CAR T-Cell Receptor Architecture for Broader Tumor Antigen Targeting
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Solution Overview
Problem
Current adoptive cell transfer therapies using T-cells transduced with Chimeric Antigen Receptors (CARs) face challenges in effectively targeting a wide range of tumor antigens, limiting their efficacy in treating various types of cancer.
Innovation Solution
Engineering immune effector cells, such as T cells and NK cells, to express CARs that bind to a diverse array of tumor antigens, including specific antigen binding domains, transmembrane domains, and intracellular signaling domains, enhancing their ability to recognize and target various tumor-associated antigens.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If T-cells are transduced with Chimeric Antigen Receptors (CARs) to target tumor antigens, then the ability to treat hematologic cancer is improved, but the ability to effectively target a wide range of tumor antigens across different cancer types is limited
Solution Approach 1:
The patent creates a universal CAR platform that can be applied across multiple cancer types by systematically characterizing and selecting transmembrane domains that function broadly. The study identifies transmembrane domains from various receptors (CD8, CD4, CD28, 4-1BB, OX40, GITR, TNFR, IL2R, IL7R, IL15R, IL21R) that can be interchangeably used in CAR constructs to target different tumor antigens, enabling one CAR design framework to serve multiple therapeutic applications beyond just hematologic cancers.
Solution Approach 2:
The patent systematically varies the transmembrane domain parameter in CAR constructs to optimize performance across different cancer types. By testing multiple transmembrane domain options and characterizing their functional properties (expression levels, signaling capacity, cell surface localization), the invention identifies optimal parameter combinations that enhance CAR versatility. This parameter optimization allows the same CAR structure to effectively target diverse tumor antigens including GD2, PSMA, and others across solid tumors and hematologic malignancies.
2Ease of manufacture
If CAR structure is simplified to improve manufacturing, then ease of manufacture is improved, but the signaling capacity and functional effectiveness may be reduced
Solution Approach 1:
The patent identifies a set of universal transmembrane domains that can be used across multiple CAR designs without requiring complex, cancer-type-specific optimizations. This universality simplifies manufacturing by providing a standardized set of interchangeable components that maintain reliable signaling capacity across different applications, eliminating the need to redesign entire CAR structures for each new target antigen.
Solution Approach 2:
The patent creates composite CAR structures by combining optimized transmembrane domains with standardized extracellular and intracellular domains. This composite approach allows modular assembly of CAR constructs using pre-characterized components, simplifying manufacturing while maintaining or enhancing signaling capacity through the synergistic combination of optimized domain elements from different receptor families.
Data Source
AI summary
The invention provides compositions and methods for treating diseases associated with expression of a cancer associated antigen as described herein. The invention also relates to chimeric antigen receptor (CAR) specific to a cancer associated antigen as described herein, vectors encoding the same, and recombinant T cells comprising the CARs of the present invention. The invention also includes methods of administering a genetically modified T cell expressing a CAR that comprises an antigen binding domain that binds to a cancer associated antigen as described herein.