GM-CSF Knockout CAR-T Cells for Lower CRS Toxicity
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current chimeric antigen receptor T cell (CART) therapies for cancer, such as CART19, are limited by cytokine release syndrome (CRS) and neurotoxicity, and have efficacy restricted to 40-60% durable remissions in lymphoma and leukemia.
Innovation Solution
Engineering T cells to have reduced expression of GM-CSF through gene knockout or knockdown using CRISPR/Cas9 technology, combined with anti-GM-CSF antibodies, to enhance anti-tumor efficacy and reduce therapy-related toxicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CART cells are administered to treat cancer, then anti-tumor efficacy is improved, but cytokine release syndrome and neurotoxicity occur due to cytokine expression
Solution Approach 1:
The patent extracts and removes the harmful cytokine GM-CSF from the CART cell system through gene knockout technology, while preserving the therapeutic anti-tumor functions. This is achieved by using CRISPR/Cas9 or other gene editing methods to specifically eliminate GM-CSF expression in CART cells, thereby resolving the contradiction between maintaining anti-tumor efficacy and eliminating cytokine release syndrome.
Solution Approach 2:
The patent changes the expression parameter of GM-CSF from normal levels to reduced or eliminated levels in CART cells. By modifying the GM-CSF expression parameter through genetic engineering, the therapy maintains effectiveness against tumors while reducing the harmful cytokine release that causes CRS and neurotoxicity.
2Object-affected harmful factors
If CART cells are engineered to reduce cytokine expression, then toxicity is reduced, but anti-tumor efficacy may be compromised
Solution Approach 1:
The patent selectively extracts only the harmful GM-CSF cytokine from the CART cell repertoire, preserving other beneficial cytokines and immune functions. This selective removal approach ensures that anti-tumor efficacy is maintained while specifically eliminating the toxicity associated with GM-CSF overexpression.
Solution Approach 2:
The patent applies local quality modification by specifically targeting GM-CSF expression for reduction while leaving other cytokine expression profiles intact. This localized genetic modification allows different parts of the immune response to have different expression levels, maintaining overall therapeutic effectiveness while eliminating specific harmful effects.
3Object-affected harmful factors
If gene knockout technology is used to reduce cytokine expression, then manufacturing complexity increases, but toxicity is reduced
Solution Approach 1:
The patent replaces traditional mechanical or chemical methods of cytokine suppression with genetic engineering approaches. By using gene knockout technology integrated into the CART cell manufacturing process, the system achieves permanent, inherent reduction of GM-CSF expression rather than requiring external suppression mechanisms, thereby reducing long-term manufacturing complexity.
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
GM-CSF knockout CART cells demonstrate enhanced proliferation, anti-tumor activity, and reduced CRS and neurotoxicity, achieving more durable disease control in leukemia models and improved therapeutic windows.
Implementation Method 1
a nucleic acid encoding a guide RNA, wherein the guide RNA is complementary to a GM-CSF messenger RNA
Implementation Method 2
GM-CSF gene inactivation, GM-CSF gene knock-down or gene knockout (GM-CSFk/o CAR-T cells)
Data Source
AI summary
This document provides methods and materials involved in treating cancer. For example, chimeric antigen receptor T cells having reduced levels of GM-CSF are provided. Also provided as methods for making and using chimeric antigen receptor T cells having reduced levels of GM-CSF.