CAR-T Cells Expressing BiTEs for Tumor Microenvironment Targeting
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Solution Overview
Problem
Current immunotherapy approaches, such as CAR-T cell therapies, face challenges in effectively targeting tumor microenvironments, particularly in reducing immunosuppression and T cell exhaustion, and delivering therapeutic agents to tumors, especially in the central nervous system, where the blood-brain barrier restricts antibody entry.
Innovation Solution
Engineering CAR-T cells to express chimeric antigen receptors (CARs) with extracellular target-binding domains and bispecific T cell engagers (BiTEs) that can specifically bind to tumor-associated antigens and Treg-associated antigens, allowing for targeted immune cell activation and therapeutic agent delivery directly to tumor sites, including the brain.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CAR-T cells are used to target tumor antigens, then tumor cell killing is improved, but the ability to penetrate the blood-brain barrier and reach central nervous system tumors is limited
Solution Approach 1:
The patent uses antibodies as intermediary molecules that can cross the blood-brain barrier to deliver CAR-T cells to CNS tumors. The antibody component acts as a mediator that facilitates transport across the barrier while the CAR-T cell component provides the therapeutic killing function.
Solution Approach 2:
The invention creates composite CAR-T cell constructs that combine multiple functional elements including antigen-binding domains, transmembrane domains, and intracellular signaling domains into a single engineered receptor that can navigate and function within the CNS tumor microenvironment.
2Measurement precision
If CAR-T cells are engineered with high specificity for tumor antigens, then targeted immune response is improved, but systemic toxicity is increased
Solution Approach 1:
The patent engineers CAR-T cells with localized functionality where the chimeric antigen receptor is specifically activated only upon binding to the target tumor antigen. This spatial and functional localization ensures that cytotoxic activity is concentrated at the tumor site rather than being systemically distributed.
Solution Approach 2:
The invention modifies the activation parameters of T cells by using chimeric antigen receptors that require specific antigen binding and co-stimulatory signals for full activation. This multi-parameter control mechanism raises the activation threshold, preventing inadvertent systemic activation while maintaining high specificity for the target antigen.
3Power
If CAR-T cells are designed to target multiple antigens, then therapeutic potency is improved, but device complexity is increased
Solution Approach 1:
The patent combines multiple antigen-binding specificities into a single chimeric antigen receptor molecule by incorporating multiple variable domains. This merging approach allows the CAR-T cell to recognize and bind to multiple different tumor antigens simultaneously through one integrated receptor structure, thereby enhancing therapeutic potency without requiring separate receptors for each antigen.
Data Source
AI summary
The invention provides methods and compositions for use in treating cancer, which advantageously may be achieved by targeting of a tumor microenvironment. The invention provides chimeric antigen receptors (CARs) that target a tumor microenvironment. In one aspect, the invention features an immune cell engineered to express: (a) a chimeric antigen receptor (CAR) polypeptide including an extracellular domain including a first antigen binding domain that binds to a first antigen and a second antigen-binding domain that binds to a second antigen; and (b) a bispecific T cell engager (BiTE), wherein the BiTE binds to a target antigen and a T cell antigen. In another aspect, the invention features a pharmaceutical composition including the immune cell. In another aspect, the invention features a method of treating a cancer in a subject in need thereof, the method comprising administering the immune cell.