Methods for predicting the usefulness of disease specific amino acid modifications for immunotherapy
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Publication Number
US-12270813-B2
Publication Date
2025-04-08
Expiration Date
Abstract
The present invention relates to methods for predicting whether peptides or polypeptides comprising disease specific amino acid modifications, in particular tumor-associated neo-antigens, comprise epitopes, in particular tumor-associated neo-epitopes, which are useful for immunotherapy such as for vaccination. The methods of the invention may be used, in particular, for the provision of vaccines which are specific for a patient's tumor and, thus, in the context of personalized cancer vaccines.
Core Innovation
The invention describes methods to make a cancer vaccine based on determining whether peptide or polypeptide fragments, each comprising the same cancer-specific amino acid modification, meet selection criteria linked to antigen presentation and T cell reactivity. For at least one cancer-specific amino acid modification within a peptide or polypeptide expressed in a cancer cell, the method determines whether the same or different fragments are presented by MHC molecules of different classes and/or, when presented by MHC molecules, are reactive with T cells restricted to different MHC classes. When the fragments meet the selection criteria, the cancer-specific amino acid modification is selected and a vaccine is produced that comprises a peptide or polypeptide containing the selected modification or a fragment thereof, or a nucleic acid encoding the vaccine component.
The invention further provides selection criteria that include MHC-class-matched and MHC-class-diverse contexts, including that the same or different fragments are reactive with T cells having different T cell receptors when presented by the same MHC molecule. In other implementations, the selection criteria include that fragments are presented by different MHC molecules of the same class and/or are reactive with different T cells restricted to the same MHC class when presented by different MHC molecules of the same class.
The invention also covers identifying a plurality of cancer-specific amino acid modifications within peptides and/or polypeptides expressed in cancer cells, determining for each modification whether same or different fragments meet selection criteria, and ranking the level of MHC presentation and/or T cell reactivity for each modification based on the determination. At least one higher-ranked cancer-specific amino acid modification is selected and a vaccine is produced comprising the selected peptide or polypeptide containing the modification or a fragment thereof, or a nucleic acid encoding the peptide or polypeptide.
Claims Coverage
The partial content includes multiple independent claims: clm-00001, clm-00003, clm-00005, clm-00007, clm-00012, clm-00014, clm-00016, and clm-00018. Across these claims, the independent inventive features are centered on selecting cancer-specific amino acid modifications using fragment-level MHC presentation and T cell reactivity criteria, optionally ranking across a plurality and producing a vaccine using a selected peptide/polypeptide fragment or an encoding nucleic acid.
MHC class selection for vaccine-making using fragment presentation and class-restricted T cell reactivity
Determining whether the same or different fragments comprising the same cancer-specific amino acid modification are presented by MHC molecules of different classes and/or, when presented by MHC molecules, are reactive with T cells restricted to different MHC classes, then selecting the cancer-specific amino acid modification and producing a vaccine comprising the peptide or polypeptide comprising the selected cancer-specific amino acid modification or a fragment thereof, or a nucleic acid encoding it.
Same MHC molecule TCR diversity selection for vaccine-making
Determining whether the same or different fragments comprising the same cancer-specific amino acid modification meet selection criteria in that, when presented by the same MHC molecule, they are reactive with T cells having different T cell receptors, then selecting the cancer-specific amino acid modification and producing a vaccine comprising the peptide or polypeptide comprising the selected cancer-specific amino acid modification or a fragment thereof, or a nucleic acid encoding it.
Same-class MHC presentation and same-class T cell reactivity selection for vaccine-making
Determining whether the same or different fragments comprising the same cancer-specific amino acid modification meet selection criteria in that are presented by different MHC molecules of the same class and/or, when presented by different MHC molecules of the same class, are reactive with different T cells restricted to the same MHC class, then selecting the cancer-specific amino acid modification and producing a vaccine comprising the peptide or polypeptide comprising the selected cancer-specific amino acid modification or a fragment thereof, or a nucleic acid encoding it.
Combined multi-set selection criteria for vaccine-making across MHC classes and TCR diversity
Determining whether the same or different fragments comprising the same cancer-specific amino acid modification meet at least two sets of selection criteria (A), (B), and (C), where (A) covers presentation by MHC molecules of different classes and/or reactivity with T cells restricted to different MHC classes, (B) covers reactivity with T cells having different T cell receptors when presented by the same MHC molecule, and (C) covers presentation by different MHC molecules of the same class and/or reactivity with T cells restricted to the same MHC class; then selecting the cancer-specific amino acid modification and producing a vaccine comprising the peptide or polypeptide comprising the selected cancer-specific amino acid modification or a fragment thereof, or a nucleic acid encoding it.
Ranking cancer-specific amino acid modifications by MHC presentation and/or T cell reactivity for vaccine selection
Identifying a plurality of cancer-specific amino acid modifications within peptides and/or polypeptides expressed in cancer cells; determining, for each modification, whether the same or different fragments of the corresponding peptide or polypeptide meet selection criteria that the same or different fragments are presented by MHC molecules of different classes and/or, when presented by MHC molecules, are reactive with T cells restricted to different MHC classes; ranking the level of MHC presentation and/or T cell reactivity for each modification based on the determination; selecting at least one modification if it meets the selection criteria and if the modification has a ranking higher than at least one other modification; and producing a vaccine that comprises a peptide or polypeptide comprising the selected cancer-specific amino acid modification or a fragment thereof, or a nucleic acid encoding the peptide.
Ranking based on same-MHC presentation with different T cell receptors for vaccine selection
Identifying a plurality of cancer-specific amino acid modifications within peptides and/or polypeptides expressed in cancer cells; determining, for each modification, whether the same or different fragments meet selection criteria in that when presented by the same MHC molecule, they are reactive with T cells having different T cell receptors; ranking the level of MHC presentation and/or T cell reactivity for each modification based on the determination; selecting at least one modification if the fragments meet the selection criteria and if the modification has a ranking higher than that of at least one other modification; and producing a vaccine comprising a peptide or polypeptide comprising the selected cancer-specific amino acid modification or a fragment thereof, or a nucleic acid encoding the peptide, polypeptide, or fragment of (a).
Ranking based on same-class MHC presentation and same-class restricted T cell reactivity for vaccine selection
Identifying a plurality of cancer-specific amino acid modifications within peptides and/or polypeptides expressed in cancer cells; determining, for each modification, whether the same or different fragments meet selection criteria in that are presented by different MHC molecules of the same class and/or, when presented by different MHC molecules of the same class, are reactive with different T cells restricted to the same MHC class; ranking the level of MHC presentation and/or T cell reactivity for each modification; selecting at least one modification if the same or different fragments meet the selection criteria and if the modification has a ranking higher than at least one other modification; and producing a vaccine comprising a peptide or polypeptide comprising the selected cancer-specific amino acid modification or a fragment thereof, or a nucleic acid encoding the peptide, polypeptide, or fragment of (a).
Multi-set selection criteria with ranking for vaccine selection
Identifying a plurality of cancer specific amino acid modifications within peptides and/or polypeptides expressed in cancer cells; determining, for each modification, whether the same or different fragments meet at least two sets of selection criteria (A), (B), and (C), where according to (A) fragments are presented by MHC molecules of different classes and/or are reactive with T cells restricted to different MHC classes; according to (B) when presented by the same MHC molecule are reactive with T cells having different T cell receptors; and according to (C) are presented by different MHC molecules of the same class and/or when presented by different MHC molecules of the same class are reactive with different T cells restricted to the same MHC class; ranking the level of MHC presentation and/or T cell reactivity for each modification; selecting at least one modification if the fragments meet at least two sets of the selection criteria (A), (B), and (C) and if the modification has a ranking higher than at least one other modification; and producing a vaccine comprising a peptide or polypeptide comprising the selected cancer-specific amino acid modification or a fragment thereof, or a nucleic acid encoding the peptide, polypeptide, or fragment of (a).
Overall, the independent claims define vaccine-making methods that select or rank cancer-specific amino acid modifications based on whether fragments meet selection criteria involving MHC presentation across different MHC classes and/or within-class MHC presentation, and T cell reactivity patterns including reactivity restricted to different MHC classes and/or reactivity with different T cell receptors. Several claims further tighten selection by requiring at least two sets of selection criteria (A), (B), and (C) and/or by ranking modifications and selecting higher-ranked modifications before producing the vaccine as a selected peptide/polypeptide or a nucleic acid encoding it.
Stated Advantages
Provides a method to select cancer-specific amino acid modifications based on MHC presentation and T cell reactivity criteria.
Enables ranking of cancer-specific amino acid modifications based on the level of MHC presentation and/or T cell reactivity, followed by selection of higher-ranked modifications.
Allows selection criteria that incorporate presentation by different MHC classes and/or different T cell receptor diversity, including within the same MHC molecule.
Produces cancer vaccine components that include peptide or polypeptide fragments comprising selected modifications or nucleic acids encoding the selected peptide or polypeptide.
Documented Applications
Personalized cancer vaccine for cancer immunotherapy, including producing a vaccine comprising a peptide or polypeptide fragment or a nucleic acid encoding a selected peptide or polypeptide modification, including optional MHC-binding peptide fragments and poly-neo-epitope RNA/polypeptide formats [procedural detail omitted for safety].
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