Universal T Cells With HLA-E Trimer to Prevent NK Cell Clearance
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Solution Overview
Problem
Current CAR T cell therapy is hampered by low yield and poor functionality of peripheral blood T cells from cancer patients, sensitivity to host natural killer (NK) cell recognition, and the risk of graft vs host disease due to lack of major histocompatibility complex class I molecule (MHC I), necessitating a 'universal' T cell product that optimizes persistence and avoids rejection.
Innovation Solution
A peptide comprising a human leukocyte antigen (HLA) signal peptide, modified beta-2-microglobulin (B2M), and HLA class I histocompatibility antigen alpha chain E (HLA-E) is engineered to inhibit NK cell-mediated killing and enhance persistence, along with a nucleic acid molecule encoding these components, resulting in a genetically engineered cell that does not express MHC I, MHC II, or native T cell receptor (TCR).
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CAR T cells are engineered to target cancer antigens, then anti-tumor efficacy is improved, but sensitivity to host NK cell recognition increases due to lack of MHC I
Solution Approach 1:
The patent introduces HLA-E as an intermediary molecule that mediates protection from NK cell recognition. HLA-E binds to leader peptides from MHC class I molecules and presents them to NK cell inhibitory receptors (NKG2A), thereby providing a protective signal that prevents NK cell-mediated killing of the engineered T cells while allowing them to maintain their anti-tumor functionality.
Solution Approach 2:
The patent modifies the MHC class I expression parameters by selectively downregulating or knocking out classical MHC class I molecules (HLA-A, HLA-B, HLA-C) while upregulating or preserving HLA-E expression. This parameter change allows the cells to evade NK cell recognition through altered MHC class I profile, specifically maintaining HLA-E to provide protective signaling.
2Adaptability or versatility
If T cells are harvested from cancer patients who received prior systemic therapy, then treatment accessibility is improved, but T cell functionality and yield deteriorate due to tumor microenvironment and pre-treatments
Solution Approach 1:
The patent applies preliminary action by pre-engineering the T cells with enhanced characteristics before adoptive transfer. Specifically, the T cells are genetically modified to express optimized CAR constructs and to have their MHC class I profile adjusted (downregulation of classical MHC I, preservation of HLA-E) prior to infusion. This preliminary engineering ensures that even if the cells are harvested from patients who received prior therapy, they will have the necessary functionality and resistance to NK cell recognition upon reinfusion.
3Duration of action of stationary object
If universal T cell product is engineered to avoid host immune rejection, then persistence is improved, but complexity of engineering increases
Solution Approach 1:
The patent applies the taking out principle by extracting and selectively removing or downregulating specific MHC class I molecules (HLA-A, HLA-B, HLA-C) that are responsible for allorecognition and rejection by host T cells. By taking out these specific molecules while preserving HLA-E, the engineered T cells achieve reduced alloresponse and improved persistence without requiring complete MHC class I deficiency, thus balancing complexity and functionality.
Data Source
AI summary
The invention provides a modified HLA-E single chain trimer construct and nucleic acid molecules encoding thereof as well as cells and compositions comprising thereof for increasing the persistence or reducing the clearance of at least one cell of interest. In some embodiments, the present invention also provides methods of preventing and/or eliminating alloresponse, allorecognition, and/or allogeneic rejection. The invention also relates to chimeric antigen receptor (CAR) cells or engineered TCR-expressing T cells comprising the modified HLA-E single chain trimer construct and/or the nucleic acid molecules encoding thereof.