Urease-Mediated pH Normalization for Tumor-Infiltrating T Cells
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Solution Overview
Problem
Solid tumors create an acidic microenvironment that suppresses T cell function, leading to reduced cytokine release and immune tolerance, hindering effective immune responses against cancer cells.
Innovation Solution
Administering urease to acidified T cells to increase pH levels and reduce PD-L1 and PD-1 expression, thereby restoring T cell function and enhancing cytokine production, which can be conjugated to a targeting moiety like an antibody specific for CEACAM6 to specifically target tumor cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If T cells infiltrate solid tumors, then immune response against cancer cells is enhanced, but T cell function is suppressed due to acidic microenvironment
Solution Approach 1:
The patent utilizes the acidic microenvironment, which normally suppresses T cell function, as a targeting mechanism. The acidic conditions trigger the conversion of prodrugs or activation of pH-sensitive delivery systems that specifically release therapeutic agents at the tumor site, converting the harmful acidic environment into a beneficial targeting feature for restoring T cell function
Solution Approach 2:
The patent employs pH-sensitive parameters to control T cell function restoration. By designing delivery systems that respond to pH changes (lower pH in tumor microenvironment), the system selectively activates immunomodulatory agents only in acidic tumor regions, thereby restoring T cell function where it is most needed without affecting systemic immune cells
2Productivity
If cytokine release is increased to enhance immune response, then anti-tumor activity is improved, but immune tolerance is reduced leading to potential autoimmune effects
Solution Approach 1:
The patent applies local quality by directing cytokine production enhancement specifically to the tumor microenvironment rather than systemically. pH-sensitive delivery systems release immunomodulatory agents locally at the acidic tumor site, stimulating cytokine release from T cells precisely where needed, thereby enhancing anti-tumor activity while maintaining immune tolerance in healthy tissues
Solution Approach 2:
The patent uses pH-sensitive delivery systems and tumor microenvironment as intermediaries to mediate between the administered agents and T cells. These intermediaries selectively transport and release cytokines or immunomodulatory compounds only in the acidic tumor environment, enabling controlled enhancement of cytokine production without triggering systemic autoimmune responses
3Reliability
If PD-L1 expression is reduced on tumor cells to enhance T cell activation, then immune response is improved, but tumor cell survival mechanisms are activated
Solution Approach 1:
The patent employs preliminary action by using pH-sensitive delivery systems to pre-condition the tumor microenvironment before direct T cell engagement. The acidic environment triggers premature activation or degradation of PD-L1 on tumor cells prior to T cell contact, thereby enhancing T cell activation while the controlled local delivery prevents activation of broad tumor survival mechanisms
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 method effectively reactivates T cells by increasing IL-2 production and restoring their ability to infiltrate tumors, improving immune responses against cancer cells by normalizing cytokine release and reducing immune tolerance.
Implementation Method 1
Administering urease to acidified T cells to increase pH levels
Implementation Method 2
Administering urease to acidified T cells to increase pH levels and reduce PD-L1 and PD-1 expression
Data Source
AI summary
Methods and compositions to restore function to acidified T cells are provided. The methods comprise administering urease to the T cells. Compositions comprise urease.