Immune Cell Gene Integration for Cytokine Release Syndrome
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Solution Overview
Problem
Current methods for engineering primary immune cells, such as CAR T-cells, face challenges including cytokine release syndrome (CRS), immune cell exhaustion, and limited lifespan, which hinder their therapeutic efficacy and safety.
Innovation Solution
The method involves genetically engineering immune cells to express soluble polypeptides that interfere with pro-inflammatory cytokine pathways, using sequence-specific endonuclease reagents for targeted gene editing, and integrating exogenous sequences under the control of endogenous promoters to enhance therapeutic potential and safety.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If primary immune cells are engineered to enhance therapeutic potential, then therapeutic efficacy is improved, but risk of cytokine release syndrome increases
Solution Approach 1:
The patent introduces soluble polypeptides as intermediary molecules that mediate between the immune cells and the cytokine environment. These polypeptides bind to pro-inflammatory cytokines (IL-1, IL-6, IL-18) and prevent them from acting on their receptors, thereby reducing CRS risk while preserving therapeutic efficacy. The soluble polypeptides act as a buffer that absorbs excess cytokine activity without compromising the immune cells' ability to fight cancer.
Solution Approach 2:
The patent converts the harmful pro-inflammatory cytokine signaling into a beneficial controlled response. By expressing soluble polypeptides that bind to these cytokines, the immune cells harness the cytokine environment to enhance their anti-tumor activity while simultaneously neutralizing the harmful effects. The cytokines that would normally cause CRS are redirected to serve the therapeutic purpose of activating immune cells against tumors.
2Reliability
If immune cells are engineered to improve functionality, then therapeutic potential is enhanced, but cell lifespan is reduced
Solution Approach 1:
The patent modifies the cellular parameters by introducing exogenous coding sequences that encode soluble polypeptides. These genetic modifications change the protein expression profile of the immune cells, enabling them to produce cytokine-neutralizing polypeptides. This parameter change in protein synthesis capability extends cell lifespan by reducing cytokine-induced exhaustion and maintaining functional activity over longer periods.
Solution Approach 2:
The patent performs preliminary gene editing before the immune cells are deployed to the tumor site. By pre-introducing the exogenous coding sequences under the control of endogenous promoters, the cells are prepared in advance to produce protective soluble polypeptides. This preliminary genetic modification ensures that when the cells encounter the tumor microenvironment, they immediately begin producing cytokine-neutralizing factors that extend their lifespan and maintain functionality.
3Reliability
If exogenous coding sequences are integrated into immune cells, then therapeutic potential is improved, but cell exhaustion increases
Solution Approach 1:
The soluble polypeptides encoded by the exogenous sequences serve as intermediary protective factors. These polypeptides bind to pro-inflammatory cytokines and prevent them from activating exhaustion pathways in the immune cells. By intercepting the harmful cytokine signals before they can cause cell exhaustion, the soluble polypeptides maintain the functional capacity of the engineered immune cells over time.
Solution Approach 2:
The patent converts the potentially harmful effect of cytokine overactivation into a beneficial protective mechanism. The exogenous coding sequences enable the cells to produce soluble polypeptides that neutralize excessive cytokine activity. This transforms the cytokine environment from a source of exhaustion into a controlled stimulus that enhances therapeutic potential while preventing cell fatigue.
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
This approach reduces the risk of CRS, enhances the lifespan and persistence of engineered immune cells, and improves their therapeutic potential by limiting cell exhaustion, thereby making them safer and more effective for cell therapy.
Implementation Method 1
sequence-specific endonuclease reagents and donor DNA vectors, such as AAV vectors, to perform such targeted insertions at said particular loci
Implementation Method 2
The soluble polypeptides are preferably not antibodies, to avoid immune rejection, but human polypeptides, such as soluble GP130, IL18-BP and soluble IL6Ra. These soluble polypeptides are encoded by exogenous coding sequences that are preferably inserted into the genome under transcriptional control of endogenous gene promoters
Implementation Method 3
expressing or over expressing soluble polypeptides that interfere with pro-inflammatory cytokine pathways, such as those involving interleukins IL1, IL6 and IL18
Data Source
AI summary
The invention pertains to the field of adaptive cell immunotherapy. It provides with the genetic insertion of exogenous coding sequence(s) into genetically engineered immune cells to prevent cytokine release syndrome to arise during the course of cell therapy. These exogenous coding sequences are more particularly soluble human polypeptides placed under the transcriptional control of endogenous gene promoters that are sensitive to immune cells activation. Such method allows the production of safer immune primary cells of higher therapeutic potential.