Modified NK Cells EP2 EP4 Knockout Metastasis
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Solution Overview
Problem
Current NK cell-based immunotherapies for treating metastatic cancer show limited success due to suppressive mechanisms developed by metastatic cancer cells, including the downregulation of tumor recognition molecules and the production of immunomodulatory molecules like prostaglandin E2 (PGE2) that suppress NK cell function.
Innovation Solution
Modified NK cells and T cells with selectively inhibited or eliminated expression and activity of prostaglandin E receptor 2 (EP2) and prostaglandin E receptor 4 (EP4) are used for the treatment and prevention of metastatic disease and cancer. These modified immune cells are generated by genetic modification or pharmacological inhibition to evade PGE2-mediated suppression.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If NK cell-based immunotherapies are used to treat metastatic cancer, then anti-metastatic activity is improved, but NK cell function is suppressed by PGE2 produced by cancer cells
Solution Approach 1:
The patent extracts and removes the EP2 and EP4 receptors from NK cells through genetic modification (knockout), eliminating the targets for PGE2 signaling. This allows NK cells to function independently of PGE2 suppression while maintaining their anti-metastatic activity, directly resolving the contradiction between therapeutic effectiveness and immune suppression.
Solution Approach 2:
The patent changes the receptor expression profile of NK cells by modifying the genetic parameters to delete EP2 and EP4 receptors. This parameter change in cell surface receptor composition prevents PGE2 from binding and suppressing NK cell function, thereby maintaining anti-metastatic activity in the presence of tumor-produced PGE2.
2Object-affected harmful factors
If EP2 and EP4 receptors are blocked in NK cells, then PGE2-mediated suppression is overcome, but cell function may be affected
Solution Approach 1:
The patent converts the harmful effect of PGE2 signaling into a benefit by selectively removing EP2 and EP4 receptors. This eliminates the suppressive pathway while preserving other essential NK cell functions through alternative signaling mechanisms, transforming a vulnerability into a selective advantage against PGE2 suppression.
Solution Approach 2:
The patent applies local quality modification by selectively deleting EP2 and EP4 receptors while maintaining other receptor and functional properties of NK cells. This localized genetic modification at the receptor level allows specific resistance to PGE2 suppression without compromising overall cellular functionality or anti-metastatic capability.
3Ease of manufacture
If conventional NK cells are used, then ease of generation is maintained, but limited success is achieved in treating metastasis
Solution Approach 1:
The patent applies preliminary action by performing genetic modification of NK cells ex vivo before administration to patients. NK cells are pre-engineered to lack EP2 and EP4 receptors in the laboratory, ensuring they are ready to resist PGE2 suppression upon encountering tumor cells in vivo, thereby improving treatment efficacy while maintaining a relatively simple generation process.
Data Source
AI summary
The present invention relates to modified immune cells, in particular modified NK cells and T cells and tumor-infiltrating lymphocytes (TILs). The present invention relates to the modified NK cells and T cells and TILs for use in the treatment and/or prevention of cancer, in particular in the treatment and/or prevention of metastases. The present invention further relates to a method of generating modified NK cells or T cells or TILs. The present invention further relates to compositions comprising said modified immune cells.