[go: up one dir, main page]

WO2025196053A1 - Peptides associés à la flagelline et leurs utilisations - Google Patents

Peptides associés à la flagelline et leurs utilisations

Info

Publication number
WO2025196053A1
WO2025196053A1 PCT/EP2025/057375 EP2025057375W WO2025196053A1 WO 2025196053 A1 WO2025196053 A1 WO 2025196053A1 EP 2025057375 W EP2025057375 W EP 2025057375W WO 2025196053 A1 WO2025196053 A1 WO 2025196053A1
Authority
WO
WIPO (PCT)
Prior art keywords
seq
peptides
cancers
composition
peptide
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/EP2025/057375
Other languages
English (en)
Inventor
Luigi Nezi
Teresa Manzo
Angeli Dominique MACANDOG
Paolo Antonio ASCIERTO
Luigi Buonaguro
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Istituto Nazionale Tumori Irccs Fondazione G Pascale
Istituto Europeo di Oncologia SRL IEO
Original Assignee
Istituto Nazionale Tumori Irccs Fondazione G Pascale
Istituto Europeo di Oncologia SRL IEO
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from EP24164184.4A external-priority patent/EP4620482A1/fr
Application filed by Istituto Nazionale Tumori Irccs Fondazione G Pascale, Istituto Europeo di Oncologia SRL IEO filed Critical Istituto Nazionale Tumori Irccs Fondazione G Pascale
Publication of WO2025196053A1 publication Critical patent/WO2025196053A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/02—Bacterial antigens
    • A61K39/08—Clostridium, e.g. Clostridium tetani
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/58—Medicinal preparations containing antigens or antibodies raising an immune response against a target which is not the antigen used for immunisation
    • A61K2039/585—Medicinal preparations containing antigens or antibodies raising an immune response against a target which is not the antigen used for immunisation wherein the target is cancer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/70—Multivalent vaccine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/80—Vaccine for a specifically defined cancer
    • A61K2039/876—Skin, melanoma

Definitions

  • the present invention relates to peptides and their use in cancer immunotherapy.
  • the present invention relates to peptides coded by flagellin-related genes of Lachnospiraceae and to their use in tumor vaccination therapies.
  • ICI immune checkpoint inhibitor
  • Flagellin an agonist of toll-like receptor 5 (TLR5), is known as a potential adjuvant that can induce innate and adaptive immune responses of host cells.
  • International patent application WO 2011/0442464 discloses a vector comprising nucleic acid encoding a secreted form of a flagellin or a toll-like receptor for use in the treatment of cancer.
  • International patent application WO 2012/097012 discloses a method for treating cancer comprising administering a TLR agonist.
  • International patent application WO 2006/116763 discloses the use of a composition comprising a flagellin in the treatment of cancer to reduce the side effects of cisplatin cancer therapy.
  • the present invention relates to the identification of peptides derived from flagellin-related proteins of Lachnospiraceae which can be useful to enhance anti -tumor immunity, in particular in patients undergoing immunotherapy. Indeed, it was found that patients with melanoma responsive to ICI can specifically mount a CD8 + T cell-mediated response directed against tumormimicking, flagellin-related peptides.
  • the use of non-endogenous peptides to stimulate the immune system against a tumor is advantageous because it lowers the risk of an auto-immune response.
  • composition comprising at least three peptides for use for the prevention and/or treatment of a cancer, wherein said at least three peptides are obtained by proteins encoded by flagellin-related genes, said protein being selected from the group consisting of A0A0M6WP36, C0FQ31, A0A127SWS0, C0FQ36, A0A396AI63, A0A0M6WMV3, A0A0M6WD36, D4KYR7, R6VY20, A0A351R0D5, A0A0M6WBR8, A0A0M6WYS8, R6EJ07, R6VQ94, G2SZK1, C7G5T8, A5Z847, A0A174K7I7, A0A1Q6SAN9, D4KYS1, D4KW84, R6EJJ6, R6EC52, A0A395V8C5, R6EJJ3, R5SPI8, R
  • said flagellin-related gene is from a bacteria of Clostridia class, more preferably of the Lachnospiraceae family, even more preferably of Roseburia genere, in particular Roseburia inulinivorans.
  • each of said peptide is coded by a flagellin-related gene selected from the group of genes encoding for proteins selected from the group consisting of: A0A0M6WP36, C0FQ31, A0A127SWS0, C0FQ36, A0A396AI63, A0A0M6WMV3, A0A0M6WD36, D4KYR7, R6VY20, A0A351R0D5, A0A0M6WBR8, A0A0M6WYS8, R6EJ07 and R6VQ94, more preferably selected from the group consisting of A0A0M6WD36, A0A0M6WMV3, A0A0M6WYS8, A0A351R0D5, R6EJ07, R6VY20, A0A396AI63, A0A0M6WP36 and R6VQ94.
  • a flagellin-related gene selected from the group of genes encoding for proteins selected from the group
  • Said numbers correspond to identification numbers of respective genes in the UniProt or in the UniParc database, January 2024 release.
  • the name of the genes may vary in subsequent or different databases releases, the skilled person is able to identify the corresponding name of the genes in different database releases according to common general knowledge in the field.
  • said at least three peptides are selected from the group consisting of peptides comprising or consisting of a sequence of any of SEQ ID Ns. 1-143, more preferably selected from the group consisting of peptides comprising or consisting of a sequence of SEQ ID Ns. 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  • the composition comprises at least three, four, five, six, seven, eight, nine or ten, peptides selected from the group consisting of peptides comprising or consisting of a sequence of any of SEQ ID Ns. 1-143, more preferably selected from the group consisting of peptides comprising or consisting of a sequence of SEQ ID Ns. 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  • composition comprises at least three peptides comprising or consisting of a sequence selected from the group consisting of:
  • SEQ ID N.10 or variants thereof, preferably in combination with at least one peptide of SEQ ID Ns. 1-143, preferably of SEQ ID Ns. 11-43.
  • Said peptides of SEQ ID Ns. 1-143 and combinations thereof are also objects of the invention.
  • composition comprising at least one peptide encoded by a flagellin-related gene or obtained by a protein encoded by a flagellin related gene wherein said protein is selected from the group consisting of: A0A0M6WP36, A0A127SWS0, C0FQ36, A0A396AI63, A0A0M6WMV3, A0A0M6WD36, D4KYR7, R6VY20, A0A351R0D5, A0A0M6WBR8, A0A0M6WYS8, R6EJ07 and R6VQ94.
  • said composition comprises at least three of said peptides.
  • composition comprising at least one peptide, preferably at least three peptides, comprising or consisting of a sequence of SEQ ID Ns. 1-143, preferably at least three peptides selected from the group consisting of peptides comprising or consisting of a sequence of SEQ ID Ns. 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. More preferably, it comprises at least three, four, five, six, seven, eight, nine or ten peptides comprising or consisting of a sequence of SEQ ID Ns. 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, optionally in combination with any other peptide of SEQ ID Ns. 1-143.
  • said composition comprises a peptide of SEQ ID N.3, a peptide of SEQ ID N.4, a peptide of SEQ ID N.5, a peptide of SEQ ID N.6, a peptide of SEQ ID N.7, a peptide of SEQ ID N.8 and a peptide of SEQ ID N.9.
  • said composition comprises a peptide of SEQ ID N.3, a peptide of SEQ ID N.4, a peptide of SEQ ID N.6, a peptide of SEQ ID N.7, a peptide of SEQ ID N.8 and a peptide of SEQ ID N.9.
  • said composition comprises a peptide of SEQ ID N.1, a peptide of SEQ ID N.2 and a peptide of SEQ ID N.10.
  • said flagellin-related gene is from a bacterium of Chlostridia class, more preferably of the Lachnospiraceae family, even more preferably of Roseburia genere, in particular Roseburia inulinivorans.
  • Said cancer may be characterized by increased expression of any known cancer antigen, such as any cancer antigen which can be found in the database Cancer Antigenic Peptide Database (https://caped.icp.ucLac.be/).
  • the cancer is characterized by increased expression of at least one of the following antigens: MAGE-A1, N-ras, CEA, alpha-actinin-4, NY-ESO- l/LAGE-2, MAGE-A3, N-ras, PAP, Preferentially Expressed Antigen in Melanoma (PRAME), Melanoma Antigen Recognized by T Cells 1 (MART-l/Melan-A), and secernin 1 (SCRN1).
  • PRAME Preferentially Expressed Antigen in Melanoma
  • MART-l/Melan-A Melanoma Antigen Recognized by T Cells 1
  • SCRN1 secernin 1
  • the cancer is selected from melanoma, lung cancers, bladder cancers, esophageal and head and neck cancers, glioblastoma, sarcomas, colorectal cancers, gastric cancers, skin cancers, cutaneous squamous cell carcinomas, thyroid cancers, undifferentiated pleomorphic sarcoma/myxofibrosarcoma, non-small cell lung cancer, small cell lung cancer, multiple myeloma, cerebral cancers, renal cancers, leukemias, lymphomas, hematopoietic and lymphoid cancers, diffuse large B-cell lymphoma, hepatocellular carcinomas, breast cancers, pancreatic cancers, and gynecology cancers.
  • a further object of the invention is a pharmaceutical composition comprising the peptides above defined and a pharmaceutically acceptable excipient and/or vehicle.
  • a vaccine or immunogenic composition comprising the peptides as above defined and a pharmaceutically acceptable vehicle or excipient and preferably an adjuvant.
  • said pharmaceutical composition or vaccine or immunogenic composition is for use in the treatment and/or prevention of cancer, preferably for use in the treatment and/or prevention of cancer characterized by increased expression of at least one of the following antigens: MAGE- Al, N-ras, CEA, alpha-actinin-4, NY-ES0-1/LAGE-2, MAGE-A3, N-ras, PAP, PRAME, MARTl/Melan-A and SCRN1.
  • said pharmaceutical composition or vaccine or immunogenic composition is for use in the treatment and/or prevention of a cancer selected from the group consisting of melanoma, lung cancers, bladder cancers, esophageal and head and neck cancers, glioblastoma, sarcomas, colorectal cancers, gastric cancers, skin cancers, cutaneous squamous cell carcinomas, thyroid cancers, undifferentiated pleomorphic sarcoma/myxofibrosarcoma, non-small cell lung cancer, small cell lung cancer, multiple myeloma, cerebral cancers, renal cancers, leukemias, lymphomas, hematopoietic and lymphoid cancers, diffuse large B-cell lymphoma, hepatocellular carcinomas, breast cancers, pancreatic cancers, and gynecology cancers.
  • a cancer selected from the group consisting of melanoma, lung cancers, bladder cancers, esophageal and head and neck
  • said pharmaceutical composition may comprise more than one composition according to the invention, i.e. it may comprise two or more compositions according to the invention, each one comprising at least one peptide of SEQ ID Ns 1-143.
  • each of the peptide according to the invention is able to bind to a MHC, in particular of class I.
  • MHC of class I indicates HLA of class I, preferably HLA-A and/or HLA-B.
  • Said peptide may be able to bind any MHC I, in particular a HLA selected from the group consisting of HLA-A01:01, HLA-A02:01, HLA-A03:01, HLA-A24:02, HLA-A26:01, HLA-B07:02, HLA-B08:01, HLA-B27:05, HLA-B39:01, HLA-B40:01, HLA-B58:01, and HLA-B15:01.
  • said MHC I is chosen from the group consisting of HLA-A* 02:01, HLA-B*07:02, HLA-B*15:01, HLA-B*40:01 and HLA-B*08:01.
  • said peptide binds a MHC class I HLA allele with a binding affinity lower than or equal to 100 nM.
  • each of said peptide binds to the same MHC -I of a tumor-associated antigen (TAA) or an epitope thereof.
  • TAA tumor-associated antigen
  • said TAA is selected from MAGE-A1, N-ras, CEA, alpha- actinin-4, NY-ESO-l/LAGE-2, MAGE-A3, N-ras, PAP, PRAME, MARTl/Melan-A and SCRN1.
  • composition comprising at least one peptide, preferably at least three peptides as above defined for use as a vaccine against cancer.
  • a dietary supplement or replacement comprising the peptides as above defined or combinations thereof.
  • dietary supplement as a nutraceutic. It is also within the scope of the invention said dietary supplement or replacement for use for the prevention and/or treatment of a cancer and/or as a vaccine against cancer.
  • composition comprising at least one peptide, preferably at least three peptides as above defined for use for increasing effectiveness of an immune checkpoint inhibitor wherein said peptide is administered to a subject in need thereof before, simultaneously or after said immune checkpoint inhibitor.
  • Increasing effectiveness means that the ICI is more effective than when administered without the peptide(s).
  • Peptides can be administered in alternative forms, such as for example nucleic acids coding for said peptides, or vectors comprising said nucleic acids or directly to cells, for example antigen presenting cells (APC), which express the peptides.
  • an expression vector that induces the expression of a peptide comprises a nucleic acid, DNA or RNA, coding for the peptide.
  • the vector may be a RNA vector, a DNA vector, a viral vector or a bacterial vector.
  • the peptides can advantageously be used to stimulate T cells ex vivo and then re-infuse said T cells in the patient either after the administration of a further therapeutic agent or in the absence of any specific pre-treatment.
  • the invention further relates to an engineered cell comprising a recombinant protein, or a polynucleotide encoding a recombinant protein, preferably said recombinant protein being a recombinant receptor, more preferably a receptor expressed on the surface of the immune cell receptor preferably, wherein the recombinant receptor specifically binds to at least one peptide of the composition as described above, preferably wherein the recombinant receptor is a recombinant T cell receptor (TCR) or a chimeric antigen receptor (CAR). Therefore, the present invention also relates to a T lymphocyte receptor capable of binding one or more peptides as previously defined in which the receptor optionally comprises one or more co-stimulatory domains.
  • the receptor is, for example, a chimeric receptor for the antigen (CAR).
  • the present invention relates to a polynucleotide comprising a nucleotide sequence (DNA or RNA) that encodes for a peptide as described above.
  • the present invention relates to an expression vector comprising a nucleotide sequence as previously defined.
  • Such polynucleotide and expression vector can also be included in a pharmaceutical composition.
  • Such polynucleotide and expression vector can also be advantageously used as a medicament, preferably in the treatment and/or prevention of cancer, preferably in the treatment and/or prevention of cancer characterized by increased expression of at least one of the following antigens: MAGE-A1, N-ras, CEA, alpha-actinin-4, NY-ES0-1/LAGE-2, MAGE-A3, N-ras, PAP, PRAME, MARTl/Melan-A and SCRN1.
  • compositions or composition also refers indiscriminately to an immunogenic composition or to a vaccine composition.
  • the composition of the invention can be administered in combination with further therapeutic regimen in a patient in need thereof.
  • the composition of the invention is administered to a subject prior to, simultaneously or sequentially with other therapeutic regimens or co-agents useful for treating, and/or stabilizing cancer and/or preventing cancer relapsing (e.g. multiple drug regimens), in a therapeutically effective amount.
  • the composition according to the present invention can be administered in the same or different composition(s) and by the same or different route(s) of administration as said co- agents.
  • Said other therapeutic regimens or co-agents may be selected from the group consisting of radiation therapy, chemotherapy, surgery, targeted therapy (including small molecules, peptides and monoclonal antibodies), adoptive cell therapy and anti-angiogenic therapy.
  • Anti-angiogenic therapy is defined herein as the administration of an agent that directly or indirectly targets tumor- associated vasculature.
  • Preferred anti-cancer agents include a chemotherapeutic agent, a targeted drug and an immunotherapeutic agent, such as an immune checkpoint modulator.
  • said co-agent is an immune checkpoint inhibitor (ICI).
  • Said ICI can be selected from an antibody anti- PD-1, an antibody anti-PD-Ll and an antibody anti-CTLA-4.
  • the composition of the invention is administered for the uses of the invention in combination with a second composition according to the invention.
  • said second composition comprises at least one peptide of SEQ ID Ns 1-143, preferably it comprises at least two, three, four, five, six, seven, eight, nine or ten peptides selected from the group consisting of peptides comprising or consisting of a sequence of SEQ ID Ns. 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  • also more than two compositions according to the invention may be administered for the uses of the invention.
  • the two or more compositions may comprise different peptides selected from peptides of SEQ ID Ns 1-143.
  • the compositions of the invention may be administered to a subject simultaneously or sequentially.
  • a first composition according to the invention is administered in combination with a second composition according to the invention for use for increasing effectiveness of an immune checkpoint inhibitor.
  • composition of the invention can also be used as a dietary supplement or replacement, meaning for example a food product or drinking product comprising the composition as defined herein.
  • compositions comprising at least one peptide as above defined for use for stimulating, preferably in vitro, expansion of tumor infiltrating lymphocytes isolated from tumor, wherein said tumor infiltrating lymphocytes are preferably isolated from melanoma, lung cancers, bladder cancers, esophageal and head and neck cancers, glioblastoma, and sarcomas, colorectal cancers, gastric cancers, skin cancers, cutaneous squamous cell carcinomas, thyroid cancers, undifferentiated pleomorphic sarcoma/myxofibrosarcoma, non-small cell lung cancer, small cell lung cancer, multiple myeloma, cerebral cancers, renal cancers, leukemias, lymphomas, hematopoietic and lymphoid cancers, diffuse large B-cell lymphoma, hepatocellular carcinomas, breast cancers, pancreatic cancers, and gynecology cancers.
  • compositions comprising at least one peptide as above defined for use for stimulating, preferably in vitro, cytotoxicity of tumor infiltrating lymphocytes isolated from tumor, wherein said tumor infiltrating lymphocytes are preferably isolated from melanoma, lung cancers, bladder cancers, esophageal and head and neck cancers, glioblastoma, and sarcomas, colorectal cancers, gastric cancers, skin cancers, cutaneous squamous cell carcinomas, thyroid cancers, undifferentiated pleomorphic sarcoma/myxofibrosarcoma, non-small cell lung cancer, small cell lung cancer, multiple myeloma, cerebral cancers, renal cancers, leukemias, lymphomas, hematopoietic and lymphoid cancers, diffuse large B-cell lymphoma, hepatocellular carcinomas, breast cancers, pancreatic cancers, and gynecology cancers.
  • tumor infiltrating lymphocytes isolated from tumor preferably isolated from melanoma, lung cancers, bladder cancers, esophageal and head and neck cancers, glioblastoma, and sarcomas, colorectal cancers, gastric cancers, skin cancers, cutaneous squamous cell carcinomas, thyroid cancers, undifferentiated pleomorphic sarcoma/myxofibrosarcoma, non-small cell lung cancer, small cell lung cancer, multiple myeloma, cerebral cancers, renal cancers, leukemias, lymphomas, hematopoietic and lymphoid cancers, diffuse large B-cell lymphoma, hepatocellular carcinomas, breast cancers, pancreatic cancers, and gynecology cancers, being expanded in vitro in the presence of the composition of the present invention so that they are expanded and improved in their cytotoxicity and tumor killing ability which can be used as a medicament and preferably
  • FIG. 1 Gut microbiota differences between response groups are reinforced during therapy.
  • A Overview of study design.
  • B Aitchison gut composition distance (PERMANOVA pseudo F-ratio) between PFS-L (PFS > 24 months) and PFS-S (PFS ⁇ 24 months) groups compared across time (0, 2-4, 5-8, and 9-13 months of therapy).
  • PFS Progression free survival.
  • Asterisk indicates PERMANOVA p-adj (di stance-Response) at the given timepoint group.
  • Gray line indicates F-ratio distance by sequence batch, for reference.
  • C Corresponding PCA plot at t9— 13 using all available samples.
  • FIG. 1 Gut variability over therapy teases out differences among RECIST responders (RECIST: Response Evaluation Criteria in Solid Tumors).
  • RECIST Response Evaluation Criteria in Solid Tumors.
  • FMT fecal microbiota transplant
  • the plot includes between-patient measurements of the two FMT donors in the study, whose respective medians are indicated with a dashed line.
  • C Within-patient gut variability over time in complete (CR), partial (PR), and not-responders (nR). Dashed line indicates cut-off timepoint for early/late grouping (tearly: ⁇ 8 months; date: >8 months). Statistics are from Wilcoxon rank sum test.
  • D Comparison of within-patient measures in CR and nCR by gut variability (top) and taxa similarity (bottom). Gut composition distances are measured by Aitchison unless otherwise stated.
  • Figure 3 Complete responder gut comprises a stable, Clostridia-dominated community.
  • A UpSet plot showing overlaps of prevalent taxa (present in >80% of samples) found in CR and nCR groups at tO, tearly, and tlate. Connected-dots indicate prevalent taxa shared between timepoint groups (“with overlap”), whereas non-connected dots indicate prevalent taxa detected only in one timepoint group (“sporadic”). Plot is filtered to exclude taxa that have overlaps across CR and nCR (not group-specific). With overlap (dark gray), spurious (ligh gray).
  • B Ranking of prevalent taxa by differential prevalence (top) and differential abundance (bottom).
  • Gray scale indicate uncreasing degree of group-specific overlap, from not group-specific (light) to overlap across all three timepoints (dark). Annotations indicate the proportion of taxa that are stable (i.e., prevalent across timepoints) among those in the 75 th percentile of differential ranking.
  • C Order- level composition of stable CR and nCR taxa (top) and the corresponding “stable taxa index” in CR and nCR (ie., log-ratio of their abundances) (bottom).
  • Asterisks indicate significance by Wilcoxon rank sum test.
  • Stable CR is defined as prevalent taxa that are present across to, teariy, and tiate
  • stable nCR is defined as prevalent taxa that are present in at least two timepoint groups.
  • Dashed line indicates cut-off for enrichment (Fisher’s exact test
  • 2); lines in dark grey indicate enrichment; lines in light gray indicate no enrichment; asterisks indicate significant enrichment at unadjusted p ⁇ 0.05 (Fisher’s exact test); whiskers depict the interval for 95% confidence.
  • FIG. 4 Stable taxa in complete responders associate with favorable blood and immune markers.
  • A Comparison of peripheral blood factors (percent of total) between CR and nCR samples at therapy timepoints. Dashed red lines indicate cuts-off for “high” or “low” based on distribution (low-lymphocyte ⁇ 0.246; low-neutrophil ⁇ 0.61; low-NLR cut-off ⁇ 2).
  • B Fisher’s test of association between stable CR taxa presence and “lymphocyte-high”, “neutrophil-low”, and “NLR-low” cases among therapy samples. Taxa are filtered to include only significantly associated taxa at p-adj ⁇ 0.01.
  • C Heatmap of quantities in serum (SD of mean pg/mL) of top cytokines, at 0, 1-4, 5-8, 9-11, and >11 months.
  • D Fisher’s test of association between stable CR taxa presence and “IL-12P70-high”, “CX3CLl/FRACTALKINE-low”, “IL7-low”, “IL8- low”, and “HGF-low” cases among therapy samples. Features are filtered to include only significantly associated taxa at p-adj ⁇ 0.01. CR (light blue), nCR (red). P-adj ⁇ 0.001 (***), p- adj ⁇ 0.01 (**), p-adj ⁇ 0.05 (*), ns (unannotated).
  • CR gut microbiome is functionally distinct and stably carries genes for fatty acid metabolism and flagellin structure.
  • A Treemap of over-represented pathways in CR at p-adj ⁇ 0.05, based on KOs associated with CR across all samples (
  • B Differentially abundant KOs in CR and nCR at late therapy timepoints.
  • FIG. 6 Peripheral CD8 + T cells of patients with melanoma responsive to ICI show higher activation upon stimulation with tumor mimicking, flagellin-related purified peptides.
  • A Structural simulation of three candidate epitopes (right of pair) predicted from CR-associated flagellin proteins, determined to have sequence and structural homology to a tumor-associated antigen (TAA) (left of pair) and strong affinity to the same HLA allele as that of the TAA ( ⁇ 100 nM).
  • TAA tumor-associated antigen
  • FIG. 7 Frequency distribution of melanoma R and nR samples across time in aggregated months (0, 2-4, 5-8, 9-13 months of therapy). Inset line segments (black) indicate number of samples from non-redundant patients.
  • B Aitchison gut composition difference between the two studies before (top) and after batch correction (bottom, p-adj>0.05, PERMANOVA).
  • D PCA plot of R and nR at therapy, using only unique patient samples at t2-4, t5- 8, and t9— 13. Statistics are from multi-variate PERMANOVA
  • (distance-Response+Patient+Timepoint) at therapy (distance-Response+Patient+Timepoint) at therapy.
  • E Frequency distribution of tumor-free reference, melanoma-R, and melanoma-nR samples sequenced in one run for tumor-free vs. melanoma comparison. Inset line segments (black) indicate number of samples from non- redundant patients (i.e., samples included at each timepoint group are all non-redundant).
  • Asterisk indicates PERMANOVA p-adj (distance-group) at the given timepoint group; p-adj ⁇ 0.0001 (****), p-adj ⁇ 0.001 (***), p- adjO.Ol (**), p-adj ⁇ 0.05 (*), ns (unannotated).
  • Figure 8. Aitchison gut composition computed from Shotgun data (one batch). Plot shows difference between PFS-L and PFS-S (PFS24) melanoma patients across timepoint groups.
  • FIG. 9 Frequency distribution of melanoma R and nR samples from the eight patients used for longitudinal analysis, across time in aggregated months (0, 2-4, 5-8, 9-13 months of therapy). Inset line segments (black) indicate number of samples from non-redundant patients.
  • C-D Baseline-normalized distance compared between R and nR groups at timepoint groups t2-4, t5- 8, and t9— 13 (C) and at tearly and date (D), based on timepoint grouping described.
  • E A median distance from baseline (
  • F Frequency distribution of R and nR samples from the eight patients used for longitudinal analysis, in which samples were aggregated into tO, tearly, and tlate. Inset line segments (black) indicate number of samples from non- redundant patients.
  • X-axis shows the median between-patient distance for each patient at day 0 pre-FMT, whereas y-axis shows the percent viable tumor determined from tumor biopsy pre-FMT.
  • D Spearman correlation of between-patient distance and tumor viability (%) in melanoma patients post-FMT 8 .
  • X-axis shows the median between-patient distance for each patient at day 65 post-FMT, whereas y-axis shows the percent viable tumor determined from tumor biopsy at day 70 post-FMT. Legend reflects RECIST response at endpoint of study.
  • E Comparison of baseline-normalized distance in melanoma R and nR from our cohort and against a longitudinal healthy dataset 18 at tearly and tlate.
  • Gut composition distances are measured by Aitchison unless otherwise stated. P-adj ⁇ 0.0001 (****), p-adj ⁇ O.OOl (***), p-adj ⁇ 0.01 (**), p-adj ⁇ O.O5 (*), ns (unannotated).
  • FIG. 11 Frequency distribution of melanoma CR and nCR samples across time in aggregated months (0, 2-8, 9-13 months of therapy). Inset line segments (black) indicate number of samples from non-redundant patients.
  • B Differentially abundant taxa overlap at tO, tearly, and date in CR and nCR. Connecting dots indicate taxa shared between timepoint groups (“with overlap”), whereas non-connected dots indicate taxa detected only in one timepoint group (“spurious”).
  • C Distribution of Fisher’s exact test p-values (-loglO(p-adj)) on taxa retrieved at increasing within-group sample prevalence cut-off, from 40% (not prevalent) to 80% (highly prevalent).
  • FIG. 12 Comparison of phylum-level Firmicutes/Bacteroidetes ratio (top), and order-level Clostridiales/Bacteroidales ratio (bottom) between complete responders (CR) and not-complete responders (nCR) at tO, tearly, and tlate. Ratios are log-transformed for visualization purposes.
  • B Prevalence barplot of stable CR taxa in CR and nCR groups at baseline (tO). Inset points indicate significance in differential prevalence ranking by Fisher’s exact test (-loglO(p-adj) > 1.3 (*); ns (.)), scaled by the maximum significance.
  • C Baseline increase in bacteria-associated flagellin genes (RPK) in R (right) or nR (left) patients across ten melanoma cohorts, including this study that shows increase in CR (right). Statistics shown are from Wilcoxon rank sum test, whereas magnitude and direction are computed from log2 (foldchange) of counts in R/nR for the nine external studies and CR/nCR for our study.
  • PBMC peripheral blood monocytic cells
  • Figure 16 Experimental binding affinities of the selected flagellin peptides towards A02:01 (left), B07:02 (center), and B08:01 (right), calculated by titrating different concentrations of the test peptide in the presence of 1 pM of protein and fixed concentration (25 nM) of probe peptide HIV-RT (left), MAGE2 (center) and ELR-IAV (right), respectively.
  • LN-1 KMSYEDIEL (SEQ. ID. No. 1);
  • LN-3 ALNETSAIL (SEQ. ID. No. 3);
  • LN-9 GLDALNNLL (SEQ. ID. No. 10); HIV-RT: ILKEPVHGV (SEQ. ID. No.
  • LN-2 MPKDGAAFI (SEQ. ID. No. 2); LN-7: SVRGRLGAF (SEQ. ID. No. 8); MAGE2: VPISHLYIL (SEQ. ID. No. 145); LN-8: FPELKHFTM (SEQ. ID. No. 9); ELR-IAV: ELRSRYWAI (SEQ. ID. No. 146).
  • Figure 17 (A) Representative flow cytometry contour plots and (B) number of TILs from four human melanoma tumors expanded with or without adding the indicated peptide pools. (C-D) Representative dot plots (C) and bar plots (D) showing cytotoxicity (measured as % of PI positive melanoma cells) of TILs expanded with or without adding the indicated peptide pools and tested on four matching melanoma patient-derived organoids.
  • FIG. 18 Representative pictures of tumor infiltrating lymphocytes (TILs) from human melanoma tumors expanded with or without adding the indicated FLach peptide pools. Legend: p-adj ⁇ O.OOl (***), p-adj ⁇ 0.01 (**), p-adj ⁇ O.O5 (*), ns (unannotated).
  • flagellin protein is intended a protein forming the filament in a bacterial flagellum.
  • flagellin-related gene is intended a gene coding for a protein which does not form the flagellum but which is associated with the activity of the flagellins.
  • Said flagellin-related gene can be present in the genoma of any bacterial organism. Preferably, it is in the genoma of bacteria of Chlostridia class, more preferably of the Lachnospiraceae family, even more preferably of Roseburia genere, in particular Roseburia inulinivorans.
  • flagellin-related gene is used to identify a gene family/ cluster of genes composed of genes related to flagellin by name or function and limited to taxonomy for bacteria. Said cluster has been generated by selection within UniRef O database. More in details, to determine flagellin-related terms from the gene family abundance table, a list was generated from the UniProt website (https://www.uniprot.org/), searching for “(taxonomy_id:2) and flagellin” within the UniRef database and matching for UniRef O hits as was used for the gene family data. With this list, were retrieved 1,563 features present in dataset and 4,241 features in the multi-cohort baseline melanoma data.
  • said at least one peptide is coded by a flagellin-related gene
  • said peptide can be obtained by reducing said protein into fragments using conventional methods, wherein said fragments are at least 9 amino acids long, preferably between 9 and 20 amino acids, preferably between 9 and 10, more preferably each fragment consists of 9 amino acids.
  • the expression “cancer characterized by increased expression of at least one of the following antigens” refers to a cancer having an increased expression of at least one of the mentioned antigens with respect to expression of the same antigen in a subject not affected by cancer.
  • nucleic acid “nucleotide sequence” and “polynucleotide” are herein used as synonyms.
  • peptide is intended a chain of amino acids linked by peptide bonds.
  • a peptide typically comprises from 2 to 50 amino acids.
  • the peptide preferably comprises from 9 to 20 amino acids.
  • peptide variant is intended a peptide having at least one different amino acid and retaining the ability to bind to the same MHC molecule to which the original peptide binds, for example peptides having one or two amino acids substituted by amino acids belonging to the same group.
  • peptide variant is also intended a peptide having at least one and a maximum of seven different amino acids and retaining the ability to bind to the same MHC molecule to which the original peptide binds, for example peptides having one or two amino acids substituted by amino acids with similar bulking or biophysical properties.
  • Peptide variants according to the invention can be synthetized according to common general knowledge in the field.
  • TILs tumor infiltrating lymphocytes, which are commonly used in immune cell therapy for cancer, wherein said therapy involves the removal of immune T cells from a tumor, their in vitro expansion, and their use as anti-cancer agent.
  • lymphocytes expansion is intended proliferation of lymphocytes after activation.
  • MPDOs melanoma patient-derived organoids
  • a matrix such as collagen gel or Matrigel
  • Peptides according to the invention can be synthetized according to common general knowledge in the field. Peptides coded by the genes herein described can be obtained by expressing the gene using routine techniques.
  • said peptide is coded by the flagellin-related gene coding for A0A127SWS0 and is selected from the group consisting of peptides comprising or consisting of the following sequences: STEKLSSGY (SEQ ID N.I 1), RMLNVTTSA (SEQ ID N.12), ALTEVHSML (SEQ ID N.13), SMLQRMNEL (SEQ ID N.M), and EVHSMLQRM (SEQ ID N.15).
  • said peptide is coded by the flagellin-related gene coding for C0FQ36 and is selected from the group consisting of peptides comprising or consisting of the following sequences: VLTTVRVPK (SEQ ID N.16), IIINMSNNK (SEQ ID N.17), MKQEDTFVL (SEQ ID N.I 8), SHIMWLQSM (SEQ ID N. I 9), FPDMQKFTL (SEQ ID N.20) and KGSKSHIMW (SEQ ID N.21).
  • said peptide is coded by the flagellin-related gene coding for A0A396AI63 and is selected from the group consisting of peptides comprising or consisting of the following sequences: TLMPCCPAV (SEQ ID N.22), YLNPVIEKA (SEQ ID N.23), YLENSFEEL (SEQ ID N.24), WLLDGQKEI (SEQ ID N.25), QAYNPLMRK (SEQ ID N.26), VFPREVHRF (SEQ ID N.27), EMADRMHEF (SEQ ID N.28), LPQKKNLSA (SEQ ID N.29), YIREKLTEL (SEQ ID N.30), NPLMRKFLI (SEQ ID N.31), RMHEFESEF (SEQ ID N.32), VLSETCAVF (SEQ ID N.33), KLCKLVTAY (SEQ ID N.34), FLREHARFY (SEQ ID N.35), LRWLLDGQK (SEQ ID N
  • said peptide is coded by the flagellin-related gene coding for A0A0M6WMV3 and is selected from the group consisting of peptides comprising or consisting of the following sequences: TSDTKQYTY (SEQ ID N.43), GMLNQTTLL (SEQ ID N.44), YIIAVNQTL (SEQ ID N.45), RMSNQQLTV (SEQ ID N.46), AVKAGNMPK (SEQ ID N.47), KTAEEMSQK (SEQ ID N.48), IYQDIDYII (SEQ ID N.49), IIIDYTAAY (SEQ ID N.50), MPKDGAAFI (SEQ ID N.2), MRVTNNMML (SEQ ID N.51), YRTNCKLTF (SEQ ID N.52), VELKTAEEM (SEQ ID N.53), SAQENLQTW (SEQ ID N.54) and KTGTLSYHY (SEQ ID N.55).
  • said peptide is coded by the flagellin-related gene coding for A0A0M6WD36 and is selected from the group consisting of peptides comprising or consisting of the following sequences: FSDEGKMSY (SEQ ID N.56), KLCDIYSEL (SEQ ID N.57), VLAKAQFAI (SEQ ID N.58), KLDDRIANA (SEQ ID N.59), ISFDEAFHV (SEQ ID N.60), KMSYEDIEL (SEQ ID N.
  • ILRVPSYYK SEQ ID N.61
  • KTFQCIADK SEQ ID N.62
  • SYYKTFQCI SEQ ID N.63
  • RYFANGKSF SEQ ID N.64
  • YYMGIEGAF SEQ ID N.65
  • YFHVRMETF SEQ ID N.66
  • VYFTYRYFM SEQ ID N.67
  • RVPSYYKTF SEQ ID N.68
  • DVREKSLSV SEQ ID N.69
  • MILRVPSYY SEQ ID N.70
  • ALCEVCTEY SEQ ID N.71
  • YRYFMRAWY SEQ ID N.72
  • YRTQAVAIL SEQ ID N.73
  • VRMETFDEL SEQ ID N.74
  • NEIWYEHIL SEQ ID N.75
  • YEDIELPDL SEQ ID N.76
  • IEGAFGERL SEQ ID N.77
  • KSGDYNEIW SEQ ID N.
  • said peptide is coded by the flagellin-related gene coding for D4KYR7 and is selected from the group consisting of peptides comprising or consisting of the following sequences: RLDSGNYNV (SEQ ID N.79), KLLEKYNAL (SEQ ID N.80), KTRKRISRK (SEQ ID N.81) and DAIMRVEAY (SEQ ID N.82).
  • said peptide is coded by the flagellin-related gene coding for R6VY20 and is selected from the group consisting of peptides comprising or consisting of the following sequences: TSENMTSAY (SEQ ID N.83), STDVPVKEY (SEQ ID N.84), AMTEISEML (SEQ ID N.85), KLLNGEYDL (SEQ ID N.86), VLEVNIPAV (SEQ ID N.87), RMNAQIEGL (SEQ ID N.88), TIKSIPLTK (SEQ ID N.89), DMAEEMTSY (SEQ ID N.90), RPSQVLQLL (SEQ ID N.91), SVRGRLGAF (SEQ ID N.8), EMLQRINEL (SEQ ID N.92), ILAQAGTSM (SEQ ID N.5), GQKLLNGEY (SEQ ID N.93), MRLDVSGAL (SEQ ID N.94), GENGFEMRL (SEQ ID N.95)
  • said peptide is coded by the flagellin-related gene coding for A0A351R0D5 and is selected from the group consisting of peptides comprising or consisting of the following sequences: RIRDTDMAK (SEQ ID N.96), KVSSQRSAL (SEQ ID N.97), ILAQAGQSM (SEQ ID N.4) and VKSSLAFSL (SEQ ID N.98).
  • said peptide is coded by the flagellin-related gene coding for A0A0M6WBR8 and is selected from the group consisting of peptides comprising or consisting of the following sequences: LADFIYQKY (SEQ ID N.99), AVAEILAMV (SEQ ID N.100), LMSDALIQI (SEQ ID N.101), FVVTALISV (SEQ ID N.102), RMMQDVPKA (SEQ ID N.103), YLAQKIKEA (SEQ ID N.104), GLADFIYQK (SEQ ID N.105), LYQAVAEIL (SEQ ID N.106), LMNSFVDIY (SEQ ID N.107), KSKELTAAF (SEQ ID N.108), RIFSKDSIF (SEQ ID N.109), QQKQLHLIM (SEQ ID N.
  • said peptide is coded by the flagellin-related gene coding for A0A0M6WYS8 and is selected from the group consisting of peptides comprising or consisting of the following sequences: FTGLQASRY (SEQ ID N.120), ALDDAIAMV (SEQ ID N.121), SIFSSTATV (SEQ ID N.122), ALNETSAIL (SEQ ID N.3), KMQAQIDAL (SEQ ID N.123), SLVLTFSGK (SEQ ID N.124), NMSAVITNK (SEQ ID N.125), TIKQPAATK (SEQ ID N.126), ETSAILQRM (SEQ ID N.127), DMAEEMTNY (SEQ ID N.128), LPQNVLSLL (SEQ ID N.129), LQRMRELSV (SEQ ID N.
  • said peptide is coded by the flagellin-related gene coding for R6EJ07 and is selected from the group consisting of peptides comprising or consisting of the following sequences: TSENMTAAY (SEQ ID N.136), AMTEISEML (SEQ ID N.85), KLLNGEFDL (SEQ ID N.137), VLEVNIPAV (SEQ ID N.87), RMNAQIEGL (SEQ ID N.88), DMAEEMTSY (SEQ ID N.90), RPSQVLQLL (SEQ ID N.91), SVRGRLGAF (SEQ ID N.8), EMLQRINEL (SEQ ID N.92), ILAQAGTSM (SEQ ID N.5), GQKLLNGEF (SEQ ID N.138), MRLDVSEAK (SEQ ID N.139) and TEFNGQKLL (SEQ ID N.7).
  • TSENMTAAY SEQ ID N.136
  • AMTEISEML SEQ ID N.85
  • said peptide is coded by the flagellin-related gene coding for R6VQ94 and is selected from the group consisting of peptides comprising or consisting of the following sequences: ILVMVTVTV (SEQ ID N.140), LQGPFVINV (SEQ ID N.141), MTVNLQGPF (SEQ ID N.142), and FPELKHFTM (SEQ ID N.9).
  • said peptide is coded by the flagellin-related gene coding for A0A0M6WP36 and is selected from the group consisting of peptides comprising or consisting of the following sequences: GLDALNNLL (SEQ ID N.10) and LTRKKGEAL (SEQ ID N.143).
  • composition of the invention comprises peptides with a length from 9 amino acids to 30 amino acids, preferably from 9 amino acids to 20 amino acids, more preferably of 9 amino acids.
  • the composition comprises a peptide of SEQ ID N.3, a peptide of SEQ ID N.4, a peptide of SEQ ID N.6, a peptide of SEQ ID N.7, a peptide of SEQ ID N.8 and a peptide of SEQ ID N.9 and, optionally a peptide of SEQ D N. 5: said peptides’ pool is also named here as FLA-R or FLach-R.
  • the composition comprises a peptide of SEQ ID N. I, a peptide of SEQ ID N.2 and a peptide of SEQ ID N.10: said peptides’ pool is also named here as FLA-G or FLach-G.
  • the peptide according to the present invention may comprise additional portions of amino acids at the N-terminus or C-terminus, which are not necessarily part of the peptide portion that serves as an epitope for the MHC molecules.However, these additional parts can be important to provide an efficient introduction of the peptide according to the present invention into the cells.
  • the peptides are bound to an antibody, or a functional part of the antibody itself, in particular peptides can be inserted into a sequence of an antibody, so as to be specifically carried by the antibody or, for example, can be fused to an antibody, or inserted into an antibody, which is specific for dendritic cells.
  • the peptides according to the present invention can be further modified or modified to improve the stability and / or the binding with the MHC molecules, in order to obtain a stronger immune response. Methods for optimizing a peptide sequence are well known in the art and include, for example, the introduction of reverse peptide bonds or non-peptide bonds.
  • Retro-inverse peptidomimetic peptides can be made using methods known in the art, such as those described in Meziere et al (1997) J. Immunol. 159, 3230- 3237, incorporated herein by reference. This approach involves the creation of pseudopeptides containing changes that involve the skeleton and not the orientation of the side chains. Meziere et al (1997) show that these pseudopeptides are useful for MHC binding and helper T cell responses. Retro-inverse peptides, which contain NH-CO bonds instead of CO-NH peptide bonds, are much more resistant to proteolysis.
  • U.S. Pat. 4,897,445 provides a method for the solid phase synthesis of non-peptide bonds (-CH2- NH) in polypeptide chains involving the use of polypeptides synthesized by standard procedures and the non-peptide bond synthesized by the reaction of an amino-aldehyde and an amino acid in the presence of NaCNBHv
  • the peptides comprising the sequences described above can be synthesized with further chemical groups present at their amino and/or carboxyl end groups, to improve the stability, bioavailability and/or affinity of the peptides.
  • hydrophobic groups such as the carbobenzyloxy, dansyl or t-butyloxycarbonyl groups can be added to the amino terminals of the peptides.
  • an acetyl group or a 9-fluorenylmethoxycarbonyl group can be placed at the amino terminals of the peptides.
  • the hydrophobic group, the t-butyloxycarbonyl or an amide group can be added to the carboxy-terminus of the peptides.
  • the peptides according to the present invention can be synthesized in such a way as to alter their steric configuration.
  • the D isomer of one or more of the amino acid residues of the peptide can be used, rather than the usual L isomer.
  • at least one of the amino acid residues of the peptides of the invention can be replaced by one of the well-known amino acid residues, not present in nature. Alterations such as these can serve to increase the stability, bioavailability and / or binding action of the peptides of the invention.
  • a peptide or a variant of the peptide according to the present invention can be chemically modified or modified by reacting specific amino acids before or after the synthesis of the peptide.
  • Chemical modification of amino acids includes, but is not limited to: modification by acylation, amidation, pyridoxylation of lysine, reductive alkylation, trinitrobenzylation of amino groups with 2,4,6- trinitrobenzenesulfonic acid (TNBS), amide modification of carboxylic groups and sulfhydryl modification by oxidation with performic acid of cysteine to cysteic acid, formation of mercurial derivatives, formation of mixed disulfides with other thiol compounds, reaction with maleimide, carboxymethylation with iodoacetic acid or iodoacetamide and carbamylation with cyanate at alkaline pH.
  • the methodologies for the chemical modification of proteins are well known to one skilled in the art.
  • the modification of arginyl residues in proteins is often based on the reaction of vicinal dicarbonyl compounds such as phenylglyoxal, 2, 3 -butanedione and 1,2-cyclohexanedione to form an adduct.
  • Another example is the reaction of methylglyoxal with arginine residues.
  • Cysteine can be modified without the concomitant modification of other nucleophilic sites such as lysine and histidine. Consequently, a large number of cysteine modification reagents are available.
  • Sigma-Aldrich www.sigma-aldrich.com
  • Disulfide bonds can be formed and oxidized during the heat treatment of biopharmaceutical products.
  • Woodward’s K reagent can be used to modify specific glutamic acid residues.
  • N-(3-(dimethylamino)propyl)-N’- ethylcarbodiimide can be used to form intra-molecular connections between a lysine residue and a glutamic acid residue.
  • diethyl pyrocarbonate is a reagent for the modification of histidyl residues in proteins. Histidine can also be modified using 4-hydroxy-2-nonenal.
  • lysine residues and other a-amino groups is, for example, useful in the binding of peptides to surfaces or in the cross-linking of proteins / peptides.
  • Lysine is the attachment site of poly (ethylene) glycol and the major modification site in protein glycosylation.
  • the methionine residues in proteins can be modified for example with iodoacetamide, bromoethylamine and chloramine T. Tetranitromethane and N-acetylimidazole can be used for the modification of tyrosyl residues.
  • Cross-linking through the formation of di-tyrosine can be accomplished with hydrogen peroxide/copper ions.
  • N-bromosuccinimide, 2-hydroxy-5-nitrobenzyl bromide or 3- bromo-3-methyl-2-(2-nitrophenylmercapto)-3H-indole have been used in some tryptophan modification studies.
  • peptides and variants can be synthesized by the Fmoc-polyamide mode of solid phase peptide synthesis, as disclosed by Lukas et al. (Solid-phase peptide synthesis under continuous flow conditions Proc. Natl Acad Sci USA, May 1981; 78 (5): 2791-2795).
  • Temporary protection of the N-amino group is provided by the 9-fluorenylmethyloxycarbonyl (Fmoc) group.
  • the invention provides at least one polynucleotide coding for at least one of the peptides disclosed herein.
  • the skilled person can design such polynucleotide according to the common general knowledge regarding nucleic acids coding for peptides.
  • expression vectors are plasmids which are used to introduce a desired nucleic acid sequence, such as a gene, into a target cell, resulting in the transcription and translation of the protein encoded by the nucleic acid sequence, i.e. the chimeric antigen receptor, the antibody or the binding molecule.
  • the expression vector in general comprises regulatory sequences, such as promoter and enhancer regions, as well as a polyadenylation site in order to direct efficient transcription of the nucleic acid sequence on the expression vector.
  • the expression vector may further comprise additional necessary or useful regions, such as a selectable marker for selection in eukaryotic or prokaryotic cells, a purification tag for the purification of the resulting protein, a multiple cloning site or an origin of replication.
  • the expression vector may be a viral or a non- viral vector.
  • various kinds of viral vectors such as retroviral vectors, e.g. lentiviral or adenoviral vectors, or plasmids may be used.
  • the invention provides, compositions, e.g., pharmaceutical compositions, which include a pharmaceutically acceptable carrier, excipient or stabilizer, and at least one of the peptides described herein.
  • the composition e.g., the pharmaceutical composition
  • the composition can also be a vaccine against a cancer.
  • vaccine against a cancer is intended that administration of the composition to a subject stimulates immunity against a cancer.
  • the cancer can be any cancer as herein defined.
  • the peptide or the pharmaceutical composition can be administered to the subject in various embodiments in a formulation comprising suitable carriers, excipients, and other agents to provide improved transfer, delivery, tolerance, and the like, and suitable for an intravenous or subcutaneous injection, or for intramuscular or oral delivery.
  • the content of the peptide in the pharmaceutical composition is not limited as far as it is useful for treatment or prevention of a cancer.
  • the choice of the carrier may depend upon the route of administration and concentration of the active agent(s) and the carrier may be in the form of a composition or an aqueous solution. Generally, an appropriate amount of a pharmaceutically acceptable salt is used in the carrier to render the composition isotonic.
  • the carrier include but are not limited to saline, Ringer’s solution and dextrose solution.
  • acceptable excipients, carriers, or stabilizers are non-toxic at the dosages and concentrations employed, including buffers such as citrate, phosphate, and other organic acids; salt-forming counter- ions, e.g.
  • low molecular weight polypeptides polypeptides
  • proteins e.g. serum albumin, or gelatine
  • hydrophilic polymers e.g. polyvinylpyrrolidone
  • amino acids such as histidine, glutamine, lysine, asparagine, arginine, or glycine
  • carbohydrates including glucose, mannose, or dextrins; monosaccharides; disaccharides; other sugars, e.g. sucrose, mannitol, trehalose or sorbitol; chelating agents, e.g. EDTA; non-ionic surfactants, e.g.
  • Tween Pluronics or polyethylene glycol; antioxidants including methionine, ascorbic acid and tocopherol; and/or preservatives, e.g. octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens, e.g. methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol).
  • antioxidants including methionine, ascorbic acid and tocopherol
  • preservatives e.g. octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol;
  • the composition may also contain at least one further active compound, such as an anti-cancer agent.
  • Preferred anti-cancer agents include a chemotherapeutic agent, a targeted drug and an immunotherapeutic agent, such as an immune checkpoint modulator.
  • said further active compound is an immune checkpoint inhibitor (ICI).
  • Said ICI can be selected from an antibody anti-PD-1, an antibody anti-PD-Ll and an antibody anti-CTLA-4.
  • the peptide is included in an effective amount.
  • effective amount refers to an amount sufficient to induce a detectable therapeutic response in the subject to which the pharmaceutical composition is to be administered.
  • the peptide or the composition according to the invention can be administered to the subject using any acceptable device or mechanism.
  • subject means a human subject or human patient.
  • melanoma or “melanoma cancer” it is intended a skin cancer that develops from the pigment-producing cells known as melanocytes. Melanoma can be of any type.
  • It is a further object of the invention a method for the treatment of a cancer comprising administering to a patient in need thereof the composition of the invention in a therapeutically effective dosage.
  • Fecal samples were processed for 16S sequencing to compare the microbiota structure and composition at baseline (tO) (i.e., before therapy) and at each cycle of therapy (tl, t2, t3... tn). Briefly, DNA was extracted from feces of melanoma patients and healthy donors using the Dneasy PowerSoil Pro kit (Qiagen), after which the V3-V4 region of 16S was amplified. Libraries were prepared following the 16S sequencing library preparation protocol (Illumina), and sequenced by a 2x250 bp paired end chemistry on a MiSeq platform.
  • Phylogenetic tree reconstruction for downstream diversity analyses was done with the q2- fragment-insertion plug-in 21 , using SILVA 128 database 22 as reference sequence.
  • the q2-feature-classifier plug-in was used. Briefly, full-length reference sequences from the SILVA 132 database were downloaded from the SILVA resources page for qiime (https://www.arb-silva.de/download/archive/qiime), after which the sequences were used to train a Naive-Bayes classifier using the fit-classifier-naive-bayes function 23 .
  • the trained classifier was run on the representative sequences output of DADA2 using the classify-skleam function to generate taxonomic assignments for each ASV.
  • raw counts tables were first transformed by centered-log-ratio (CLR) following the mixOmics workflow for pre-processing microbiota data 29 , and batch effect correction was applied using COMBAT with non-parametric setting 30 .
  • CLR centered-log-ratio
  • the overall composition of the samples was projected into a PCA after computing the Aitchison distance on the transformed abundance, testing group differences on the abundance table by PERMANOVA while checking for balance in dispersion by PERMDISP.
  • batch correction was performed more conservatively: first, by mean-centering CLR-transformed raw counts from each sequence batch within a group; this ensures that correction is performed by batch while preventing within-batch between-group differences from being corrected; then, by merging the separately batch-corrected groups together as one dataset. Composition was visualized as described above.
  • the usedist package 31 was used: dist subset for subsetting distances, dist get for retrieving specific group-wise distances, dist groups for sorting within- and between- group distances.
  • Within-patient gut distance To normalize for patient variability in the longitudinal analysis of 16S data, within-patient gut distance was used as measure, computing the Euclidean distance between a baseline and a timepoint sample from taxonomic abundance data (CLR-transformed and batch-corrected), and doing boxplot group comparisons on this distance, using non-parametric Wilcoxon rank sum as statistical test.
  • DNA extracts from fecal samples of select melanoma samples from the study were subjected to metagenomic sequencing, where libraries were prepared using the Illumina DNA Prep Kit according to manufacturer’s protocol. Libraries were multiplexed using dual indexing and sequencing was performed with a 3OO-bp paired-end chemistry, using the Illumina NovaSeq6000 platform according to manufacturer’s protocol.
  • Shotgun metagenomic sequencing was performed at the NGS Core Facility at University of Trento.
  • the quality of all sequenced metagenomes was controlled using the preprocessing pipeline implemented in https://github.com/SegataLab/preprocessing, which consists of three main stages: (1) initial quality control by removing low-quality reads (quality score ⁇ Q20), fragmented short reads ( ⁇ 75 bp) and reads with more than two ambiguous nucleotides; (2) contaminant DNA removal using Bowtie 2 32 and the sensitive local parameter, removing both the phiX174 Illumina spike-in and human-associated reads (hg!9); and (3) sorting and splitting for the creation of standard forward, reverse and unpaired reads output files for each metagenome.
  • Metagenomic sequence data from current study as well as from previously published baseline melanoma cohorts 11 were run through the biobakery 3 pipeline 33 , which leverages a set of 99,200 high-quality and fully annotated reference microbial genomes spanning 16,800 species and the 87.3 million UniRef90 34 functional annotations available in UniProt as of January 2019.
  • Taxonomic profiling of taxa composition of all metagenomic samples was performed with MetaPhlAn v4.0.3 35 using default parameters and CHOCOPhlAnSGB v202103 as database. Functional potential analysis of the metagenomic samples was performed with HUMAnN v3.6 33 using default parameters. Stable taxa analysis.
  • “Stable” taxa were thus determined as prevalent taxa detected in all three timepoint groups for CR (tO, tearly, and date), and in at least two timepoint groups nCR (tO and tearly or tO and date).
  • Taxonomic differential ranking is a measure of Taxonomic differential ranking.
  • Differential ranking was performed on the hits by sorting the features by the -loglO(p-adj) of each feature, determining the group of association by the sign of either the log2 fold-change (for differential abundance) or Fisher’s OR (for differential prevalence).
  • Differential abundance and prevalence indices of stable taxa were measured by taking the size of stable taxa and dividing against the size of topranking hits.
  • differential abundance was performed using Maaslin2 40 .
  • gene family abundances from Humann were re-grouped from gene family terms (Uniprot90 IDs) to KEGG orthologs (KOs).
  • Group-associated KOs were determined by converting abundances in RPK to rpm, linearly modelling log-transformed relative abundances against response status of samples at tO, tearly, and date. Significance for differential abundance was set at p-adj ⁇ 0.05.
  • LM coefficient! > 1.5 were taken as input, filtering for those taxa associated with the given group by the sign of LM coefficient (eg., +LM values only for comparison group; -LM values only for reference group).
  • log2 fold-change was computed by getting the median abundance of each flagellin across samples within CR and nCR, and, using the gtools package 36 , getting the fold-change (foldchange) of the group medians and converting it to log-ratio (foldchange21ogratio).
  • the top 14 flagellin markers with the highest log2 fold-change were identified as candidate CR flagellin markers.
  • SB strong-binding
  • Molsoft Mol Browser (version 3.8-7d) (Molsoft LLC, San Diego, CA) was used for epitope modelling and molecular docking and conformation calculations for the shortlisted peptides and matching TAAs.
  • Luminex 200 platform Luminex Inc.,
  • custom kits of pre-mixed antibody-coated beads R&D System Inc., MN
  • CCLl l eotaxin CCL13 MCP4, CCL17 TARC, CCL2 MCP1, CCL22 MDC, CCL26 EOTAXIN3, CCL5 RANTES, CCL8 MCP2, CD25_IL2Ra, CX3CL1 FRACTALKINE, CXCLI GROa, CXCL10 IP10, CXCL11 ITAC1, CXCL13 BLC BCA1, CXCL4 PF4, CXCL5 ENA78, CXCL6 GCP2, EGF, IFNg, GMCSF, HGF, IL10, ILlra_ILlF3, IL7, IL8 CXCL8, TRAIL, VEGFA, ILlb_ILlF2, IL5, IL6, IL-17F,
  • the assay was run based on manufacturer recommendations. Briefly, 50ml of samples together with kit standards were added to each well in duplicate and incubated with the diluted Microparticle Cocktail at 4C, overnight, on a shaker at 850rpm. Unbound soluble molecules were removed by washing the plate. The Biotin- Antibody Cocktail specific to the analytes of interest was added to each well for Ih at RT. After washing again, the Streptavidin-Phycoeriythrin conjugated was added for 30 minutes at RT. After the final washing steps, the microparticles are resuspended in kit buffer and read on a Luminex 200 platform.
  • the outputs (pg/mL) were visualized and statistically analyzed in R upon centering and scaling using the scale function in R (SD from mean pg/mL) 44
  • Data were visualized together with sample annotations using the ComplexHeatmap package 45 .
  • Group comparisons were visualized as boxplots using the ggpubr package and statistically analyzed by applying the non-parametric Wilcoxon signed-rank test on the values, where significance is set at p-value ⁇ 0.05.
  • White blood cell counts (% of total WBC) and soluble factor data (mean-centered and scaled by SD of pg/mL) were analyzed, making group comparison on the quantities by Wilcoxon rank sum test.
  • Enrichment analysis was performed by Fisher’s exact test. Briefly, contingency tables were computed; binary categories for feature states were generated, by prevalence (prevalent:
  • re-analysis of publicly available longitudinal metagenomic data from two independent studies whose recipients received anti-PD- 1 treatment in combination with FMT 8, 10 revealed increasing differences across therapy between patients with melanoma responsive or non-responsive to ICI (Figure 8B-C).
  • Stable taxa in complete responders associate with blood markers.
  • CR gut microbiome is functionally distinct and stably carries metabolic and flagellin- associated genes.
  • top CR-associated flagellin genes retrieved from our dataset were mostly annotated to Lachnospiraceae taxa (especially to butyrate-producer Roseburia inulinivorans,. Table 4 and Table 5), which have been shown to play a synergistic role in host immune tolerance 60 and anti-tumor immunity 61 .
  • gut-residing Lachnospiraceae can be a rich source of tumor-mimicking epitopes 42
  • TAAs tumor-associated antigens
  • Table 6 List of predicted epitopes fortop CR-associated flagellin-related gene encoded proteins.
  • TAAs Three showed strong HLA-1 affinity ( ⁇ 100 nM) and sequence homology to four TAAs. Strikingly, three of these matching TAAs were known to associate with melanoma, namely Preferentially Expressed Antigen in Melanoma (PRAME), a melanoma-associated antigen expressed in 87% of metastatic and 83.2% of primary melanomas 63 , Melanoma Antigen Recognized by T Cells 1 (MART-l/Melan-A), one of the oldest identified tumor antigens found in most melanomas 64 ' 65 , and secerning 1 (SCRN1), a protein involved in MMP2/9 exocytosis 66 ' 67 and overexpressed in amelanotic melanoma 68 .
  • PRAME Preferentially Expressed Antigen in Melanoma
  • MART-l/Melan-A Melanoma Antigen Recognized by T Cells 1
  • SCRN1 secerning 1
  • CD8 + T cells of complete responders demonstrated greater activation following peptide stimulation, as measured by CD25 upregulation (Figure 15D) and increased proportion of IFNy-secreting CD8 + T cells in 5/7 and 6/7 of CR tested with FLA-G and FLA-R mix, respectively (peptide mix/control ratio 1.3 ⁇ 0.2 vs 0,6 ⁇ 0.1 FLA-G and 1 ,4 ⁇ 0.2 vs 0.3 ⁇ 0.2 FLA-R, Figures 6B-C). While providing evidence of their immunogenicity, the differential reactivity proves that patients with melanoma responsive to ICI can specifically mount a CD8 + T cell-mediated response directed against tumormimicking, flagellin-related peptides.
  • MHC-I restricted peptides derived from proteins coded by flagellin-related Lachnospiraceae genes show structural homology with human tumor-associated antigens (TAAs). Binding affinity of FLach to purified MHC-I in vitro was measured, demonstrating that some of the bacterial-derived 9-mers bind their predicted MHC-I with a higher affinity than prototypic control peptides, the results are shown in Figure 16 and Table 8. These data demonstrate that analysis of stable gut metagenomes associated with complete response to ICI lead to the identification of MHC-I restricted bacterial antigens with previously unexplored tumor-antigen mimicry potential.
  • TILs expansion was significantly higher in the presence of FLach compared to control, especially with the FLach- G pool (which contained SB FLach SB matching SB TAAs), indicating a specific reactivity of TILs against those FLach antigens mimicking known melanoma-associated TAAs, the results are shown in figure 17.
  • the FLach-G pool (alternatively named through the invention as FLA-G) includes the 3 SB bacterial-derived peptides that share structural homology with melanoma SB TAAs.
  • the FLach- R pool (alternatively named through the invention as FLA-R) is a mix of the 6 SB bacteria- derived peptides matching low affinity TAAs. They both are reported in Table 9.
  • Aff. Affinity
  • SB Strong Binder
  • F Flach pool (G or R)
  • Direct TIL killing ability on melanoma patient-derived organoids was assessed and the results are shown in Figure 18. More in details, in figure 18 the photograph on the left shows the tumor infiltrating lymphocytes (TILs) from human melanoma tumors expanded without adding any of the peptide pools, while the photograps in the middle and on the right refer to the TIL expanded with, respectively, the indicated FLach- G and FLach-R pool s .
  • TILs tumor infiltrating lymphocytes
  • Beta diversity distances were computed from the relative 148 abundances using the calculate diversity.R function from MetaPhlAn, setting the method to ‘aitchison’. The distances were ordinated by PCoA using the ape::pcoa function. Beta-diversity group differences were computed from the distance matrices by PERMANOVA 28 , checking for balance in dispersion by PERMDISP. All reported significant p-values by PERMANOVA were checked to have nonsignificant dispersion. The overall composition of the samples was projected into a PCA after computing the Aitchison distance on the transformed abundance, testing group differences on the abundance table by PERMANOVA while checking for balance in dispersion by PERMDISP.
  • HLA-B*0801 and HLA-B*0702 molecules were reconstituted in vitro as described previously 86 . Briefly, urea-solubilized inclusion bodies of class I heavy chain (HC) (1 mM) and b?m (2 mM) were combined with a synthetic peptide (10 mM) (FLRGRAYGL SEQ ID No. 158 for HLA- B*0801; APRTVALTA SEQ ID No. 159 for HLA-B*0702) in an oxidative refolding buffer. The refolding mixtures containing MHC I/peptide complexes were concentrated and purified on a Superdex 200 Increase 10/300 gel filtration column at 4°C. Stock solutions of purified MHC I/peptide complexes (10-30 mg/mL) in 20 mM Tris-HCl, pH 290 7.5, 150 mM NaCl, were kept at -80°C.
  • Cryopreserved PBMCs of patients with melanoma R and NR were used for the in vitro stimulation after challenge with FLA peptides.
  • RPMI-1640 Euroclone, Cat. No. ECM2001L
  • FBS Euroclone, Cat. No. ECS0165L
  • lOmM Hepes Synigna, Cat. No. H0087
  • IX Sodium Pyruvate Euroclene, Cat. No. ECM0742D
  • IXPen/Strep Euroclone, Cat. No.
  • ECB3001D ECB3001D
  • 100 U/ml IL2 PROLEUKIN
  • cells were plated at lxl06/ml (200,000 cells/well), pulsed with peptides (lug/ml), and incubated for 5 days, after which the media was changed.
  • lug/ml peptides
  • cells were restimulated with 2ug/ml of peptide and 56 lug/ml of anti-CD28/49d (BD, Cat. No. 347690) for 6h.
  • Golgi plug BD, Cat. No. 555029
  • Staining was performed using Fixable Viability Stain BV510 (BD, Cat. No. 564406), CCR7 BV421 (BD, Cat. No.
  • CD8 BV605 (BD, Cat. No. 564116), CD25 BV786 (BD, Cat. No. 741035), CD45RA PE (BD, Cat. No. 561883), CD69 APC (BD, Cat. No. 555533), CD3 APCR700 (BD, Cat. No. 565119) and CXCR3 PerCP-Cy5.5 (BD, Cat. No. 560832); then, cells were fixed and permeabilized using Fixation/Permeabilization Solution Kit (BD, Cat # 554714), and stained intracellularly with an antibody cocktail (IL17A FITC (Invitrogen, Cat. No. 11- 7179-42), IFNG PE-CF594 (BD, Cat. No.
  • HEK reporter cell line purchased from Invivogen (San Diego, USA). This reporter cell line expresses Secreted Embryonic Alkaline Phosphatase (SEAP), which is coupled to the nuclear factor KB/Activating protein-1 (NF-KB/AP-1) promotor.
  • SEAP Secreted Embryonic Alkaline Phosphatase
  • NF-KB/AP-1 nuclear factor KB/Activating protein-1
  • the HEK-Blue hTLR5 cell line expressing TLR5 was cultured in DMEM medium, containing 10% heat-inactivated FBS, 2 mM l-glutamine, 4.5 g L-l glucose, 50 U mL-1 and 50 mg 8 mL-1 penicillin/streptomycin and 100 mg mL-1 Normocin. All reporter cell lines were cultured for 3 passages before they were maintained in a cell medium containing selective antibiotics (blasticidin lOug/mL, zeocin 300ug/mL).
  • HEK cells were seeded into a flatbottom 96-well plate at a cell density following the manufacturer's protocol (25000 cells in 180 ul per well) directly into Hek-Blue Detection medium.
  • TLR5 TLR5 by the pool peptides
  • cells were stimulated 16h (37 °C, 5% CO2) with 20 uL of lug/mL of the pools G and R as well as increasing concentrations of the Ultrapure flagellin from Salmonella Typhimurium from InvivoGen (San Diego, USA). After 16h, the plate was read at 643 nm by Tecan spectrophotometer.
  • the expression of TLR5 was also measured in PBMCs from R and NR patients by means of flow cytometry.
  • the staining was performed using Fixable Viability Stain BV510 (BD, Cat. No. 564406), HLADR BV605 (BD, Cat. No. 562845) and TLR5 APCR700 (Bio-techne, Cat. No. FAB6704N). Then, cells were fixed (BD, Cat. No. 554722) and acquired using a FACSCelesta 392 BVYG equipped with FACSDiva software version 8.0.1.
  • the inventors validated insights about the long-term ICI-exposed gut and host immune state using multiple external cohorts and, experimentally, on patient-derived samples.
  • Parallel evaluation of the gut microbiota and the systemic immune state of CR patients helped reduce the overwhelming influence of heterogeneity when matching clinical and biological features throughout the study.
  • this approach identified a group of Clostridia-dominated taxa that stably inhabits the gut and associates with distinctly low neutrophil/lymphocyte ratio (NLR) and high levels of IL- 12p70.
  • NLR neutrophil/lymphocyte ratio
  • IL-12p70 is produced by dendritic cells either upon antigenic stimulation (where it is implicated in helper T-cell differentiation) 73 or in response to the IFNg released by anti-PD- 1 activated T cells41.
  • IL-12p70 has been associated with severe immune related adverse events (irAEs) 89 and enhancement of anti-PD-1 response 89,90, respectively. Future experiments should be designed to disentangle any mechanistic link between stable gut microbes and immune markers.
  • ICI-induced translocation of specific enteric bacteria from the gut to secondary lymphoid organs has been recently demonstrated in preclinical models, eliciting anti-tumor T-cell activity systemically 52 .
  • the results obtained suggest that defined shared functions rather than individual taxa may be key to immune modulation.
  • genes for starch and sucrose metabolism are stably carried in CR gut metagenomes.
  • Starch granules are abundant in many natural foods (i.e. potatoes, rice, and cereal grains) and include polymers of glucose linked to an a-glucan by linkages either soluble (amylopectin) or resistant to enzymatic degradation (amylose).
  • SCFA short-chain fatty acids
  • measuring the gut dynamic could be developed as a tool for decision-making, either in the neoadjuvant (e.g., determining optimal surgery time) or adjuvant (e.g., guiding therapy completion) therapies.
  • the functional data herein obtained reveal a previously unappreciated role for flagellins in the microbiota-host crosstalk during ICI.
  • Significantly increased flagellin related gene families were detected in the CR metagenomes, both in studied patients as well as in responders of various international cohorts, and their presence at baseline suggests that they were not incidentally emerging from lifestyle and diet changes during therapy.
  • the results obtained in this invention demonstrate that FLach peptides can also be used therapeutically to either improve the expansion of autochthonous TILs for adoptive T cell therapy or, potentially, as a pre-conditioning treatment on selected patients undergoing ICI therapy.
  • the immune response elicited by ICI therapy shapes a host niche favorable for gut taxa that synergistically support immune cell function and tumor recognition, while being well-adapted to host conditions, such as flagellin carrying gut commensals under the Clostridia clade.
  • NLR Baseline neutrophil-to-lymphocyte ratio
  • derived NLR could predict overall survival in patients with advanced melanoma treated with nivolumab. J Immunother Cancer 6, 1-7 (2016). 55. Bender, M. J. et al. Dietary tryptophan metabolite released by intratumoral Lactobacillus reuteri facilitates immune checkpoint inhibitor treatment. Cell 186, 1846-1862. e26 (2023).
  • HLA-A2-peptide complexes refolding and crystallization of molecules expressed in Escherichia coli and complexed with single antigenic peptides. Proc Natl Acad Sci U S A 89, 3429-3433. 10.1073/PNAS.89.8.3429.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Biochemistry (AREA)
  • Zoology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Genetics & Genomics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biophysics (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Molecular Biology (AREA)
  • Toxicology (AREA)
  • Immunology (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Epidemiology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)

Abstract

La présente invention concerne des peptides codés par des gènes liés à la flagelline bactérienne et leur utilisation dans des thérapies de vaccination tumorale. En particulier, l'invention concerne une composition comprenant au moins un peptide destiné à être utilisé pour la prévention et/ou le traitement d'un cancer, ledit au moins un peptide étant codé par un gène lié à la flagelline.
PCT/EP2025/057375 2024-03-18 2025-03-18 Peptides associés à la flagelline et leurs utilisations Pending WO2025196053A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP24164184.4A EP4620482A1 (fr) 2024-03-18 2024-03-18 Peptides associés à la flagelline et leurs utilisations
EP24164184.4 2024-03-18
EP24191684.0 2024-07-30
EP24191684 2024-07-30

Publications (1)

Publication Number Publication Date
WO2025196053A1 true WO2025196053A1 (fr) 2025-09-25

Family

ID=95065458

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2025/057375 Pending WO2025196053A1 (fr) 2024-03-18 2025-03-18 Peptides associés à la flagelline et leurs utilisations

Country Status (1)

Country Link
WO (1) WO2025196053A1 (fr)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4897445A (en) 1986-06-27 1990-01-30 The Administrators Of The Tulane Educational Fund Method for synthesizing a peptide containing a non-peptide bond
WO2006116763A2 (fr) 2005-04-28 2006-11-02 Boehringer Ingelheim Vetmedica, Inc. Proteines immunologiques de lawsonia intracellularis
WO2009102818A1 (fr) 2008-02-11 2009-08-20 Cleveland Biolabs, Inc. Procédé de réduction des effets de la chimiothérapie à l’aide de polypeptides associés à la flagelline
WO2011044246A1 (fr) * 2009-10-06 2011-04-14 Cleveland Biolabs, Inc. Utilisation de récepteur de type toll et agoniste pour le traitement du cancer
WO2012097012A1 (fr) 2011-01-10 2012-07-19 Cleveland Biolabs, Inc. Utilisation d'un agoniste de récepteur de type toll pour le traitement du cancer
WO2020163782A2 (fr) * 2019-02-08 2020-08-13 The Uab Research Foundation Composition pour le traitement et la prévention de la maladie inflammatoire chronique de l'intestin

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4897445A (en) 1986-06-27 1990-01-30 The Administrators Of The Tulane Educational Fund Method for synthesizing a peptide containing a non-peptide bond
WO2006116763A2 (fr) 2005-04-28 2006-11-02 Boehringer Ingelheim Vetmedica, Inc. Proteines immunologiques de lawsonia intracellularis
WO2009102818A1 (fr) 2008-02-11 2009-08-20 Cleveland Biolabs, Inc. Procédé de réduction des effets de la chimiothérapie à l’aide de polypeptides associés à la flagelline
WO2011044246A1 (fr) * 2009-10-06 2011-04-14 Cleveland Biolabs, Inc. Utilisation de récepteur de type toll et agoniste pour le traitement du cancer
WO2012097012A1 (fr) 2011-01-10 2012-07-19 Cleveland Biolabs, Inc. Utilisation d'un agoniste de récepteur de type toll pour le traitement du cancer
WO2020163782A2 (fr) * 2019-02-08 2020-08-13 The Uab Research Foundation Composition pour le traitement et la prévention de la maladie inflammatoire chronique de l'intestin

Non-Patent Citations (94)

* Cited by examiner, † Cited by third party
Title
"Remington's Pharmaceutical Sciences", 1985, MACK PUBLISHING CO.
ALDAHMANI, S.ZOUBEIDI, T.ALDAHMANI, M. S., PACKAGE 'GGRIDGE'., 2021
ANDERSON, M. J.: "In Wiley StatsRef: Statistics Reference Online", vol. 1-15, 2017, JOHN WILEY & SONS, LTD, article "Permutational Multivariate Analysis of Variance (PERMANOVA"
ANDREWS, M. C.REUBEN, A.GOPALAKRISHNAN, V.WARGO, J. A.: "Concepts Collide: Genomic, immune, and microbial influences on the tumor microenvironment and response to cancer therapy", FRONT IMMUNOL, vol. 9, 2018, pages 355224
AUGUIE, B.ANTONOV, A.AUGUIE, M. B.: "Package 'gridExtra", MISCELLANEOUS FUNCTIONS FOR ''GRID'' GRAPHICS, 2017
BARUCH, E. N. ET AL.: "Fecal microbiota transplant promotes response in immunotherapy-refractory melanoma patients", SCIENCE, vol. 371, no. 1979, 2021, pages 602 - 609, XP055938746
BAUMAN, J. ET AL.: "798 Safety, tolerability, and immunogenicity of Mrna-4157 in combination with pembrolizumab in subjects with unresectable solid tumors (KEYNOTE-603): an update", J IMMUNOTHER CANCER, vol. 8, 2020, pages 477
BEGHINI, F. ET AL.: "Integrating taxonomic, functional, and strain-level profiling of diverse microbial communities with bioBakery 3", ELIFE, vol. 10, 2021, pages 65088
BENDER, M. J. ET AL.: "Dietary tryptophan metabolite released by intratumoral Lactobacillus reuteri facilitates immune checkpoint inhibitor treatment", CELL, vol. 186, 2023, pages 1846 - 1862
BITTINGER, K.BITTINGER, M. K., PACKAGE 'USEDIST, 2022
BJORK, J. R. ET AL.: "Longitudinal gut microbiome changes in immune checkpoint blockade-treated advanced melanoma", NAT MED, vol. 30, 2024, pages 785 - 796
BLANCO-MÍGUEZ, A. ET AL.: "Extending and improving metagenomic taxonomic profiling with uncharacterized species using MetaPhlAn 4", NAT BIOTECHNOL, vol. 1-12, 2023
BOKULICH, N.A.KAEHLER, B.D.RIDEOUT, J.R. ET AL.: "Optimizing taxonomic classification of marker-gene amplicon sequences with QIIME 2's q2-feature-classifier plugin", MICROBIOME, vol. 6, 2018, pages 90, Retrieved from the Internet <URL:https://doi.org/10.1186/s40168-018-0470-z>
BOLYEN, E. ET AL.: "Reproducible, interactive, scalable and extensible microbiome data science using QIIME 2", NAT BIOTECHNOL, vol. 37, 2019, pages 852 - 857, XP036850011, DOI: 10.1038/s41587-019-0209-9
CALLAHAN, B. J. ET AL.: "DADA2: High resolution sample inference from Illumina amplicon data", NAT METHODS, vol. 13, 2016, pages 581 - 583, XP093249850, DOI: 10.1038/nmeth.3869
CAPONE, M. ET AL.: "Baseline neutrophil-to-lymphocyte ratio (NLR) and derived NLR could predict overall survival in patients with advanced melanoma treated with nivolumab", J IMMUNOTHER CANCER, vol. 6, 2018, pages 1 - 7, XP021258815, DOI: 10.1186/s40425-018-0383-1
CERCEK, A. ET AL.: "PD-1 Blockade in Mismatch Repair-Deficient, Locally Advanced Rectal Cancer", N ENGL J MED, vol. 386, 2022, pages 2363 - 2376
CERQUEIRA, F. M.PHOTENHAUER, A. L.POLLET, R. M.BROWN, H. A.KOROPATKIN, N. M.: "Starch Digestion by Gut Bacteria: Crowdsourcing for Carbs", TRENDS MICROBIOL, vol. 731, no. 28, 2020, pages 95 - 108
CHEN, Y. E. ET AL.: "Engineered skin bacteria induce antitumor T cell responses against melanoma", SCIENCE, vol. 380, 1979, pages 203 - 210
CHOI, Y. ET AL.: "Immune checkpoint blockade induces gut microbiota translocation that augments extraintestinal antitumor immunity", SCI IMMUNOL, vol. 8, 2023
CLASEN, S. J. ET AL.: "Silent recognition of flagellins from human gut commensal bacteria by Toll-like receptor 5", SCI IMMUNOL, vol. 8, 2023
COULIE, P. G. ET AL.: "A new gene coding for a differentiation antigen recognized by autologous cytolytic T lymphocytes on HLA-A2 melanomas", JOURNAL OF EXPERIMENTAL MEDICINE, vol. 180, 1994, pages 35 - 42, XP002080835, DOI: 10.1084/jem.180.1.35
COUTZAC, C. ET AL.: "Systemic short chain fatty acids limit antitumor effect of CTLA-4 blockade in hosts with cancer", NATURE COMMUNICATIONS, vol. 11, no. 1, 2020, pages 1 - 13
DANNE, C.SOKOL, H.: "Butyrate, a new microbiota-dependent player in CD8+ T cells immunity and cancer therapy", CELL REP MED, vol. 2, 2021
DAVAR DIWAKAR ET AL: "Fecal microbiota transplant overcomes resistance to anti-PD-1 therapy in melanoma patients", vol. 371, no. 6529, 5 February 2021 (2021-02-05), US, pages 595 - 602, XP055938683, ISSN: 0036-8075, Retrieved from the Internet <URL:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8097968/pdf/nihms-1695944.pdf> DOI: 10.1126/science.abf3363 *
DAVAR, D. ET AL.: "Fecal microbiota transplant overcomes resistance to anti-PD-1 therapy in melanoma patients", SCIENCE, vol. 371, no. 1979, 2021, pages 595 - 602, XP055938683, DOI: 10.1126/science.abf3363
DAVAR, D.ZAROUR, H. M.: "Facts and Hopes for Gut Microbiota Interventions in Cancer Immunotherapy", CLINICAL CANCER RESEARCH, vol. 28, no. 43, 2022, pages 70 - 43
DIEHL, A. ET AL.: "Relationships between lymphocyte counts and treatment-related toxicities and clinical responses in patients with solid tumors treated with PD-1 checkpoint inhibitors", ONCOTARGET, vol. 8, 2017, pages 114268 - 114280
FRANKEL, A. E. ET AL.: "Metagenomic Shotgun Sequencing and Unbiased Metabolomic Profiling Identify Specific Human Gut Microbiota and Metabolites Associated with Immune Checkpoint Therapy Efficacy in Melanoma Patients", NEOPLASIA, vol. 19, 2017, pages 848 - 855, XP055540712, DOI: 10.1016/j.neo.2017.08.004
FURUSAWA, Y. ET AL.: "Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells", NATURE, vol. 504, no. 7480, 2013, pages 446 - 450, XP037474495, DOI: 10.1038/nature12721
GARBOCZI, D.N.HUNG, D.T.WILEY, D.C.: "HLA-A2-peptide complexes: refolding and crystallization of molecules expressed in Escherichia coli and complexed with single antigenic peptides", PROC NATL ACAD SCI U S A, vol. 89, 1992, pages 3429 - 3433, XP002131059, DOI: 10.1073/pnas.89.8.3429
GARRIS, C. S. ET AL.: "Successful Anti-PD-1 Cancer Immunotherapy Requires T Cell- Dendritic Cell Crosstalk Involving the Cytokines IFN- and IL-12", IMMUNITY, vol. 49, 2018, pages 1148 - 1161, XP055727087
GOPALAKRISHNAN, V. ET AL.: "Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients", SCIENCE, vol. 359, no. 1979, 2018, pages 97 - 103, XP055554925, DOI: 10.1126/science.aan4236
GU, Z.: "Complex heatmap visualization", IMETA, vol. 1, 2022, pages 43
HAJAM, I. A.DAR, P. A.SHAHNAWAZ, I.JAUME, J. C.LEE, J. H.: "Bacterial flagellin-a potent immunomodulatory agent", EXPERIMENTAL & MOLECULAR MEDICINE, vol. 49, no. 9, 2017, pages e373 - e373, XP055465854, DOI: 10.1038/emm.2017.172
HALFVARSON, J. ET AL.: "Dynamics of the human gut microbiome in inflammatory bowel disease", NATURE MICROBIOLOGY, vol. 2, no. 5, 2017, pages 1 - 7, XP055649075, DOI: 10.1038/nmicrobiol.2017.4
HAYASE, E.JENQ, R. R.: "Role of the intestinal microbiome and microbial-derived metabolites in immune checkpoint blockade immunotherapy of cancer", GENOME MEDICINE, vol. 13, 2021, pages 107
HE, Y. ET AL.: "Gut microbial metabolites facilitate anticancer therapy efficacy by modulating cytotoxic CD8+ T cell immunity", CELL METAB, vol. 33, 2021, pages 988 - 1000
IANIRO, G. ET AL.: "Variability of strain engraftment and predictability of microbiome composition after fecal microbiota transplantation across different diseases", NATURE MEDICINE, vol. 28, no. 9, 2022, XP093179888, DOI: 10.1038/s41591-022-01964-3
JANSSEN, S. ET AL.: "Phylogenetic Placement of Exact Amplicon Sequences Improves Associations with Clinical Information", MSYSTEMS, vol. 3, 2018
JOHNSON, W. E.LI, C.RABINOVIC, A.: "Adjusting batch effects in microarray expression data using empirical Bayes methods", BIOSTATISTICS, vol. 8, 2007, pages 118 - 127, XP055067729, DOI: 10.1093/biostatistics/kxj037
KAIKO, G. E. ET AL.: "The Colonic Crypt Protects Stem Cells from Microbiota-Derived Metabolites", CELL, vol. 165, 2016, pages 1708 - 1720, XP029612945, DOI: 10.1016/j.cell.2016.05.018
KASSAMBARA, A., RSTATIX: PIPE-FRIENDLY FRAMEWORK FOR BASIC STATISTICAL TESTS, 2020
KASSAMBARA, A.KASSAMBARA, M. A., PACKAGE 'GGPUBR'., 2020
KAWAKAMI, Y. ET AL.: "Cloning of the gene coding for a shared human melanoma antigen recognized by autologous T cells infiltrating into tumor", PROC NATL ACAD SCI U S A, vol. 91, 1994, pages 3515 - 3519, XP000770221, DOI: 10.1073/pnas.91.9.3515
KAZEMIAN, N. ET AL.: "The trans-kingdom battle between donor and recipient gut microbiome influences fecal microbiota transplantation outcome", SCIENTIFIC REPORTS, vol. 10, no. 1, 2020, pages 1 - 10
KELLY, C. R. ET AL.: "Update on Fecal Microbiota Transplantation 2015: Indications, Methodologies, Mechanisms, and Outlook", GASTROENTEROLOGY, vol. 149, 2015, pages 223 - 237, XP055382743, DOI: 10.1053/j.gastro.2015.05.008
KEMBEL, S.: "An introduction to the picante package", R PROJ, vol. 1-16, 2010
LANGMEAD, B.SALZBERG, S. L.: "Fast gapped-read alignment with Bowtie 2", NATURE METHODS, vol. 9, 2012, pages 357 - 359, XP002715401, DOI: 10.1038/nmeth.1923
LAUTÉ-CALY, D. L. ET AL.: "The flagellin of candidate live biotherapeutic Enterococcus gallinarum MRx0518 is a potent immunostimulant", SCI REP, vol. 9, 2019, XP055560064, DOI: 10.1038/s41598-018-36926-8
LE, D. T. ET AL.: "Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade", SCIENCE, vol. 357, no. 1979, 2017, pages 409 - 413, XP055906155, DOI: 10.1126/science.aan6733
LEE KARLA A ET AL: "Cross-cohort gut microbiome associations with immune checkpoint inhibitor response in advanced melanoma", NATURE MEDICINE, NATURE PUBLISHING GROUP US, NEW YORK, vol. 28, no. 3, 28 February 2022 (2022-02-28), pages 535 - 544, XP037768826, ISSN: 1078-8956, [retrieved on 20220228], DOI: 10.1038/S41591-022-01695-5 *
LEE, K. A. ET AL.: "Cross-cohort gut microbiome associations with immune checkpoint inhibitor response in advanced melanoma", NATURE MEDICINE, vol. 28, no. 3, 2022, pages 535 - 544, XP037768826, DOI: 10.1038/s41591-022-01695-5
LEE, Y. J. ET AL.: "Peripheral lymphocyte count as a surrogate marker of immune checkpoint inhibitor therapy outcomes in patients with non-small-cell lung cancer", SCI REP, vol. 12, 2022
LEZCANO, C.JUNGBLUTH, A. A.NEHAL, K. S.HOLLMANN, T. J.BUSAM, K. J.: "PRAME Expression in Melanocytic Tumors", AMERICAN JOURNAL OF SURGICAL PATHOLOGY, vol. 42, 2018, pages 1456 - 1465
LIN, H.PEDDADA, S.D.: "Analysis of microbial compositions: a review of normalization and differential abundance analysis", NPJ BIOFILMS MICROBIOMES, vol. 6, 2020, pages 60, Retrieved from the Internet <URL:https://doi.org/10.1038/s41522-020-00160-w>
LIN, S. ET AL.: "Secernin-1 Contributes to Colon Cancer Progression through Enhancing Matrix Metalloproteinase-2/9 Exocytosis", DIS MARKERS, vol. 2015, 2015
LUKAS ET AL., SOLID-PHASE PEPTIDE SYNTHESIS UNDER CONTINUOUS FLOW CONDITIONS PROC. NATL ACAD SCI USA, vol. 78, no. 5, May 1981 (1981-05-01), pages 2791 - 2795
LUKE, J. J.FLAHERTY, K. T.RIBAS, A.LONG, G. V.: "Targeted agents and immunotherapies: optimizing outcomes in melanoma", NATURE REVIEWS CLINICAL ONCOLOGY, vol. 14, no. 8, 2017, pages 463 - 482, XP037922969, DOI: 10.1038/nrclinonc.2017.43
LUU, M. ET AL.: "Microbial short-chain fatty acids modulate CD8+ T cell responses and improve adoptive immunotherapy for cancer", NATURE COMMUNICATIONS, vol. 12, no. 1, 2021, pages 1 - 12, XP055905612, DOI: 10.1038/s41467-021-24331-1
LUU, M. ET AL.: "Regulation of the effector function of CD8+ T cells by gut microbiota-derived metabolite butyrate", SCIENTIFIC REPORTS, vol. 8, no. 1, 2018, pages 1 - 10
MALLICK, H. ET AL.: "Multivariable association discovery in population-scale meta-omics studies", PLOS COMPUTATIONAL BIOLOGY, vol. 17, 2021, pages 1009442
MANDAL, S. ET AL.: "Analysis of composition of microbiomes: a novel method for studying microbial composition", MICROB ECOL HEALTH DIS, vol. 26, 2015
MATSON, V. ET AL.: "The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients", SCIENCE, vol. 359, no. 1979, 2018, pages 104 - 108, XP055564226, DOI: 10.1126/science.aao3290
MCCULLOCH, J. A. ET AL.: "Intestinal microbiota signatures of clinical response and immune-related adverse events in melanoma patients treated with anti-PD-1", NATURE MEDICINE, vol. 28, no. 3, 2022, pages 545 - 556, XP037768832, DOI: 10.1038/s41591-022-01698-2
MEZIERE ET AL., J. IMMUNOL., vol. 159, 1997, pages 3230 - 3237
MILITARU, I. V.RUS, A. A.MUNTEANU, C. V. A.MANICA, G.PETRESCU, S. M.: "New panel of biomarkers to discriminate between amelanotic and melanotic metastatic melanoma", FRONT ONCOL, vol. 12, 2023, pages 1061832
MONTALBAN-ARQUES, A. ET AL.: "Commensal Clostridiales strains mediate effective anti-cancer immune response against solid tumors", CELL HOST MICROBE, vol. 29, 2021, pages 1573 - 1588
MONTES M. ET AL: "Optimum in vitro expansion of human antigen-specific CD8+ T cells for adoptive transfer therapy", CLINICAL AND EXPERIMENTAL IMMUNOLOGY, vol. 142, no. 2, 1 November 2005 (2005-11-01), GB, pages 292 - 302, XP055793641, ISSN: 0009-9104, DOI: 10.1111/j.1365-2249.2005.02914.x *
NOMURA, M. ET AL.: "Association of Short-Chain Fatty Acids in the Gut Microbiome With Clinical Response to Treatment With Nivolumab or Pembrolizumab in Patients With Solid Cancer Tumors", JAMA NETW OPEN, vol. 3, 2020, pages e202895 - e202895
OKSANEN, J. ET AL., THE VEGAN PACKAGE, 2009
PHYLOSEQ: AN R PACKAGE FOR REPRODUCIBLE INTERACTIVE ANALYSIS AND GRAPHICS OF MICROBIOME CENSUS DATA I PLOS ONE, Retrieved from the Internet <URL:https:jjjournals.plos.orgjplosonejarticle?id=1O.1371jjournal.pone.0061217.>
QUAST, C. ET AL.: "The SILVA ribosomal RNA gene database project: improved data processing and web-based tools", NUCLEIC ACIDS RES, vol. 41, 2013, pages D590 - D596, XP055252806, DOI: 10.1093/nar/gks1219
R. LUNDBLAD: "Chemical Reagents for Protein Modification", 2005, CRC PRESS
RAGONE, C. ET AL.: "Molecular mimicry between tumor associated antigens and microbiota-derived epitopes", J TRANSL MED, vol. 20, 2022, pages 316 - 18
RASMUSSEN, M. ET AL.: "Pan-specific prediction of peptide-MHC class I complex stability, a correlate of T cell immunogenicity", THE JOURNAL OF IMMUNOLOGY, vol. 197, 2016, pages 1517 - 1524, XP093101339, DOI: 10.4049/jimmunol.1600582
ROBERT, C. ET AL.: "Nivolumab in Previously Untreated Melanoma without BRAF Mutation", NEW ENGLAND JOURNAL OF MEDICINE, vol. 372, 2015, pages 320 - 330
ROHART, F.GAUTIER, B.SINGH, A.LÊ CAO, K.-A.: "mixOmics: An R package for `omics feature selection and multiple data integration", PLOS COMPUT BIOL, vol. 13, 2017
ROOKS, M. G.GARRETT, W. S.: "Gut microbiota, metabolites and host immunity", NATURE REVIEWS IMMUNOLOGY, vol. 16, no. 6, 2016, pages 341 - 352
ROUTY, B. ET AL.: "Fecal microbiota transplantation plus anti-PD-1 immunotherapy in advanced melanoma: a phase I trial", NATURE MEDICINE, vol. 29, no. 8, 2023, pages 2121 - 2132
ROUTY, B. ET AL.: "Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors", SCIENCE, vol. 359, no. 1979, 2018, pages 91 - 97, XP055554928, DOI: 10.1126/science.aan3706
SCHNAEKER, E. M. ET AL.: "Microtubule-Dependent Matrix Metalloproteinase-2/Matrix Metalloproteinase-9 ExocytosisPrerequisite in Human Melanoma Cell Invasion", CANCER RES, vol. 64, 2004, pages 8924 - 8931, XP055475816, DOI: 10.1158/0008-5472.CAN-04-0324
SIMPSON, R. C. ET AL.: "Diet-driven microbial ecology underpins associations between cancer immunotherapy outcomes and the gut microbiome", NATURE MEDICINE, vol. 28, no. 11, 2022, pages 2344 - 2352
SPENCER, C. N. ET AL.: "Dietary fiber and probiotics influence the gut microbiome and melanoma immunotherapy response", SCIENCE, vol. 374, 2021, pages 1632 - 1640
SUZEK, B. E. ET AL.: "UniRef clusters: a comprehensive and scalable alternative for improving sequence similarity searches", BIOINFORMATICS, vol. 31, 2015, pages 926 - 932
TRINCHIERI, G.: "Interleukin-12 and the regulation of innate resistance and adaptive immunity", NATURE REVIEWS IMMUNOLOGY, vol. 3, no. 2, 2003, pages 133 - 146, XP055543141, DOI: 10.1038/nri1001
WARNES, G. R.BOLKER, B.LUMLEY, T.WARNES, M. G. R.: "Package 'gtools", R PACKAGE, 2015
WEBER, J. S. ET AL.: "Individualised neoantigen therapy mRNA-4157 (V940) plus pembrolizumab versus pembrolizumab monotherapy in resected melanoma (KEYNOTE-942): a randomised, phase 2b study", LANCET, vol. 403, 2024, pages 632 - 644, XP087469992, DOI: 10.1016/S0140-6736(23)02268-7
WICKHAM, H.FRANCOIS, R.HENRY, L.MULLER, K., DPLYR. IN USER! CONFERENCE, 2014
WU, T. ET AL.: "clusterProfiler 4.0: A universal enrichment tool for interpreting omics data", THE INNOVATION, vol. 2, 2021, pages 100141
YIN, P. ET AL.: "CpG-induced antitumor immunity requires IL-12 in expansion of effector cells and down-regulation of PD-1", ONCOTARGET, vol. 7, 2016, pages 70223 - 70231
ZENG, Y. ET AL.: "Dynamic gut microbiota changes in patients with advanced malignancies experiencing secondary resistance to immune checkpoint inhibitors and immune-related adverse events", FRONT ONCOL, vol. 13, 2023, pages 1144534
ZHENG, J. H. ET AL.: "Two-step enhanced cancer immunotherapy with engineered Salmonella typhimurium secreting heterologous flagellin", SCI TRANSL MED, vol. 9, 2017, XP055532509, DOI: 10.1126/scitranslmed.aak9537
ZITVOGEL, L.DAILLERE, R.ROBERTI, M. P.ROUTY, B.KROEMER, G.: "Anticancer effects of the microbiome and its products", NATURE REVIEWS MICROBIOLOGY, vol. 15, no. 8, 2017, pages 465 - 478

Similar Documents

Publication Publication Date Title
Naghavian et al. Microbial peptides activate tumour-infiltrating lymphocytes in glioblastoma
Huot et al. SARS-CoV-2 viral persistence in lung alveolar macrophages is controlled by IFN-γ and NK cells
JP6005051B2 (ja) 免疫療法の転帰を予測する新規バイオマーカー
JP6298101B2 (ja) ヘルパーｔ細胞の活性化方法
Morisaki et al. Neoantigens elicit T cell responses in breast cancer
JP2018519243A5 (fr)
JP2018521641A5 (fr)
JP7034931B2 (ja) ネオエピトープのウイルス送達のための改善された組成物および方法ならびにその使用
CA3131766A1 (fr) Biomarqueurs du cancer pour un bienfait clinique durable
CN101384716A (zh) Hla-a*3303限制性wt1肽和包含此肽的药物组合物
Kang et al. Type 3 innate lymphoid cells are associated with a successful intestinal transplant
Du Plessis et al. The functional response of B cells to antigenic stimulation: a preliminary report of latent tuberculosis
WO2019036043A2 (fr) Procédé de génération d&#39;un cocktail de vaccins anticancéreux personnalisés à partir de modifications génétiques dérivées de tumeur pour le traitement du cancer
US20230173045A1 (en) Ranking neoantigens for personalized cancer vaccine
Vito et al. Immune checkpoint blockade in triple negative breast cancer influenced by B cells through myeloid-derived suppressor cells
CN110195040A (zh) 辅助性t细胞的活化方法
CN115785252A (zh) 原发性肝癌相关抗原的胸腺依赖性淋巴细胞抗原表位肽及其应用
JP7231665B2 (ja) ライム病を診断するためのおよび治療後のライム病スピロヘータ除去を予測するための組成物および方法
CN107312861A (zh) 一种b‑all患者预后风险评估标记物
WO2012140068A1 (fr) Nouveaux vaccins destinés à la prévention et au traitement de la tuberculose
WO2025196053A1 (fr) Peptides associés à la flagelline et leurs utilisations
EP4620482A1 (fr) Peptides associés à la flagelline et leurs utilisations
CN119751570A (zh) 肺癌相关抗原Cyfra21-1的胸腺依赖性淋巴细胞抗原表位肽及应用
US20240319207A1 (en) Method for identifying t-cell epitope sequence, and application of same
Lu et al. Identification of HLA-A* 1101-restricted cytotoxic T lymphocyte epitopes derived from epidermal growth factor pathway substrate number 8

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 25713311

Country of ref document: EP

Kind code of ref document: A1