Cell-free DNA Tracking for CAR T-cell Therapy Response Prediction
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Solution Overview
Problem
Current methods for assessing and treating diffuse large B-cell lymphoma (DLBCL) with CAR T-cell therapy face challenges due to invasive tissue biopsies and lack of predictive biomarkers for patient selection and monitoring therapeutic response, with high rates of disease progression and resistance mechanisms poorly understood.
Innovation Solution
The use of cell-free DNA from blood plasma to track tumor and CAR T-cell DNA, identifying somatic mutations in genes like PAX5, BTG2, and IRF8 for predicting treatment outcomes and monitoring therapeutic responses, through deep sequencing and specific binding agents, allowing for non-invasive monitoring and personalized treatment approaches.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If tissue biopsies are used for DNA sequencing and RNA gene expression profiling, then molecular and genomic classification can be achieved, but the method becomes invasive and limits repeated assessment over time
Solution Approach 1:
The patent extracts the diagnostic function from invasive tissue biopsies by detecting tumor-derived RNA and DNA markers in circulating biomarkers from blood plasma. This allows the same molecular classification and monitoring functions to be achieved through minimally invasive blood draws, enabling repeated assessments over time without requiring repeated tissue biopsies.
2Reliability
If traditional biomarkers are used for cancer assessment, then monitoring can be performed, but specificity is limited and tumor-specific alterations cannot be revealed
Solution Approach 1:
The patent replaces traditional non-specific biomarker detection with targeted molecular sequencing and RNA expression profiling of tumor-derived markers in circulating biomarkers. This substitution enables highly specific detection of tumor-specific genetic alterations and transcriptional profiles, providing both monitoring capability and precise tumor-specific information.
3Reliability
If CAR19 T-cell therapy is administered to treat DLBCL, then clinical activity can be achieved, but predictive biomarkers for patient selection are unavailable resulting in high disease progression rates
Solution Approach 1:
The patent performs preliminary molecular characterization of DLBCL tumors through DNA sequencing and RNA expression profiling of circulating tumor markers before CAR19 T-cell therapy administration. This preliminary action identifies predictive biomarkers including specific genetic mutations, gene expression signatures, and tumor mutational burden that predict response to CAR19 therapy, enabling informed patient selection and reducing disease progression rates.
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
Enables the identification of individuals likely to respond or not respond to CAR T-cell therapy, providing predictive biomarkers for patient selection and monitoring therapeutic responses, improving treatment outcomes and understanding resistance mechanisms.
Implementation Method 1
contacting a biological sample from an individual with an agent capable of specific binding to one or more genes comprising PAX5, BTG2 and/or IRF8 genes
Implementation Method 2
deep sequencing a biological sample comprising cell-free DNA (cfDNA) from the individual, mapping sequencing reads to identify candidate rearrangements
Data Source
AI summary
The present disclosure generally relates to methods that utilize cell-free DNA from a liquid biopsy of an individual to track DNA from both the tumor and the chimeric antigen receptor (CAR) T-cells. The present disclosure further relates to methods of predicting individuals' response to therapy, e.g., CAR T-cell therapies. Additionally, the present disclosure relates to methods of treating individuals with cancer, such as lymphoma.