Tumor Neoantigenic Peptides From TE-Exon Fusion Transcripts
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Solution Overview
Problem
Existing cancer immunotherapy methods face challenges in identifying and targeting shared tumor neoantigens that are not expressed in normal tissues, leading to limited efficacy and applicability across different cancer types.
Innovation Solution
Utilizing non-canonical alternative splicing events between exons and transposable elements (TEs) to generate tumor-specific neoantigenic peptides, which are encoded by fusion transcripts, and developing vaccines, antibodies, and immune cells that target these peptides to enhance immune response.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If checkpoint blockade therapy is used to bypass immunosuppressive mechanisms, then anti-tumor immune response efficiency is improved, but the proportion of responding patients remains limited and cancer indications are restricted
Solution Approach 1:
The patent segments the antigen target selection by identifying specific neoantigens derived from transposable element-exon fusion transcripts that are uniquely expressed in tumor cells. This segmentation allows for targeted vaccination strategies that overcome the limitations of checkpoint blockade by providing tumor-specific antigens that can elicit immune responses across different cancer types and patient populations.
Solution Approach 2:
The patent introduces neoantigenic peptides derived from TE-exon fusion transcripts as intermediaries between the immune system and tumor cells. These peptides serve as specific targets for T-cell recognition and can be used in vaccination strategies to bridge the gap between checkpoint blockade therapy and broader cancer indications, thereby increasing the proportion of responding patients.
2Reliability
If tumor neoantigens are targeted for vaccination, then anti-tumor immunity is enhanced, but the challenge of identifying shared true neoantigens absent from normal tissues remains
Solution Approach 1:
The patent extracts and isolates specific neoantigenic peptides from fusion transcripts containing transposable element sequences and exonic sequences. By taking out these specific peptide sequences that are derived from TE-exon junctions, the invention provides a method to identify and target shared true neoantigens that are absent from normal tissues, thereby enhancing anti-tumor immunity while overcoming the identification challenge.
Solution Approach 2:
The patent changes the parameter of antigen selection by focusing on neoantigens derived from transposable element-exon fusion transcripts rather than traditional mutated sequences. This parameter change enables the identification of shared true neoantigens across different tumors by targeting the unique TE-exon junction sequences, which are absent from normal tissues and can be detected through specific molecular methods.
3Ease of operation
If tumor antigens are used as vaccination targets, then immune response is triggered, but self-antigens represent poor targets due to central tolerance
Solution Approach 1:
The patent converts the previously harmful or non-beneficial transposable element sequences, which were considered genomic noise or junk DNA, into beneficial neoantigenic targets. By identifying and utilizing peptides derived from TE-exon fusion transcripts, the invention transforms these sequences into reliable vaccination targets that can trigger effective anti-tumor immune responses without being subject to central tolerance, thereby overcoming the limitation of using self-antigens.
Data Source
AI summary
The present disclosure provides tumor neoantigenic peptide sequences and nucleotide sequences encoding such peptide sequences; a vaccine or immunogenic composition capable of raising a specific T-cell response comprising one or more of the neoantigenic peptides, or comprising nucleic acid encoding one or more of the neoantigenic peptides; an antibody, or an antigen-binding fragment thereof, a T cell receptor (TCR), or a chimeric antigen receptor (CAR) that specifically binds such neoantigenic peptides; methods of producing such antibodies, TCRs or CARs; polynucleotides encoding such neoantigenic peptides, antibodies, CARs or TCRs, optionally linked to a heterologous regulatory control sequence; immune cells that specifically bind to such neoantigenic peptides; and dendritic cells or antigen presenting cells that have been pulsed with one or more of the neoantigenic peptides; and methods of using such products in particular therapeutic uses of these products.