Disrupting PTGIR in CD8 T-Cells to Resist Prostanoid Suppression
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Solution Overview
Problem
Current cancer treatments, such as chemotherapy, can become ineffective, and existing immunotherapy methods face challenges in enhancing the efficacy of immune cells against cancer, particularly due to immune checkpoint suppression and side effects from adoptive cell therapies.
Innovation Solution
Genetic modification of CD8 T-cells to disrupt the expression of the prostacyclin receptor (PTGIR) gene, using methods such as introducing interfering RNA, CRISPR systems, or knocking out the PTGIR gene, to enhance anti-tumor immune responses.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If adoptive cell therapy is used to treat cancer, then anti-tumor immune response is enhanced, but undesirable side effects occur and immune checkpoint suppression reduces effectiveness
Solution Approach 1:
The patent extracts and removes the PTGIR gene from CD8 T-cells through genetic modification methods (CRISPR/Cas9, shRNA, or other gene editing techniques). This extraction eliminates the prostacyclin receptor that mediates harmful immunosuppressive effects, thereby removing the source of undesirable side effects while preserving anti-tumor activity. The modified T-cells without PTGIR expression can effectively attack tumors without being suppressed by prostacyclin signaling.
Solution Approach 2:
The patent changes the genetic parameter of CD8 T-cells by modifying their gene expression profile - specifically reducing or eliminating PTGIR gene expression. This parameter change (from normal PTGIR expression to reduced/absent expression) fundamentally alters the cellular response to prostacyclin, transforming the cells from being immunosuppressed to being resistant, thereby improving reliability while reducing harmful effects.
2Reliability
If PTGIR expression is disrupted in CD8 T-cells, then anti-tumor response is improved, but the complexity of genetic modification procedures increases
Solution Approach 1:
The patent applies preliminary action by performing genetic modification of CD8 T-cells ex vivo before administration to the patient. The T-cells are collected, genetically modified to reduce PTGIR expression, expanded, and then re-infused. This preliminary modification ensures that the cells arrive at the tumor site already prepared to resist prostacyclin suppression, avoiding the need for complex in vivo modification approaches.
Solution Approach 2:
The patent uses an intermediary approach by employing established genetic modification tools (such as viral vectors, CRISPR components, or other delivery mechanisms) as intermediaries to transfer the gene editing function into T-cells. These intermediaries simplify the overall process by providing a standardized, controllable method to achieve PTGIR reduction without requiring direct manipulation of the cells in complex ways.
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 disruption of PTGIR expression in CD8 T-cells improves anti-tumor T-cell responses, enhances antigen-specific T-cell expansion, and increases the levels of functional immune cells, leading to more effective cancer treatment.
Implementation Method 1
the expression of PTGIR is disrupted by introducing an interfering RNA or trigger RNA into the CD8 T-cells
Implementation Method 2
the expression of PTGIR is disrupted with a CRISPR system
Data Source
AI summary
A composition includes genetically modified leukocytes, the modification including a deleted or silenced prostacyclin receptor PTGIR that confers resistance to the immunosuppressive effects of prostanoids.