Corrected Tumor Mutation Burden Prediction for Immune Checkpoint Blockade
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Solution Overview
Problem
Current methods for assessing tumor mutation burden (TMB) are limited by low tumor purity and intra-tumoral heterogeneity, leading to inaccurate predictions of response to immune checkpoint blockade, and existing biomarkers lack calibration and harmonization across sequencing platforms.
Innovation Solution
Correction of TMB for tumor purity, combined with genomic alterations in receptor tyrosine kinase (RTK) genes and HLA class I genetic variation, to accurately predict patient outcomes for immune checkpoint blockade, using whole exome sequence data and targeted next-generation sequencing.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If tissue-based TMB estimates are used in low tumor purity samples, then the assessment can be performed, but the accuracy of TMB estimation deteriorates
Solution Approach 1:
The patent introduces tumor purity correction as an intermediary step between raw TMB measurement and final interpretation. By applying correction factors based on tumor purity estimates, the method mediates the relationship between imperfect tissue samples and accurate TMB assessment, allowing reliable predictions even in low-purity samples without requiring perfect tissue specimens
Solution Approach 2:
The patent transforms the TMB parameter by applying purity-based correction factors to obtain corrected TMB (cTMB). This parameter transformation adjusts the raw TMB values according to tumor purity levels, converting inaccurate measurements in low-purity samples into accurate predictive values that maintain clinical utility across diverse sample qualities
2Adaptability or versatility
If multiple next-generation sequencing platforms are used, then more tumors can be assessed, but calibration and harmonization across platforms deteriorates
Solution Approach 1:
The patent creates a universal correction framework that functions across multiple sequencing platforms and tumor types. The purity-based correction methodology serves as a platform-agnostic approach that can be applied universally to harmonize TMB estimates regardless of the specific sequencing technology used, enabling consistent predictions across diverse clinical settings
Solution Approach 2:
The patent applies standardized parameter transformation across different platforms by correcting TMB values based on tumor purity. This universal parameter adjustment approach harmonizes measurements across heterogeneous sequencing platforms, converting platform-specific variations into consistent, comparable cTMB values that maintain calibration integrity
3Reliability
If high TMB is used as a biomarker, then response to immune checkpoint blockade can be predicted, but false predictions occur in tumors with high TMB that do not respond
Solution Approach 1:
The patent transforms the TMB parameter into a more reliable predictive marker by applying purity-based correction. This parameter transformation converts raw TMB into corrected TMB (cTMB), which maintains the association with immune checkpoint blockade response while eliminating false predictions caused by tumor purity variations, thereby improving both reliability and precision of response prediction
Solution Approach 2:
The patent incorporates tumor purity estimation as a feedback mechanism that informs the interpretation of TMB. By measuring tumor purity and using it to adjust TMB values, the system creates a feedback loop that continuously refines the accuracy of response predictions, ensuring that cTMB values reflect true mutational burden rather than sampling artifacts
Data Source
AI summary
This document relates to methods and materials involved in assessing and/or treating a mammal having a cancer. For example, methods and materials provided herein can be used to determine the corrected tumor mutation burden (cTMB) of one or more cells (e.g., one or more cancer cells) from a mammal having cancer, thereby identifying the cancer as being likely to respond to a particular cancer treatment (e.g., a cancer immunotherapy). This document also provides methods and materials for treating a mammal identified as having a cancer likely to respond to a particular cancer treatment.