FOXP1-Ablated Chimeric T Cells for Ovarian Cancer
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current immunotherapies face challenges in effectively targeting and eliminating ovarian cancer cells due to the immunosuppressive environment created by the upregulation of FOXP1 in T cells, which prevents CD8+ T cells from proliferating and activating in response to tumor antigens.
Innovation Solution
Non-viral methods are developed to ablate FOXP1 in T cells, allowing for the effective expression of chimeric receptors that redirect the effector activity of T cells against FSHR+ ovarian cancer cells. This involves site-specific insertion of transgenes using gene editing techniques like CRISPR to disrupt FOXP1 expression and activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If FOXP1 is upregulated in T cells to maintain immunosuppressive environment, then tumor growth is promoted, but T cell effector activity is suppressed
Solution Approach 1:
The patent extracts and removes the harmful FOXP1 transcription factor from T cells using CRISPR-Cas9 gene editing technology. By specifically targeting and ablating FOXP1 expression in adoptively transferred T cells, the invention eliminates the immunosuppressive mechanism while preserving the desired anti-tumor effector functions of the T cells.
Solution Approach 2:
The patent changes the expression level parameter of FOXP1 from high (immunosuppressive state) to low or absent (effector-active state) through genetic ablation. This parameter change transforms the T cells from an immunosuppressive phenotype to an activated effector phenotype capable of robust anti-tumor responses.
2Reliability
If CAR transgenes are inserted into T cells to enhance anti-tumor activity, then T cell killing capability is improved, but FOXP1-mediated suppression persists
Solution Approach 1:
The patent converts the harmful effect of FOXP1 into a beneficial outcome by using CRISPR-Cas9 to target and eliminate FOXP1. The same gene editing technology that could potentially cause unwanted modifications is instead harnessed to precisely remove the immunosuppressive FOXP1 factor, transforming a potential harm into a therapeutic benefit.
Solution Approach 2:
The patent performs preliminary ablation of FOXP1 in the adoptively transferred T cells before administering them to the patient. This pre-treatment ensures that the T cells are already primed and free from immunosuppressive mechanisms, allowing them to immediately exert robust anti-tumor effector activity upon encountering tumor cells.
3Productivity
If gene editing is used to ablate FOXP1, then T cell proliferation is enhanced, but genomic integrity risks increase
Solution Approach 1:
The patent uses the CRISPR-Cas9 system as an intermediary tool to achieve precise FOXP1 ablation. This molecular machinery acts as a mediator that can specifically recognize and cut the FOXP1 gene sequence, enabling controlled genomic modification without random integration events that could compromise genomic integrity.
Solution Approach 2:
The patent applies gene editing with high spatial precision, targeting only the specific FOXP1 gene locus while leaving the rest of the T cell genome intact. This localized modification approach ensures that only the necessary gene is altered, minimizing off-target effects and preserving overall genomic integrity while achieving the desired proliferative enhancement.
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 ablation of FOXP1 in CD8+ T cells enhances their proliferation and activation in response to tumor antigens, leading to improved anti-tumor immunity. Preliminary results show that FOXP1-deficient lymphocytes can induce rejection of incurable tumors and provide protection against tumor re-challenge, significantly delaying the progression of established orthotopic tumors.
Implementation Method 1
site-specific insertion of transgenes using gene editing techniques like CRISPR to disrupt FOXP1 expression and activity
Data Source
AI summary
Disclosed herein are non-viral methods to ablate FOXP1 in T cells while effectively expressing chimeric receptors. Therefore, disclosed herein is a chimeric cell expressing a chimeric receptor, wherein the chimeric receptor is encoded by a transgene, and wherein the transgene is inserted in the genome of the cell at a location that disrupts expression or activity of an endogenous FOXP1 protein.