Genetically Modified Cells for NK-Mediated Immune Evasion
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Solution Overview
Problem
The primary challenge in allogeneic cellular therapies is the host immune response against transplanted cells, leading to rejection and potential adverse reactions, which current strategies like immunosuppressive drugs and donor-recipient matching fail to adequately address, limiting therapeutic efficacy.
Innovation Solution
Genetically modified cells engineered to express specific genes such as CLEC2D, TRAIL, and SERPINB9, or variants thereof, to inhibit natural killer cell cytotoxicity, combined with modifications like B2M gene attenuation, enhancing immune evasion and cell survival.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If allogeneic cells are transplanted to treat disease, then therapeutic benefit is provided, but host immune response causes cell rejection and adverse reactions
Solution Approach 1:
The patent converts the harmful immune response into a beneficial outcome by engineering cells to express immune evasion molecules. The engineered cells express proteins like CLEC2D, SERPINB9, and TRAIL that actively suppress natural killer cell cytotoxicity and modulate immune responses, transforming the previously harmful immune system into a protective mechanism that enables allogeneic cell survival and therapeutic efficacy without requiring immunosuppressive drugs
Solution Approach 2:
The patent changes the biological parameters of the transplanted cells by genetically modifying them to express specific proteins that alter immune cell recognition and interaction. By modifying expression levels of immune evasion molecules and adjusting cell surface protein profiles, the cells acquire enhanced resistance to immune attack while maintaining their therapeutic function, resolving the contradiction between immune recognition and therapeutic efficacy
2Duration of action of stationary object
If immunosuppressive drugs are used to prevent rejection, then cell survival improves, but side effects and complications increase
Solution Approach 1:
The patent enables the transplanted cells to self-protect against immune rejection through genetic engineering. The engineered cells autonomously express immune evasion molecules such as CLEC2D, SERPINB9, and TRAIL that actively suppress natural killer cell cytotoxicity and modulate immune responses, eliminating the need for external immunosuppressive drugs and their associated side effects while maintaining prolonged cell survival and therapeutic efficacy
3Object-affected harmful factors
If donor-recipient matching is performed to reduce immune response, then rejection risk decreases, but treatment complexity and time increase
Solution Approach 1:
The patent extracts the immune recognition problem from the donor-recipient matching equation by engineering cells to express universal immune evasion molecules. This approach removes the need for complex HLA matching procedures by equipping all engineered cells with intrinsic protection against immune attack through expressed proteins like CLEC2D, SERPINB9, and TRAIL, simplifying the therapeutic process while maintaining immunoprotection
Data Source
AI summary
This disclosure provides methods and populations of cells, engineered to modulate the expression of select genes and thereby reduce natural killer cell mediated cytotoxicity. For example, this disclosure provides engineered cells equipped with one or more heterologous nucleic acid sequences encoding polypeptides that, when expressed, impede the typical cytotoxicity of natural killer cells as compared to comparable cell devoid of heterologous nucleic acid sequence.