Genome-Edited CAR-T Cells for Malignancy Treatment
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Solution Overview
Problem
Current CAR-T cell therapy is limited by inefficiencies in production, high costs, and challenges in targeting T cell malignancies due to shared antigen expression, leading to fratricide and allogenic reactivity issues.
Innovation Solution
A method of producing genome-edited CAR-T cells by first editing the genome of T cells and then activating them, allowing for efficient expansion of the edited cell population, which can be used for immunotherapy in treating T and B cell malignancies.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If T cells are activated before genome editing, then T cell proliferation and expansion occur, but genome editing efficiency decreases and off-target effects increase
Solution Approach 1:
The patent applies preliminary action by performing genome editing on T cells before activation rather than after. This sequence ensures that editing occurs when cells are in a more receptive state, improving editing efficiency while maintaining safety. The method establishes the genetic modification in quiescent or minimally activated cells, then subsequently activates and expands the edited population, thereby resolving the contradiction between editing efficiency and off-target effects.
2Reliability
If CAR-T cells are produced using conventional methods, then therapeutic efficacy is achieved, but production time and cost increase significantly
Solution Approach 1:
The patent applies preliminary action by pre-editing T cells with desired characteristics (such as TCR knockout or other genetic modifications) before activation and expansion. This preliminary genetic setup allows for more efficient subsequent processing and faster production of therapeutic CAR-T cells while maintaining efficacy, directly addressing the time loss issue in conventional production methods.
Solution Approach 2:
The patent utilizes parameter changes by modifying key cellular parameters through genome editing (such as knocking out TCR to prevent fratricide, or adjusting activation thresholds). These parameter changes enable more efficient cell processing, faster expansion, and reduced production time while preserving or enhancing therapeutic efficacy against malignancies.
3Adaptability or versatility
If T cells expressing target antigens are used for CAR-T therapy, then broad antigen recognition is achieved, but fratricide of CAR-T cells occurs
Solution Approach 1:
The patent applies the extraction principle by removing the harmful capability from CAR-T cells through genome editing. Specifically, the TCR alpha chain gene (TRAC) is knocked out to eliminate endogenous T cell receptor function, thereby preventing fratricide while preserving CAR-mediated antigen recognition. This selective removal of the harmful component (endogenous TCR) while maintaining the useful function (CAR recognition) resolves the contradiction between broad antigen recognition and fratricide prevention.
Solution Approach 2:
The patent applies local quality by creating heterogeneity in the T cell population through targeted genome editing. Different T cell subsets receive specific genetic modifications (such as TCR knockout in some cells while preserving CAR expression), allowing certain cells to recognize antigens broadly without suffering from fratricide. This localized genetic modification approach enables different functional qualities within the same cell population.
4Productivity
If allogeneic T cells are used in CAR-T therapy, then cell availability increases, but allogenic reactivity and graft-versus-host disease occur
Solution Approach 1:
The patent applies extraction by removing the components responsible for allogenic reactivity through genome editing. TCR knockout eliminates the primary mechanism for recognizing foreign MHC molecules, thereby preventing graft-versus-host disease and allogenic rejection. This selective removal allows allogeneic T cells to be used as CAR-T sources without the harmful reactivity, directly resolving the contradiction between cell availability and safety.
Solution Approach 2:
The patent utilizes parameter changes by fundamentally altering the immunogenic parameters of allogeneic T cells through genetic modification. By knocking out TCR and potentially other immunogenic elements, the cells' ability to recognize foreign antigens is changed, reducing allogenic reactivity while maintaining their effector functions against tumor antigens via CAR. This parameter modification enables safe use of allogeneic cells with improved availability.
Data Source
AI summary
Disclosed herein are methods of genome-editing and transduction of T cells and methods of immunotherapy in using them. In particular, the disclosure relates to engineered chimeric antigen receptor (CAR)-bearing T cells and methods of using the same for the treatment of cancer.