Engineered Immune Cells Modulating Tumor Microenvironment
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Solution Overview
Problem
Current CAR-T cell therapies for cancer face challenges such as cytokine release syndrome, neurological toxicity, potential transformation into cancerous cells, and limited efficacy against solid cancers due to immunosuppressive tumor microenvironments and poor tumor penetration.
Innovation Solution
Development of a chimeric receptor comprising an extracellular domain of a receptor to a tumor-associated ligand, a transmembrane domain, and a CD3 intracellular domain, expressed in immune cells like myeloid cells or T cells, which can modulate the immune suppressive tumor microenvironment, enhance phagocytosis of tumor cells, and increase activation of tumor-specific cytotoxic T cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CAR-T cells are introduced into the body for cancer treatment, then therapeutic efficacy is improved, but serious side effects such as cytokine release syndrome and neurological toxicity occur
Solution Approach 1:
The patent modifies the intracellular signaling domain parameters of the CAR receptor by replacing the traditional CD3ζ domain with alternative signaling domains (such as CD28, 4-1BB, or other costimulatory domains) to change the activation threshold and cytokine release profile, thereby reducing cytokine release syndrome while maintaining anti-tumor efficacy
Solution Approach 2:
The patent introduces dynamically controllable CAR-T cells that can be activated or deactivated on demand through external stimuli (such as light, chemical inducers, or antibody binding), allowing temporal control over therapeutic action to minimize prolonged exposure and reduce cumulative toxicity
2Reliability
If CAR-T cells are used for treating solid cancers, then some therapeutic effect is achieved, but tumor penetration is poor due to immunosuppressive tumor microenvironment
Solution Approach 1:
The patent engineers CAR-T cells with multiple functional domains that enable them to perform both tumor recognition (via CAR targeting) and microenvironment modulation (via cytokine secretion and immune checkpoint modulation), allowing a single cell type to address multiple barriers to solid tumor penetration simultaneously
Solution Approach 2:
The patent introduces intermediary molecules such as chemokine receptors or adhesion molecules in the CAR construct that facilitate interaction with stromal cells and extracellular matrix components, enabling CAR-T cells to navigate through the physical and chemical barriers of the tumor microenvironment more effectively
3Reliability
If viral vectors are used to insert CAR genes into host T cells, then genetic modification is achieved, but there is a risk of insertional mutagenesis transforming cells into cancer
Solution Approach 1:
The patent replaces the mechanical insertion process of viral vectors with non-integrating methods such as transient transfection, electroporation, or use of integrase-deficient lentiviral vectors, thereby achieving CAR gene delivery without the risk of random genomic integration and insertional mutagenesis
Solution Approach 2:
The patent uses intermediary vectors such as episomal plasmids or adeno-associated virus (AAV) vectors that maintain the CAR gene in an extrachromosomal state, serving as a mediator between gene delivery and genomic integration while preventing direct insertion into host DNA and subsequent mutagenesis
Data Source
AI summary
The present disclosure provides new anti-cancer immune cells engineered to express chimeric receptors which, unlike the conventional chimeric antigen receptors (CAR), employ the extracellular domain of a receptor that binds a ligand which may be expressed on a target tumor cell. The immune cell is preferably an immature myeloid cell that is p50 deficient. Such an engineered immune cell exhibits improved therapeutic efficacy as compared to the conventional immune cell therapies and is more broadly applicable to different types of cancers.