Peptide-Based Neoantigen Screening for TIL Reactivity
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Solution Overview
Problem
Current methods for identifying cancer neoantigens are costly, limited in scalability, and inefficient, making it challenging to effectively screen for relevant neoantigens for clinical applications, particularly due to the complexity of identifying true epitopes and the unknown or incomplete pMHC II binding affinity.
Innovation Solution
A method involving obtaining cancerous tissue samples, culturing and expanding tumor infiltrating lymphocytes (TILs), sequencing, bioinformatics analysis to identify putative neoantigens, co-culturing with TILs, and assaying for reactivity using techniques like ELISA and TCRVβ sequencing to confirm neoantigens, along with isolating and administering reactive T cells or neoantigens for treatment.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If traditional neoantigen identification methods are used, then neoantigens can be identified, but the process is costly and limited in scalability
Solution Approach 1:
The patent segments the neoantigen identification process into distinct modules: (1) tumor tissue sequencing to identify mutations, (2) in silico prediction of neoantigens, (3) synthesis of predicted neoantigens, and (4) screening against patient-derived TILs. This modular segmentation enables parallel processing and scaling while maintaining identification accuracy through systematic validation at each stage.
Solution Approach 2:
The patent introduces patient-derived tumor-infiltrating lymphocytes (TILs) as an intermediary validation system. Instead of relying solely on computational predictions, the predicted neoantigens are synthesized and screened against actual patient TILs that have been expanded in vitro. This intermediary step bridges the gap between in silico predictions and clinical relevance, enabling scalable validation without sacrificing accuracy.
2Quantity of substance
If comprehensive neoantigen screening is performed, then more neoantigens can be identified, but the expense increases significantly
Solution Approach 1:
The patent performs preliminary in silico filtering and prediction of neoantigens before synthesis and experimental validation. By using computational methods to pre-screen and rank predicted neoantigens based on binding affinity and immunogenicity features, the approach reduces the number of candidates that require expensive synthesis and screening against TILs, thereby identifying a sufficient number of relevant neoantigens at lower cost.
Solution Approach 2:
The patent uses synthetic peptides as copies or representations of the predicted neoantigens rather than requiring isolation and characterization of actual tumor-derived neoantigens. These synthesized peptide copies can be produced at lower cost and in greater quantities, enabling comprehensive screening of multiple candidates while reducing the expense associated with obtaining and validating each individual neoantigen from patient samples.
3Reliability
If all predicted neoantigens are validated, then true epitopes can be confirmed, but the process becomes inefficient
Solution Approach 1:
The patent implements a dynamic, iterative screening process where predicted neoantigens are tested against patient-derived TILs in a ranked order based on computational predictions. The process is adaptive: neoantigens that show positive reactivity are confirmed and can be used for therapy, while negative results allow rapid elimination of false positives. This dynamic approach maintains high validation accuracy by using actual patient immune responses as the gold standard while improving efficiency through iterative elimination rather than exhaustive validation of all candidates.
Data Source
AI summary
Disclosed are methods for identifying neoantigens and methods of treating cancer using neoantigens identified by said methods. The disclosure herein provide for methods for identifying neoantigens that can be used as a target for the treatment of a cancer, immunize a subject against a cancer, stimulate/induce immune responses, and/or isolate T cells that are reactive to said neoantigens.