Chimeric Antigen Receptor T Cells for Selective Pathologic T-Cell Elimination
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current treatments for immune activation disorders, such as autoimmune diseases and transplant rejection, lack specificity and often cause significant side effects, with few therapies effectively targeting pathogenic T cells while minimizing harm to non-pathogenic cells.
Innovation Solution
Development of a chimeric antigen receptor (CAR) expressed by immune cells, comprising specific domains that bind to CD8+ T cells, including a beta-2 microglobulin leader peptide, cognate peptide, linker domains, MHC class I molecules, and intracellular signaling domains, to selectively target and induce cell death of pathologic T cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If pan-T cell treatments are used to treat autoimmune diseases, then treatment effectiveness is improved, but side effects such as infection, malignancy, and cardiovascular disease increase significantly
Solution Approach 1:
The CAR T cell therapy applies local quality by engineering T cells to express chimeric antigen receptors that specifically recognize and bind to autoantigens (such as myelin oligodendrocyte protein, glutamic acid decarboxylase, or islet antigens). This specificity ensures that only pathogenic T cells targeting these particular autoantigens are eliminated, while other T cells remain unaffected, thereby reducing broad immunosuppression and associated side effects like infections and malignancies
Solution Approach 2:
The therapy segments the T cell population by creating a specialized subset of CAR T cells that are directed against specific autoantigens. This segmentation allows for targeted elimination of pathogenic clones while preserving the functionality and diversity of the broader T cell repertoire, maintaining immune surveillance against infections and preventing unwanted immunosuppression
2Reliability
If current therapies are used to target pathogenic T cells, then some treatment effect is achieved, but specificity is insufficient and non-pathogenic T cells are also affected
Solution Approach 1:
The chimeric antigen receptor acts as an intermediary that bridges the engineered T cell and the specific autoantigen on pathogenic T cells. The CAR structure includes an extracellular domain that binds with high specificity to the autoantigen (such as MOG, GAD65, or islet antigens), ensuring that only T cells expressing these specific autoantigens are targeted. This intermediary mechanism provides precise targeting while leaving non-pathogenic T cells that do not express these markers unaffected
Data Source
AI summary
The disclosure describes T cells that express chimeric antigen receptors (CARs), as well as pharmaceutical compositions comprising T cells and methods of making and using such T cells. Particularly, this disclosure describes T cells expressing a CAR that specifically bind to pathologic T-cells, and methods of use in the treatment of autoimmune disease, transplant rejection, T cell malignancies, and chronic inflammatory disease.