CAR-NK Cell DNA Crosslinking to Limit Post-Infusion Proliferation
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Existing CAR-NK cell therapies face safety concerns such as on-target/off-tumor effects, graft-versus-host-disease, cytokine release syndrome, and toxicity to normal tissues, necessitating improved methods and compositions for safer administration.
Innovation Solution
Introduce interstrand crosslinks and/or adducts into the genomic nucleic acids of CAR-NK cells through reaction with a nucleic acid targeting compound to inhibit further division while maintaining immunologic function, using compounds like psoralen activated by UVA irradiation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If CAR-NK cells are expanded in vitro to increase therapeutic dosage, then the quantity of cells increases, but the risk of uncontrolled proliferation and off-target effects in the recipient increases
Solution Approach 1:
The patent applies preliminary action by introducing nucleic acid targeting compounds (such as psoralen) and UV irradiation to the CAR-NK cells before administration to the recipient. This pre-treatment creates DNA crosslinks and adducts that permanently inhibit cell division, ensuring that the cells cannot proliferate uncontrollably after infusion. The harmful proliferation risk is addressed in advance, allowing safe expansion to therapeutic dosages without compromising safety.
2Reliability
If nucleic acid targeting compounds are introduced to inhibit cell proliferation, then safety against uncontrolled division improves, but the ability of cells to divide and expand therapeutically is reduced
Solution Approach 1:
The patent applies local quality by differentiating between two functional requirements: therapeutic expansion (which requires proliferation) and long-term safety (which requires proliferation inhibition). The nucleic acid targeting compounds are introduced at controlled levels and timings to achieve local quality control - allowing sufficient cell expansion to reach therapeutic dosages while simultaneously establishing permanent proliferation limits. This creates a spatial and temporal distinction between the expansion phase and the safety enforcement phase.
Solution Approach 2:
The patent applies parameter changes by carefully controlling the concentration, timing, and type of nucleic acid targeting compounds (such as psoralen) to modulate the degree of DNA modification. By adjusting these parameters, the invention achieves an optimal balance where enough cells are generated for therapeutic effect while sufficient DNA crosslinks are formed to prevent future uncontrolled proliferation. The parameters of compound concentration, UV irradiation dose, and treatment timing are optimized to simultaneously satisfy both productivity and safety requirements.
3Reliability
If CAR-NK cells are activated to enhance cytotoxic function, then efficacy against target cells improves, but the risk of cytokine release syndrome and GVHD increases
Solution Approach 1:
The patent applies preliminary action by introducing nucleic acid targeting compounds (such as psoralen) and UV irradiation to the CAR-NK cells before administration to the recipient. This pre-treatment creates DNA crosslinks and adducts that permanently inhibit cell division, ensuring that the cells cannot proliferate uncontrollably after infusion. The harmful proliferation risk is addressed in advance, allowing safe expansion to therapeutic dosages without compromising safety.
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 modified CAR-NK cells effectively target and destroy cancer cells or viral-infected cells with reduced proliferation, minimizing off-target effects and toxicity, thereby enhancing safety and efficacy of the therapy.
Implementation Method 1
using compounds like psoralen activated by UVA irradiation
Data Source
AI summary
The present disclosure relates to the preparation and use of CAR-NK cells which are modified by a nucleic acid targeting compound.