CAR Dendritic Cells With Dectin-1/FcRγ Signaling for Solid Tumors
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Solution Overview
Problem
Conventional DC-based cancer vaccines exhibit limited efficacy due to immunosuppressive factors in the tumor microenvironment, inhibiting anti-tumor T cell responses, with only 5% to 15% of patients achieving an objective immune response.
Innovation Solution
Engineering dendritic cells (DCs) with a chimeric antigen receptor (CAR) comprising an extracellular domain, CD8a hinge and transmembrane domains, and intracellular Dectin-1 and FcR gamma domains to enhance tumor antigen recognition and signaling, combined with radiotherapy to activate DCs and overcome immunosuppression.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional DC-based cancer vaccines are used, then safety is maintained, but anti-tumor efficacy is limited due to immunosuppressive factors in the tumor microenvironment
Solution Approach 1:
The patent introduces CAR-DCs as intermediary cells that mediate between the tumor microenvironment and the immune system. These engineered DCs express CARs on their surface, allowing them to directly interact with tumor cells and present antigens to T cells, thereby overcoming the immunosuppressive barrier while maintaining safety profiles of conventional vaccines
Solution Approach 2:
The patent modifies the functional parameters of dendritic cells by introducing CAR transgenes that change their antigen recognition capability. This parameter change enables DCs to specifically target tumor antigens and activate T cells more effectively, transforming them from non-specific stimulators to targeted anti-tumor effectors
2Productivity
If only 5% to 15% of patients achieve objective immune response, then the limitation is quantified, but the underlying cause remains immunosuppression
Solution Approach 1:
The patent converts the harmful immunosuppressive microenvironment into a beneficial setting by using CAR-DCs to actively counteract suppression. The engineered DCs express CARs that recognize tumor antigens, leading to enhanced T cell activation and cytokine production that opposes the immunosuppressive forces, thereby transforming a hostile environment into a therapeutic opportunity
Solution Approach 2:
The patent performs preliminary action by pre-engaging DCs with tumor antigens through CAR expression before administration to patients. This preliminary antigen presentation and T cell activation occurs in the laboratory, priming the immune response before the cells are injected into the tumor microenvironment, thereby countering immunosuppression proactively rather than reactively
Data Source
AI summary
The present application belongs to the technical field of biomedicine, and discloses a chimeric antigen receptor (CAR), an engineered dendritic cell (DC), and a use thereof. The CAR of the present application includes an extracellular domain, a CD8a hinge domain, a CD8a transmembrane domain, and an intracellular domain. The extracellular domain includes a guide sequence and a single-chain antibody sequentially. The intracellular domain includes a Dectin-1 intracellular domain and an intracellular domain of FcR gamma. Chimeric antigen receptor-modified dendritic cells (CAR-DCs) prepared with the CAR of the present application can efficiently recognize a tumor antigen. The combined administration of the CAR-DC and radiotherapy for treating a solid tumor can effectively overcome the immunosuppression of the tumor microenvironment and improve the clinical treatment effect. Therefore, the present application provides an effective immunotherapy strategy for clinical tumor patients, and provides a new idea and method for tumor immunotherapy.