EBV-Reactive CDR3 Profiling for Cancer Survival Prediction
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Solution Overview
Problem
Existing methods for profiling T-cell receptor (TCR)/B-cell receptor (BCR) repertoires in EBV-positive cancers fail to account for biochemically plausible but non-identical interactions and lack correlation with clinical outcomes, particularly in EBV-associated malignancies, limiting their utility in predicting patient prognosis and treatment response.
Innovation Solution
Analyzing tumor-infiltrating lymphocyte (TIL)-derived complementarity determining region 3 (CDR3) sequences for reactivity against EBV, using both sequence matching and chemical complementarity between host immune receptors and EBV epitopes, to determine overall survival and guide treatment decisions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If exact sequence identity matching between patient-derived TCRs/BCRs and previously annotated clones is used, then the method is simple to implement, but it fails to account for biochemically plausible but non-identical interactions and lacks correlation with clinical outcomes
Solution Approach 1:
The patent changes the matching parameters from requiring exact sequence identity to allowing sequence variation within defined thresholds, and introduces chemical complementarity scoring as an additional parameter. This enables detection of biochemically plausible interactions while maintaining computational feasibility through standardized scoring algorithms.
Solution Approach 2:
The patent introduces chemical complementarity scoring as an intermediary metric between sequence similarity and functional interaction. This mediator accounts for biochemical plausibility by evaluating physicochemical properties of amino acid interactions, bridging the gap between sequence data and functional prediction.
2Measurement precision
If comprehensive immune receptor profiling with chemical complementarity analysis is implemented, then the accuracy of predicting patient prognosis and treatment response is improved, but the computational complexity and resource requirements increase
Solution Approach 1:
The patent segments the immune receptor profiling process into distinct computational modules: sequence extraction, similarity matching, chemical complementarity scoring, and clinical outcome correlation. This segmentation allows each module to be optimized independently and facilitates parallel processing to reduce overall computational burden.
Solution Approach 2:
The patent implements partial action by applying chemical complementarity analysis selectively to TCR/BCR clones that meet initial filtering criteria (e.g., minimum sequence similarity threshold). This approach achieves comprehensive functional assessment where needed while avoiding unnecessary computational expense for clearly non-relevant sequences.
3Loss of time
If existing TCR/BCR repertoire profiling methods are used, then the process is quick and straightforward, but the results lack correlation with clinical outcomes in EBV-associated malignancies
Solution Approach 1:
The patent performs preliminary action by pre-computing and storing chemical complementarity scores for common amino acid pairs and pre-identifying known EBV-reactive TCR sequences. This preprocessing enables rapid analysis of patient samples while maintaining high correlation with clinical outcomes, as the computationally intensive aspects are prepared in advance.
Solution Approach 2:
The patent incorporates feedback mechanisms by iteratively refining the chemical complementarity thresholds and matching criteria based on correlation with clinical outcome data. This feedback loop ensures that the analysis parameters are optimized for predicting prognosis and treatment response in EBV-associated malignancies while maintaining computational efficiency.
Data Source
AI summary
The present disclosure relates to methods, systems and compositions for determining and improving overall survival probabilities in EBV-positive cancer subjects and the role of tumor infiltrating lymphocytes in cancer immunotherapy.