TALE-nuclease T-cell Gene Editing for Immunotherapy
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Solution Overview
Problem
Current immunotherapy approaches face challenges in effectively activating T-cells for cancer treatment due to immune checkpoint proteins, which limit T-cell activity and are associated with adverse events when using antibody treatments, and there is a need for more efficient methods to inactivate multiple immune checkpoint genes in T-cells for enhanced therapeutic efficacy.
Innovation Solution
The use of specific TALE-nucleases to precisely target and inactivate multiple immune checkpoint genes, such as PD1 and CTLA-4, in T-cells, allowing for the generation of highly active T-cells that can be used for immunotherapy by introducing rare-cutting endonucleases to create double mutants, thereby enhancing T-cell activity and reducing adverse events.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If antibody treatments are used to block immune checkpoints, then T-cell activity is improved, but adverse events increase
Solution Approach 1:
The patent extracts the immune checkpoint proteins (PD-1, CTLA-4) from the T-cell surface by using TALE-nucleases to create double-strand breaks in their encoding genes. This permanent genetic modification removes the harmful inhibitory molecules from the T-cell, eliminating the need for external antibody treatments and their associated adverse events while maintaining enhanced T-cell activity.
Solution Approach 2:
The patent performs preliminary genetic modification of T-cells ex vivo by introducing TALE-nucleases that target and inactivate immune checkpoint genes before the T-cells are deployed for therapy. This preliminary action of gene inactivation prevents the harmful effects of immune checkpoints from manifesting during therapy, avoiding adverse events while preserving T-cell functionality.
2Reliability
If multiple immune checkpoint genes are inactivated in T-cells, then T-cell activity is enhanced, but the complexity of genetic modification increases
Solution Approach 1:
The patent merges the functions of multiple TALE-nucleases into a single delivery system using lentiviral vectors. Each vector construct contains the TALE-nuclease protein and its corresponding guide RNA, allowing simultaneous targeting of multiple genes (PD-1 and CTLA-4) through a unified genetic modification approach rather than separate procedures.
Solution Approach 2:
The patent uses lentiviral vectors as intermediaries to deliver TALE-nucleases and guide RNAs into T-cells. This intermediary system simplifies the genetic modification process by providing a standardized, efficient method for introducing multiple gene-targeting components simultaneously, reducing the overall complexity compared to direct gene editing approaches.
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
This method enables the production of highly active T-cells that can effectively target tumor cells or infected cells, potentially leading to improved cancer treatment outcomes with reduced adverse effects by specifically modifying T-cells to inactivate immune checkpoint genes, enhancing their therapeutic potential for immunotherapy.
Implementation Method 1
The use of specific rare cutting endonucleases, in particular TALE-nucleases (TAL effector endonuclease), to precisely target a selection of key genes in T-cells
Data Source
AI summary
The present invention relates to methods for developing engineered T-cells for immunotherapy and more specifically to methods for modifying T-cells by inactivating at immune checkpoint genes, preferably at least two selected from different pathways, to increase T-cell immune activity. This method involves the use of specific rare cutting endonucleases, in particular TALE-nucleases (TAL effector endonuclease) and polynucleotides encoding such polypeptides, to precisely target a selection of key genes in T-cells, which are available from donors or from culture of primary cells. The invention opens the way to highly efficient adoptive immunotherapy strategies for treating cancer and viral infections.