Identifying Shared Tumor Antigens via Inverted TCR Clonotype Analysis
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Solution Overview
Problem
Current methods for identifying tumor-specific T cell receptors (TCRs) and their corresponding antigens are limited in their ability to find common antigens shared among multiple patients, which is essential for developing off-the-shelf therapeutic approaches for cancer.
Innovation Solution
A method that analyzes T cell repertoires in tumors of different cancer patients to identify specific effects originating from shared tumor antigens. This involves detecting TCR clonotypes that are uniquely or highly similarly present in tumors of multiple patients, particularly those with matching HLA types, to predict tumor-specificity and identify shared antigens.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If whole exome sequencing approaches are used to identify tumor-specific mutated antigens, then tumor-specificity is improved, but the antigens become patient-specific rather than shared
Solution Approach 1:
Instead of starting with patient-specific mutations and working forward to personalized therapies, the invention inverts the approach by searching for common TCR clonotypes across multiple patients first, then working backward to identify shared antigens. This inversion enables the discovery of universal tumor antigens that can serve as targets for multi-patient therapies.
Solution Approach 2:
The invention identifies TCR clonotypes that are present across multiple patients with different tumor types, suggesting these TCRs recognize shared tumor antigens. This universality allows a single TCR therapy to potentially treat multiple patients and tumor types, transforming personalized medicine into a universal approach.
2Adaptability or versatility
If mass spectroscopy-based approaches are used to detect shared HLA-presented peptides, then shared antigen potential is improved, but proof of immunogenicity and tumor-specificity becomes challenging
Solution Approach 1:
The invention uses feedback from functional assays and TCR sequencing data to validate and refine the identification of shared antigens. By observing which TCR clonotypes are functionally active across multiple patients and correlating this with their CDR3 sequences, the method provides robust proof of immunogenicity and tumor-specificity for the identified shared antigens.
3Reliability
If personalized TCR therapies are developed for each patient, then tumor-specificity is improved, but time consumption and cost increase
Solution Approach 1:
The invention performs preliminary identification of common TCR clonotypes and shared antigens across multiple patients before individual therapy development. By pre-characterizing the TCR repertoires and identifying universal targets in advance, the method enables rapid deployment of off-the-shelf therapies that can be quickly adapted to different patients without requiring de novo development for each case.
4Adaptability or versatility
If TCR clonotypes are analyzed across multiple patients to identify common patterns, then shared antigen identification is improved, but complexity of the analysis method increases
Solution Approach 1:
The invention segments the complex analysis into distinct functional modules: (1) TCR sequence acquisition from multiple patients, (2) CDR3 region extraction and alignment, (3) Clonotype frequency calculation and comparison, (4) Shared antigen prediction based on CDR3 similarity, and (5) Validation through functional assays. This segmentation makes the complex multi-step analysis more manageable and reproducible.
Data Source
AI summary
The present invention relates to a method for identification of common patient-spanning tumor-specific T cell receptors (TCRs) and their corresponding antigens. The invention also relates to these TCR sequences, a nucleic acid encoding the TCR, and a T cell comprising the TCR and/or the encoding nucleic acid.