Chimeric NK Receptor T Cells for Rapid Tumor Targeting
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Solution Overview
Problem
Current methods for obtaining tumor-specific T cells are time-consuming, laborious, and challenging due to low antigen-specific T cell frequencies, and there is a need for more efficient strategies to activate immune cells for targeted cancer treatment.
Innovation Solution
A nucleic acid construct encoding a chimeric receptor composed of a C-type lectin-like natural killer cell receptor, such as NKG2D, fused to an immune signaling receptor like CD3ζ, is introduced into T cells to enhance their ability to recognize and kill tumor cells, with a suicide gene to prevent unintended inflammation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If traditional methods are used to obtain tumor-specific T cells, then the process is simple in principle, but it is time-consuming and laborious due to low antigen-specific T cell frequencies
Solution Approach 1:
The patent uses a chimeric receptor as an intermediary molecule that combines NK cell recognition domains with T cell signaling domains. This chimeric receptor enables T cells to recognize tumor antigens through NK cell ligands (such as MIC-A, MIC-B, ULBP-1, ULBP-2, ULBP-3) while providing T cell activation signals, thereby bypassing the need to isolate rare antigen-specific T cells and dramatically improving productivity while reducing time requirements
2Reliability
If full-length T cell receptors are used to redirect T cells against tumor cells, then antigen specificity is maintained, but the complexity of genetic modification increases
Solution Approach 1:
The patent segments the T cell receptor function into two separate components: (1) the chimeric receptor that provides tumor recognition through NK cell ligand binding, and (2) the endogenous T cell receptor that maintains antigen specificity. This segmentation allows the T cell to retain its antigen-specificity while gaining enhanced tumor recognition capability through the chimeric NK cell receptor, reducing the complexity of complete receptor redesign
3Speed
If NK cells are used to recognize and eliminate tumor cells, then fast kinetics are achieved without prior sensitization, but the ability to discriminate between abnormal and healthy tissues is limited
Solution Approach 1:
The patent applies local quality by making the chimeric receptor specific to certain tumor-associated ligands (MIC-A, MIC-B, ULBP-1, ULBP-2, ULBP-3) that are locally expressed on tumor cells but not on normal tissues. This ligand-specificity provides localized recognition capability that enables fast NK-cell-like kinetics while maintaining tissue discrimination, as the chimeric receptor only activates on cells expressing the specific tumor ligands
Data Source
AI summary
The present invention relates to chimeric immune receptor molecules for reducing or eliminating tumors. The chimeric receptors are composed a C-type lectin-like natural killer cell receptor, or a protein associated therewith, fused to an immune signaling receptor containing an immunoreceptor tyrosine-based activation motif. Methods for using the chimeric receptors are further provided.