LiquidTME cfDNA Methylation for TIL Detection
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Solution Overview
Problem
Current methods for assessing immunotherapy response in cancer patients are invasive, unreliable, and lack sensitivity, particularly in detecting tumor infiltrating leukocytes (TILs) in the tumor microenvironment, which are critical for predicting treatment outcomes.
Innovation Solution
A non-invasive liquid biopsy approach called LiquidTME, utilizing methylation sequencing of plasma-derived cell-free DNA to detect and quantify TILs through ultra-high-resolution digital cytometry, enabling early prediction of immunotherapy response by analyzing co-associated CpG methylation patterns and methylation haplotype blocks.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If invasive biopsy methods are used to assess immunotherapy response, then reliability of assessment is improved, but ease of operation deteriorates and loss of time increases
Solution Approach 1:
The patent uses cell-free DNA as an intermediary substance that carries methylation signatures from tumor infiltrating leukocytes. Instead of directly accessing TILs through invasive biopsy, the method extracts and analyzes cfDNA from blood samples, which contain methylation patterns that serve as proxies for TIL presence and state, thereby maintaining reliability while eliminating surgical intervention
Solution Approach 2:
The patent replaces the mechanical/surgical biopsy system with a biochemical analysis system. Instead of physically removing tissue through surgical instruments, the method uses chemical extraction of DNA from blood plasma followed by methylation sequencing, substituting mechanical invasion with non-invasive liquid biopsy chemistry
2Ease of operation
If current methods are used to detect TILs, then ease of operation is maintained, but measurement precision deteriorates
Solution Approach 1:
The patent changes the detection parameter from general DNA sequencing to specific methylation status analysis at CpG sites. By focusing on methylation patterns rather than just DNA presence, the method achieves higher sensitivity in detecting TILs, as methylation signatures provide more specific information about cell state and origin
Solution Approach 2:
The patent applies local quality by focusing analysis on specific differentially methylated CpG sites that are characteristic of TILs. Rather than analyzing the entire genome uniformly, the method identifies and targets specific local regions (CpG sites) that have distinct methylation patterns in TIL-derived cfDNA, enhancing detection precision
3Measurement precision
If methylation sequencing of cell-free DNA is performed, then measurement precision of TIL detection is improved, but device complexity increases
Solution Approach 1:
The patent segments the complex methylation sequencing process into distinct modular steps: cfDNA extraction from plasma, library preparation with methylation conversion, targeted sequencing of CpG sites, and bioinformatic analysis. This segmentation allows each module to be optimized independently and facilitates implementation using existing commercial platforms
4Measurement precision
If invasive biopsy is used to obtain tissue samples, then measurement precision is improved, but loss of time increases
Solution Approach 1:
The patent performs preliminary action by using cfDNA that has already been released from cells into the bloodstream before sampling. The DNA is pre-extracted and circulating in plasma, eliminating the need for time-consuming tissue processing, cell isolation, and fresh sample preparation that would be required with invasive biopsy methods
Data Source
AI summary
Among the various aspects of the present disclosure is the provision of methods and systems for detecting cell states in a biological sample. An aspect of the present disclosure provides for a method of determining cell type or cell states. In some embodiments, the method comprises providing or having been provided a sample comprising DNA or RNA and generating a methylation profile for the DNA or RNA in the sample or providing or having been provided a methylation profile of the DNA or RNA in the sample.