CAR-T Cell Adduct Modification for Cytokine Release Syndrome Control
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Solution Overview
Problem
Current CAR-T cell therapies face challenges with cytokine release syndrome (CRS), a potentially lethal complication due to uncontrolled expansion and immune activation, particularly in patients with large tumor burdens, where severe CRS can lead to multiorgan system failure.
Innovation Solution
Introducing adducts into the genomic nucleic acids of CAR-T cell-derived effector cells to inhibit further division and proliferation, while maintaining immunologic function, thereby reducing the severity of cytokine release syndrome and ensuring targeted disease treatment.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CAR-T cells are expanded and activated to mediate clinical benefit, then antitumor efficacy is improved, but cytokine release syndrome severity increases
Solution Approach 1:
The patent applies preliminary action by introducing nucleic acid targeting compounds into CAR-T cells before infusion to pre-limit their proliferation capacity. This preventive measure ensures that while cells maintain full antitumor activity, they cannot undergo uncontrolled expansion that would trigger severe CRS, thus resolving the contradiction between efficacy and safety
Solution Approach 2:
The patent changes the proliferative parameter of CAR-T cells by introducing nucleic acid adducts that specifically inhibit cell division without affecting cytolytic function. This parameter modification allows cells to exert therapeutic effect while preventing the excessive proliferation that causes cytokine release syndrome
2Productivity
If high-levels of CAR-T cell expansion are achieved, then clinical benefit is improved, but cytokine release syndrome incidence increases
Solution Approach 1:
The patent applies partial action by allowing sufficient CAR-T cell expansion to achieve clinical benefit while intentionally limiting excessive expansion through nucleic acid targeting compounds. This controlled partial proliferation prevents CRS incidence while maintaining enough cell numbers for therapeutic effect
3Reliability
If CAR-T cells are infused to treat cancer, then disease treatment is achieved, but multiorgan system failure risk increases
Solution Approach 1:
The patent applies preliminary anti-action by pre-treating CAR-T cells with nucleic acid targeting compounds that counteract the potential for uncontrolled proliferation before infusion. This preemptive measure eliminates the root cause of multiorgan failure risk while preserving the cells' ability to treat cancer effectively
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 approach effectively limits CAR-T cell proliferation in vivo, reducing the severity of cytokine release syndrome and maintaining the cells' ability to target cancer cells, thus enhancing the safety and efficacy of CAR-T cell-based therapies.
Implementation Method 1
modifying the nucleic acid of the T cells in the expanded T cell population by reaction with a nucleic acid targeting compound that reacts directly with the nucleic acid
Implementation Method 2
the adducts are introduced with a frequency necessary to prevent cell division
Data Source
Figure 1A~1B
Figure 2
AI summary
The present invention relates to the preparation and use in recipients of CAR-T cell-derived effector cells which are modified to limit their proliferation within the recipient. This is accomplished through the introduction of adducts into the nucleic acids of CAR-T cell-derived effector cells following expansion in vitro to provide expanded and activated CAR-T cell-derived effector cells that retain immunologic function, including the expression of one ore more cytokines.