Hypoimmunogenic CAR-T Cells Evading Immune Rejection
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Solution Overview
Problem
The vigorous host-versus-graft immune response against histoincompatible T cells limits the expansion and persistence of allogeneic CAR-T cells, reducing the efficacy of cell-based therapies for treating various disorders.
Innovation Solution
Engineered cells with reduced expression of Y chromosome genes and MHC class I and/or class II human leukocyte antigens, combined with a first exogenous polynucleotide encoding CD47, are propagated from primary T cells or derived from induced pluripotent stem cells, to evade immune detection and rejection.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If allogeneic CAR-T cells are used for therapy, then ease of manufacturing and quality control are improved, but host-versus-graft immune response causes vigorous rejection and limits expansion and persistence
Solution Approach 1:
The patent extracts and removes the immunogenic components (Y chromosome antigens and MHC molecules) from the allogeneic CAR-T cells through genetic modification. This extraction of harmful immunogenic elements allows the cells to maintain the manufacturing advantages of allogeneic sources while eliminating the host-versus-graft rejection that limited their persistence and expansion.
Solution Approach 2:
The patent changes the immunogenic parameters of the CAR-T cells by reducing expression of Y chromosome genes and MHC class I and class II molecules. This parameter modification transforms the cells from highly immunogenic allogeneic cells into hypoimmunogenic cells that can persist and expand in the host without vigorous rejection, while maintaining the manufacturing simplicity of allogeneic production.
2Object-affected harmful factors
If Y chromosome genes and MHC molecules are reduced to evade immune detection, then immune recognition is avoided, but cell identity and function may be compromised
Solution Approach 1:
The patent applies local quality modification by specifically targeting and reducing only the immunogenic components (Y chromosome antigens and MHC molecules) while preserving all other essential cell functions and identities. This localized genetic modification allows the cells to evade immune recognition through reduced antigen presentation without compromising their therapeutic functionality or cellular characteristics.
Data Source
AI summary
Disclosed herein are engineered cells and/or hypoimmunogenic cells including engineered cells and/or hypoimmunogenic stem cells, engineered cells and/or hypoimmunogenic cells differentiated therefrom, and engineered cells and/or hypoimmunogenic CAR-T cells (primary or differentiated from engineered and/or hypoimmunogenic stem cells) and related methods of their use and generation comprising reduced expression of one or more Y chromosome genes and reduced expression of MHC I and/or MHC II human leukocyte antigen molecules and overexpression of CD47. Provided herein are cells further exhibiting reduced expression of T-cell receptors.