intracellular signaling region rather than uniformly distributing them. The CD3ζ, 4-1BB, and GM-CSF domains are arranged in a localized tandem configuration that optimizes signaling efficiency while minimizing off-target effects, thereby reducing side effects without sacrificing killing enhancement.
4Reliability
If CAR-T cells are used against solid tumors, then anti-tumor response is triggered, but immune microenvironment suppression prevents effective infiltration
Solution Approach 1:
The patent introduces GM-CSF as an intermediary substance that mediates between CAR-T cells and the tumor microenvironment. GM-CSF acts as a chemoattractant and immunomodulator that facilitates CAR-T cell infiltration into solid tumors while simultaneously enhancing the anti-tumor immune response, thereby resolving the contradiction between triggering anti-tumor response and achieving effective infiltration.
Data Source
AI summary
The present invention relates to the field of bioengineering, and in particular to a chimeric antigen receptor (CAR) expression vector and use thereof. The CAR expression vector comprising a polynucleotide encoding a CAR and full length or fragment of a polynucleotide encoding a granulocyte-macrophage colony-stimulating factor (GM-CSF). The CAR-GM-T cell constructed by the present invention is capable of expressing high-level GM-CSF, not only directly enhancing killing activity of the CAR-GM-T cell per se but also facilitating the infiltration of the CAR-GM-T cell into a solid tumor. The CAR-GM-T cell has a stronger immune modulation function compared to the conventional CAR-T cell and systematically triggers the endogenous anti-tumor immune response, thereby achieving superior therapeutic efficacy against a solid tumor.