Universal CAR-T Cells Knocking Out TCR and HLA-A for Neuroblastoma
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Solution Overview
Problem
Current CAR-T cell therapies face challenges in expanding autologous T cells in vitro, leading to insufficient or poor-quality products, and allogeneic universal CAR-T cells are prone to graft versus host disease (GVHD) and immune rejection, limiting their effectiveness and applicability in treating neuroblastoma and glioma.
Innovation Solution
Development of a universal CAR-T cell that knocks out TCR and HLA-A genes to enhance anti-tumor efficacy, prolong cell survival, and reduce immune rejection, equipped with a chimeric antigen receptor (CAR) targeting GD2, utilizing a CRISPR/Cas9 system for gene editing and modification.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If autologous T cells are used for CAR-T cell therapy, then the product is specific to the patient, but the T cells have difficulty expanding in vitro resulting in insufficient amount or poor quality
Solution Approach 1:
The patent uses allogeneic universal CAR-T cells instead of autologous T cells, allowing a single donor's T cells to be used for multiple patients. This universal approach enables high amplification efficiency while maintaining therapeutic effectiveness across different patients, resolving the contradiction between patient specificity and productivity.
2Productivity
If universal CAR-T cells are used, then amplification efficiency and activity are improved, but graft versus host disease and immune rejection occur
Solution Approach 1:
The patent removes the TCR (T cell receptor) from the CAR-T cells through gene editing. By taking out the TCR component, the cells lose their ability to recognize endogenous antigens and present MHC molecules, thereby eliminating graft versus host disease and immune rejection while preserving the CAR-mediated anti-tumor activity.
Solution Approach 2:
The patent changes the immunological parameters of the CAR-T cells by knocking out TCR and HLA-A genes. This parameter change transforms the cells from being immunologically active (prone to rejection) to immunologically inert (resistant to rejection), while maintaining their tumor-targeting capability through the CAR.
3Duration of action of stationary object
If TCR and HLA-A genes are knocked out, then immune rejection is reduced and cell survival is prolonged, but the complexity of cell preparation increases
Solution Approach 1:
The patent performs gene editing (TCR and HLA-A knockout) during the initial cell preparation phase before the CAR-T cells are activated and expanded. This preliminary action ensures that the cells are already modified for long-term survival and reduced rejection before they are administered, avoiding the need for complex post-preparation modifications.
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 modified universal CAR-T cells demonstrate improved amplification efficiency, reduced immune rejection, and enhanced anti-tumor activity, offering a promising therapeutic approach for neuroblastoma and glioma with reduced preparation costs and time.
Implementation Method 1
The CRISPR/Cas9 system is the most commonly used gene editing method, and can be used for producing T cells with TCR deficiency and HLA class I molecule deficiency
Data Source
AI summary
A modified immune effector cell may be one in which the functions of a T cell antigen receptor (TCR) and major histocompatibility complexes (MHCI, MHCII) in the modified immune effector cell are inhibited in a T cell. Such a modified immune effector cell may include a chimeric antigen receptor (CAR) targeting GD2. Such a modified immune effector cell may knock out TCR and HLA-A genes expressed by the cell while recognizing surface antigens of tumor cells, so that multiple effects of improving the anti-tumor effect of CAR-T cells, prolonging the survival time of the cells, and reducing the immune rejection response caused by allogeneic cell therapy may be reduced.