Engineered CAR T Cells Without CD38/CD70/CS1 Self-Recognition
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Solution Overview
Problem
Current adoptive immunotherapy using autologous T cells is hindered by technical and logistic challenges, including the need for expensive facilities, expert personnel, and variable efficacy and safety, while allogeneic cell therapies face rejection and graft versus host disease issues due to antigen markers like CD38, CD70, and CS1 also expressed on T cells.
Innovation Solution
Genetically engineer T cells with a transcription activator-like effector (TALE)-nuclease to inactivate CD38, CD70, and CS1 genes, creating allogeneic T cells with chimeric antigen receptors (CARs) that target these markers, reducing self-recognition and enabling standardized, off-the-shelf therapies.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If allogeneic T cells are used for immunotherapy, then standardized and affordable treatment is achieved, but host versus graft rejection and graft versus host disease occur due to antigen markers like CD38, CD70, and CS1 expressed on T cells
Solution Approach 1:
The patent extracts and removes the problematic antigen markers (CD38, CD70, CS1) from the T cell surface through genetic modification. By specifically deleting the genes encoding these antigens, the T cells retain their therapeutic function while eliminating the molecules that cause host versus graft rejection and graft versus host disease, enabling safe allogeneic cell therapy production.
Solution Approach 2:
The patent changes the genetic parameters of the T cells by inactivating specific genes (CD38, CD70, CS1) through homology-directed repair. This genetic parameter modification alters the antigen expression profile of the T cells, making them compatible for allogeneic transplantation while maintaining their immunotherapeutic capabilities.
2Manufacturing precision
If T cells express CARs targeting antigens also present on immune cells, then targeting capability is improved, but self-recognition and mutual destruction of T cells occur
Solution Approach 1:
The patent applies local quality modification by selectively removing specific antigen markers (CD38, CD70, CS1) from the T cell surface while preserving other necessary surface molecules. This localized genetic modification ensures that the T cells do not recognize and attack themselves or other immune cells expressing these same antigens, preventing autoimmunity and mutual destruction.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The engineered T cells can effectively target pathological cells without self-destruction, offering a standardized, safe, and efficient treatment for cancer, infections, and autoimmune diseases.
Implementation Method 1
a transcription activator-like effector (TALE)-nuclease able to target said gene
Data Source
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AI summary
Methods of developing genetically engineered immune cells for immunotherapy, which can be endowed with Chimeric Antigen Receptors targeting an antigen marker that is common to both the pathological cells and said immune cells (ex: CD38, CS1 or CD70) by the fact that the genes encoding said markers are inactivated in said immune cells by a rare cutting endonuclease such as TALEN, Cas9 or argonaute.