taNK Cells Expressing TCR Complex for Cancer Treatment
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Solution Overview
Problem
T cell receptors recognizing antigens on cancer cells can become exhausted, limiting the effectiveness of immunotherapy in targeting cancer cells.
Innovation Solution
Genetically modifying immunocompetent cells, such as NK cells, to express a T cell receptor complex or portion thereof, specifically binding to tumor-specific neoepitopes or antigens, to induce, maintain, or augment a cellular immune response against cancer cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If T cell receptors are used to recognize antigens on cancer cells, then the immune response is activated, but the T cell receptors become exhausted over time, limiting treatment effectiveness
Solution Approach 1:
The patent combines the antigen recognition capability of T cell receptors (TCR) with the cytotoxic killing ability of natural killer (NK) cells to create a hybrid cell (taNK cell) that merges the strengths of both cell types, enabling sustained anti-tumor activity without T cell exhaustion
Solution Approach 2:
The taNK cell is designed to perform multiple functions: it can recognize tumor antigens via TCR, activate through NK cell receptors, and execute cytotoxic killing, making it a multi-functional cell that overcomes the limitations of single-function T cells or NK cells
2Measurement precision
If T cells are used to target cancer cells specifically, then antigen-specific immunity is achieved, but the cells cannot effectively target cells missing MHC class 1 markers
Solution Approach 1:
The taNK cell expresses both TCR for MHC-restricted antigen recognition and NK cell receptors for MHC-independent recognition, enabling the cell to adaptively target both MHC-positive and MHC-negative tumor cells through multiple recognition pathways
3Reliability
If genetically modified immunocompetent cells are created to express T cell receptor complex, then the cellular immune response is enhanced, but the complexity of cell engineering increases
Solution Approach 1:
The T cell receptor complex is segmented into separate expression units (alpha chain and beta chain genes) that can be independently introduced into NK cells, simplifying the genetic engineering process while maintaining full TCR functionality
Solution Approach 2:
Viral vectors serve as intermediaries to deliver the TCR genes into NK cells, simplifying the transduction process and enabling efficient expression of the foreign genes without requiring complex direct genetic manipulation methods
Data Source
AI summary
Compositions, methods and uses of genetically modified NK cells to treat a patient with a tumor are presented. The genetically modified NK cells express a protein complex having an α chain and a β chain T cell receptor, at least a portion of which is specific to a patient- or tumor-specific neoepitope, or a tumor associated antigen, and at least a portion of CD3δ, and at least a portion of CD3γ. The genetically modified NK cells can be administered to a cancer patient to induce, maintain or augment a T cell immune response against the cancer or the tumor.