Genetically Modified T Cell Generation Method
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Solution Overview
Problem
Current methods for generating genetically engineered T cells are inefficient, leading to contamination with modulatory agents and lentiviral vectors, which can cause adverse reactions and unwanted immune responses upon infusion, and require extensive processing time, often resulting in cytokine release syndrome and other severe side effects.
Innovation Solution
A method is developed to rapidly generate genetically modified T cells within 24-72 hours by removing modulatory agents and lentiviral vectors, using a process that includes polyclonal activation, genetic modification, and enzymatic removal of contaminants, allowing for in vivo expansion and reducing the risk of adverse reactions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If T cells are activated and genetically modified using conventional methods, then genetically modified T cells are produced, but the process takes extended time (often exceeding 144 hours) and results in contamination with modulatory agents and lentiviral vectors
Solution Approach 1:
The patent applies the extraction principle by removing modulatory agents and lentiviral vectors from the system at critical stages. Specifically, modulatory agents are removed after T cell activation (step f), and lentiviral vectors are removed after transduction (step g), resulting in purified genetically modified T cells free from contaminants that could cause adverse reactions.
Solution Approach 2:
The patent applies preliminary action by performing T cell activation and genetic modification in a streamlined sequence within a compressed timeframe. The method pre-plans the entire process to complete critical steps (activation, transduction, and cleanup) within 144 hours or less, eliminating unnecessary intermediate steps and optimizing the timeline for clinical application.
2Productivity
If modulatory agents and lentiviral vectors are not removed from the cell product, then the manufacturing process is simpler and faster, but severe adverse reactions occur upon infusion including cytokine release syndrome, fever, hypotension, organ failure and deaths
Solution Approach 1:
The patent converts the potentially harmful presence of modulatory agents and lentiviral vectors into a beneficial outcome by systematically removing them. The contaminants that would normally cause severe toxicity are eliminated through structured cleanup steps, transforming a harmful process into a safe therapeutic product while maintaining manufacturing efficiency.
Solution Approach 2:
The patent applies preliminary anti-action by proactively removing harmful substances before the cell product is administered to patients. Modulatory agents are removed after activation (step f) and lentiviral vectors are removed after transduction (step g), preventing potential adverse reactions before they can occur during infusion.
3Quantity of substance
If extensive in-vitro expansion is performed to reach therapeutic cell numbers, then sufficient cell dosage is achieved, but the processing time is extended and contamination risk increases
Solution Approach 1:
The patent applies partial action by performing minimal in-vitro expansion (less than 10-fold, preferably less than 5-fold) rather than extensive expansion. The method recognizes that moderate expansion combined with efficient in-vivo expansion after infusion can achieve therapeutic cell numbers without the time loss and contamination risk associated with prolonged in-vitro culture.
4Loss of time
If the manufacturing process is simplified and completed rapidly, then processing time is reduced, but the risk of contamination and insufficient cell quality may increase
Solution Approach 1:
The patent maintains continuity of useful action by implementing a streamlined yet comprehensive process that continuously progresses through activation, transduction, and cleanup steps without unnecessary interruptions. The method ensures that quality control measures (removal of modulatory agents and lentiviral vectors) are integrated into the continuous workflow, maintaining high reliability within a compressed 144-hour timeframe.
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 results in genetically modified T cells that can effectively target cancer cells with reduced toxicity and side effects, demonstrating robust antitumoral activity and improved safety profiles by minimizing in vitro expansion and contamination, thus enabling quicker antitumor responses.
Implementation Method 1
genetic modification of the activated T cells by transduction with lentiviral vector particles
Implementation Method 2
activation of the enriched T cells using modulatory agents
Data Source
AI summary
The present invention provides a method for the generation of genetically modified T cells comprising the steps a) a sample provided comprising T cells, b) preparation of said sample by centrifugation, c) enrichment of the T cells, d) activation of the T cells using modulatory agents, e) genetic modification of the T cells by transduction with lentiviral vector particles, f) removal of said modulatory agents, thereby generating a sample of genetically modified T cells, wherein said method is performed in equal or less than 144 hours, less than 120 hours, less than 96 hours, less than 72 hours, less than 48 hours, or less than 24 hours. In one embodiment of the invention said enrichment of T cells is performed by magnetic cell separation using magnetic particles that are directly or indirectly coupled to antibodies or antigen binding fragments thereof specific for CD4 and/or CD8 wherein said magnetic particles can be removed from the cells after separation.