Microbial analogs of tumor-associated antigens and uses thereof

Abstract

The present invention relates to tumor antigens and their use in cancer immunotherapy. Specifically, the present invention relates to the identification of microbiota sequence analogs of the tumor-associated epitope sequence, which can be used in tumor vaccination therapies for the treatment and prevention of cancer and have a significant effect on cancer progression and prognosis.

Description

Technical Field

[0001] The present invention relates to tumor antigens and their use in cancer immunotherapy. In particular, the present invention relates to the identification of microbiota sequence analogs of tumor-associated antigen epitope sequences, which can be used for tumor vaccination therapy for the treatment and prevention of cancer and have a significant impact on cancer progression and prognosis. Background Art

[0002] The gut microbiome profile is unique to each individual and contains different species as the individual transitions from birth to infancy. While healthy core native microbiota remain relatively stable in adulthood, they are significantly influenced by multiple individual factors throughout life.

[0003] Over the past few years, local and systemic effects of the microbiota on cancer onset, progression, and response to treatments such as immunotherapy have been extensively described. Several mechanisms have been elucidated to explain this effect.

[0004] This invention provides a new perspective, proposing the role of the microbiota based on molecular mimicry of tumor-associated antigens by microbiome-associated antigens. In fact, this may affect T cell immunity, have a significant impact on anti-cancer immunity, and thus affect cancer progression and prognosis.

[0005] The human gastrointestinal tract is home to approximately 10 14 The gut microbiome contains approximately 1,000 times the number of human cells and 10,000 times the DNA content of human cells (1). The gut microbiome contains a wide variety of microorganisms, including bacteria, yeast, and viruses. However, there are only a few phyla in the gut microbiome, accounting for more than 160 species, of which the Firmicutes and Bacteroidetes together account for 90% of the gut microbiome (2). The human gut microbiome exhibits inter- and intra-individual differences due to infant transitions, age, and environmental factors (including antibiotic use). Gestational age at birth is the main determinant of the composition of the gut microbiome and has a major impact on the maturation of systemic immunity (3,4). In addition, the mode of delivery (5), feeding method (6), and weaning period (7) also have a major impact on the composition of the microbiome in the first year of life. Its diversity increases over the next few months, and around the age of three, the composition and diversity of the child's gut microbiome are most similar to those of adults, influenced by genetics, environment, diet, lifestyle, and intestinal physiology (8). Once established, the core composition of an individual’s gut microbiota changes throughout life in response to a variety of factors, including enterotype, body mass index (BMI) level, lifestyle, exercise frequency, ethnicity, diet, and cultural habits (9).

[0006] Intestinal bacteria are major regulators of gastrointestinal digestion and protect against bacterial invasion by maintaining the integrity of the intestinal epithelium (10). In addition, commensal bacteria and their products have been shown to regulate the development, homeostasis, and function of innate and adaptive immune cells through nutrient- and metabolite-dependent mechanisms (11). In addition to physiological roles, the microbiota has been shown to play a role in human disease (12, 13) and influence tumor development and therapeutic response (14). Specifically, specific microbiota populations have been shown to positively or negatively influence cancer initiation and progression, depending on their composition. This is because the metabolites produced may have an effect on tumor cells and / or anti-tumor immune responses (15). In addition, while components such as LPS or MPL are able to activate immune T cell-mediated responses against cancer cells (16), the bacterial virulence factor Fap2 inhibits natural killer cells (17). In addition, TLR signaling and polysaccharide A on dendritic cells can drive the development of Tregs (18, 19), and Th17 can be induced by specific bacterial subsets such as segmented filamentous bacteria (SFB) (20).

[0007] In addition to this “universal” regulatory mechanism, the impact of the gut microbiota on anticancer immune responses can also be driven by “molecular mimicry” between bacteria and tumor-associated antigens. The gut microbiome encodes more than 3 million genes, while the entire human genome consists of approximately 23,000 genes (21). This means that there is a high probability of nucleic acid and protein sequences with homology between the microbiota and cellular antigens. This can lead to overlapping peptidome representations, considering that a single TCR can recognize at least 10 6 Different MHC-bound peptides, this overlapping peptidomic representation is likely to be targeted by a cross-reactive CD8+ T cell receptor (TCR) (22,23). In fact, epitopes bind to HLA molecules with specific residues (anchor residues) located at fixed positions in the sequence, and only the central residues are exposed for TCR recognition (http: / / www.cbs.dtu.dk / services / NetMHC / logos.php) (24,25). Therefore, two unrelated antigens that share the same central residues facing the TCR, or show conservative variations at these positions, are likely to be recognized by the same TCR even if the peripheral residues are different, without affecting the structural conformation of the entire epitope.

[0008] Based on this hypothesis, the inventors recently demonstrated that the peptides described in the literature and in the Cancer Peptide Database ( https: / / caped.icp.ucl.ac.be / Peptide / list) have sequence homology with viral sequences (26). This homology suggests that if the expressed TAAs are similar to viral epitopes, the viral antigens will elicit memory CD8+ T cells that may cross-react with tumor antigens that control the growth of cancers that occur throughout life. This may ultimately represent a relevant selective advantage for cancer patients and could lead to the generation of new preventive anticancer vaccine strategies (27).

[0009] WO2018 / 065628 provides a method to identify bacterial proteins in the human microbiome and to identify peptides from these bacterial proteins that can be presented by specific MHC molecules, and to specifically identify the bacterial peptide IL13RA2 as a candidate peptide for preventing or treating cancer.

[0010] In view of the need to identify alternative cancer treatment methods and the limitations encountered in this field, such as induced immune tolerance and / or undesirable autoimmune side effects, the object of the present invention is to provide novel microbiota sequence variants of tumor-associated antigen epitope sequences and their use in cancer immunotherapy. Summary of the invention

[0011] The present invention relates to the identification of peptides derived from species of the Firmicutes and Bacteroidetes microbiota that have sequence homology with tumor-associated antigens (TAAs).

[0012] The object of the present invention is a composition comprising at least one peptide derived from human microbiota and at least one pharmaceutically acceptable excipient, wherein the at least one peptide comprises a core sequence of 9 amino acids, wherein the core sequence has 6, 7 or 8 identical amino acids at the same position as the tumor-associated antigen epitope sequence GLYDGMEHL (SEQ ID No 1), and the remaining amino acids are different from the amino acids at the same position of the epitope sequence.

[0013] Preferably, the at least one peptide is selected from the group consisting of SEQ ID No 13-90, more preferably selected from the group consisting of SEQ ID No 13, 16, 21, 23, 24, 27, 28, 29, 30, 33, 36, 38, 39, 40, 41, 43, 44, 45, 46, 55, 66, 67, 72, 73, 74, 75, 76, 77, 78, 79, 82, 82, 84, 85, 86, 87 and 88, even more preferably selected from the group consisting of SEQ ID No 13, 23, 24, 75, 76 and 79.

[0014] Another object of the present invention is a composition consisting of at least one peptide derived from human microbiota; and at least one pharmaceutically acceptable excipient, wherein the at least one peptide comprises a core sequence of 9 amino acids, wherein the core sequence has 6, 7 or 8 identical amino acids at the same position as the tumor-associated antigen epitope sequence GLYDGMEHL (SEQ ID No 1), and the remaining amino acids are different from the amino acids at the same position of the epitope sequence. Preferably, the at least one peptide is selected from the group consisting of SEQ ID No 13-90, more preferably selected from the group consisting of SEQ ID No 13, 16, 21, 23, 24, 27, 28, 29, 30, 33, 36, 38, 39, 40, 41, 43, 44, 45, 46, 55, 66, 67, 72, 73, 74, 75, 76, 77, 78, 79, 82, 82, 84, 85, 86, 87 and 88, even more preferably selected from the group consisting of SEQ ID No 13, 23, 24, 75, 76 and 79.

[0015] Preferably, the composition comprises or consists of at least one peptide as defined above, said at least one peptide comprising at least one other peptide selected, wherein said at least one other peptide comprises a core sequence of 9 amino acids, wherein said core sequence has 6, 7 or 8 amino acids that are identical and in the same position as a tumor-associated antigen epitope sequence selected from the group consisting of:

[0016] - KVAELVHFL (SEQ ID No. 2); or

[0017] - FLWGPRALV (SEQ ID No 3); or

[0018] - VLPDVFIRV (SEQ ID No 4); or

[0019] - KVLEYVIKV (SEQ ID No 5); or

[0020] - KVVEFLAML (SEQ ID No 6); or

[0021] -ALKDVEERV (SEQ ID No 7); or

[0022] -KASEKIFYV(SEQ ID No 8); or

[0023] -NYNNFYRFL (SEQ ID No 9); or

[0024] - EYLSLSDKI (SEQ ID No 10); or

[0025] - EYLQLVFGI (SEQ ID No 11); or

[0026] -LYATVIHDI (SEQ ID No 12).

[0027] Preferably, the at least one other peptide is selected from the group consisting of SEQ ID No 91-631, preferably from the group consisting of SEQ ID No 134, 136, 137, 138, 142, 144, 146, 147, 150, 152, 153, 154, 155, 156, 160, 162, 163, 164, 166, 167, 169, 170, 274, 276, 177, 178, 282, 183, 184, 185, 186, 187, 188, 189, 190, 191, 194, 195, or 196, preferably from the group consisting of SEQ ID No 99, 100, 102, 134, 137, 138, 160, 162, 164, 182, 183, 184.

[0028] Another object of the present invention is a composition comprising at least one peptide derived from a microbiota, wherein said at least one peptide comprises a core sequence of 9 amino acids, wherein said core sequence has at least 6 amino acids identical and in the same position as a tumor-associated antigen epitope sequence selected from the group consisting of:

[0029] - KVAELVHFL (SEQ ID No. 2); or

[0030] - FLWGPRALV (SEQ ID No 3); or

[0031] - VLPDVFIRV (SEQ ID No 4); or

[0032] - KVLEYVIKV (SEQ ID No 5); or

[0033] - KVVEFLAML (SEQ ID No 6); or

[0034] -ALKDVEERV (SEQ ID No 7); or

[0035] -KASEKIFYV(SEQ ID No 8); or

[0036] -NYNNFYRFL (SEQ ID No 9); or

[0037] - EYLSLSDKI (SEQ ID No 10); or

[0038] - EYLQLVFGI (SEQ ID No 11); or

[0039] -LYATVIHDI (SEQ ID No 12);

[0040] and pharmaceutically acceptable carriers or excipients.

[0041] In a preferred embodiment, the composition of the present invention comprises at least one peptide derived from a microbiota, wherein the at least one peptide comprises a core sequence of 9 amino acids, wherein the core sequence has 6, 7 or 8 amino acids that are identical and in the same position as a tumor-associated antigen epitope sequence selected from the following group:

[0042] - KVAELVHFL (SEQ ID No. 2); or

[0043] - FLWGPRALV (SEQ ID No 3); or

[0044] - VLPDVFIRV (SEQ ID No 4); or

[0045] - KVLEYVIKV (SEQ ID No 5); or

[0046] - KVVEFLAML (SEQ ID No 6); or

[0047] -ALKDVEERV (SEQ ID No 7); or

[0048] -KASEKIFYV(SEQ ID No 8); or

[0049] -NYNNFYRFL (SEQ ID No 9); or

[0050] - EYLSLSDKI (SEQ ID No 10); or

[0051] - EYLQLVFGI (SEQ ID No 11); or

[0052] -LYATVIHDI (SEQ ID No 12);

[0053] The remaining amino acids are different from the amino acids at the same position of the tumor-associated antigen epitope sequence

[0054] Preferably, the at least one peptide is selected from the following list: SEQ ID No. 91-209 or SEQ ID No. 211-327 or SEQ ID No. 329-507 or SEQ ID No. 509-631; more preferably selected from the following list: SEQ ID No 91-197; even more preferably, the at least one peptide is selected from the following group: SEQ ID No 194, 195 or 196, preferably selected from the group consisting of SEQ ID No 99, 100, 102, 134, 137, 138, 160, 162, 164, 182, 183, 184.

[0055] Another object of the invention is the composition as defined above for use in the treatment and / or prevention of cancer, wherein said cancer is characterized by an increased expression of at least one of the following antigens: GnTV, LRPAP1, MAGE-A10, MAGE-A3, MAGE-C1, MAGE-C2, SSX-2, KM-HN-1, KM-HN-2, MAGE-A2, SAGE.

[0056] Preferably, the cancer is a solid tumor, preferably the solid tumor is selected from melanoma, lung cancer, bladder cancer, esophageal cancer and head and neck cancer, and sarcoma, colorectal cancer, gastric cancer, cutaneous squamous cell carcinoma, undifferentiated pleomorphic sarcoma / myxofibrosarcoma, non-small cell lung cancer, diffuse large B-cell lymphoma, hepatocellular carcinoma, breast cancer, pancreatic cancer, gynecological cancer.

[0057] Also preferably, the compositions of the present invention are used in combination with other anti-cancer therapeutic agents.

[0058] Another object of the invention is a vaccine or immunogenic composition comprising a composition of peptides as defined above and a pharmaceutically acceptable carrier or excipient, and preferably an adjuvant. Preferably, the 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 an increased expression of at least one of the following antigens: GnTV, LRPAP1, MAGE-A10, MAGE-A3, MAGE-C1, MAGE-C2, SSX-2, KM-HN-1, KM-HN-2, MAGE-A2, SAGE. Even more preferably, the vaccine or immunogenic composition is for the treatment and / or prevention of solid tumors, and in other preferred embodiments, the solid tumor is selected from melanoma, lung cancer, bladder cancer, esophageal cancer and head and neck cancer, as well as sarcoma, colorectal cancer, gastric cancer, cutaneous squamous cell carcinoma, undifferentiated pleomorphic sarcoma / myxofibrosarcoma, non-small cell lung cancer, diffuse large B-cell lymphoma, hepatocellular carcinoma, breast cancer, pancreatic cancer, gynecological cancer.

[0059] Another object of the present invention is a dietary supplement or substitute comprising at least one peptide derived from the human microbiota, wherein the at least one peptide comprises a core sequence of 9 amino acids, wherein the core sequence has 6, 7 or 8 identical amino acids at the same positions as the tumor-associated antigen epitope sequence GLYDGMEHL (SEQ ID No 1), and the remaining amino acids are different from the amino acids at the same positions of the epitope sequence.

[0060] Preferably, the at least one peptide is selected from the group consisting of SEQ ID No. 13 to 90. More preferably, the at least one peptide is selected from the group consisting of SEQ ID No 13, 16, 21, 23, 24, 27, 28, 29, 30, 33, 36, 38, 39, 40, 41, 43, 44, 45, 46, 55, 66, 67, 72, 73, 74, 75, 76, 77, 78, 79, 82, 82, 84, 85, 86, 87 and 88, preferably selected from the group consisting of SEQ ID No 13, 23, 24, 75, 76 and 79.

[0061] In a preferred embodiment, the dietary supplement or substitute comprises at least one other peptide derived from the human microbiota, wherein the at least one other peptide comprises a core sequence of 9 amino acids, wherein the core sequence has at least 6 amino acids identical to and in the same position as a tumor-associated antigen epitope sequence selected from the group consisting of:

[0062] - KVAELVHFL (SEQ ID No. 2); or

[0063] - FLWGPRALV (SEQ ID No 3); or

[0064] - VLPDVFIRV (SEQ ID No 4); or

[0065] - KVLEYVIKV (SEQ ID No 5); or

[0066] - KVVEFLAML (SEQ ID No 6); or

[0067] -ALKDVEERV (SEQ ID No 7); or

[0068] -KASEKIFYV(SEQ ID No 8); or

[0069] -NYNNFYRFL (SEQ ID No 9); or

[0070] - EYLSLSDKI (SEQ ID No 10); or

[0071] - EYLQLVFGI (SEQ ID No 11); or

[0072] -LYATVIHDI (SEQ ID No 12).

[0073] Preferably, the at least one other peptide is selected from the group consisting of SEQ ID No. 91-631. More preferably, the at least one other peptide is selected from the group consisting of SEQ ID No 91-197, preferably SEQ ID No 134, 136, 137, 138, 142, 144, 146, 147, 150, 152, 153, 154, 155, 156, 160, 162, 163, 164, 166, 167, 169, 170, 274, 276, 177, 178, 282, 183, 184, 185, 186, 187, 188, 189, 190, 191, 194, 195 or 196, preferably selected from the group consisting of SEQ ID No 99, 100, 102, 134, 137, 138, 160, 162, 164, 182, 183, 184.

[0074] Another object of the present invention is a dietary supplement or substitute comprising at least one peptide derived from a microbiota, wherein said at least one peptide comprises a core sequence of 9 amino acids, wherein said core sequence has at least 6 amino acids identical and in the same position as a tumor-associated antigen epitope sequence selected from the group consisting of:

[0075] - KVAELVHFL (SEQ ID No. 2); or

[0076] - FLWGPRALV (SEQ ID No 3); or

[0077] - VLPDVFIRV (SEQ ID No 4); or

[0078] - KVLEYVIKV (SEQ ID No 5); or

[0079] - KVVEFLAML (SEQ ID No 6); or

[0080] -ALKDVEERV (SEQ ID No 7); or

[0081] -KASEKIFYV(SEQ ID No 8); or

[0082] -NYNNFYRFL (SEQ ID No 9); or

[0083] - EYLSLSDKI (SEQ ID No 10); or

[0084] - EYLQLVFGI (SEQ ID No 11); or

[0085] -LYATVIHDI (SEQ ID No 12).

[0086] Another object of the present invention is a dietary supplement or substitute comprising at least one peptide derived from a microbiota, wherein said at least one peptide comprises a core sequence of 9 amino acids, wherein said core sequence has at least 6, 7 or 8 amino acids identical and in the same position as a tumor-associated antigen epitope sequence selected from the group consisting of:

[0087] -GLYDGMEHL (SEQ ID No 1); or

[0088] - KVAELVHFL (SEQ ID No. 2); or

[0089] - FLWGPRALV (SEQ ID No 3); or

[0090] - VLPDVFIRV (SEQ ID No 4); or

[0091] - KVLEYVIKV (SEQ ID No 5); or

[0092] - KVVEFLAML (SEQ ID No 6); or

[0093] -ALKDVEERV (SEQ ID No 7); or

[0094] -KASEKIFYV(SEQ ID No 8); or

[0095] -NYNNFYRFL (SEQ ID No 9); or

[0096] - EYLSLSDKI (SEQ ID No 10); or

[0097] - EYLQLVFGI (SEQ ID No 11); or

[0098] -LYATVIHDI (SEQ ID No 12);

[0099] The remaining amino acids are different from the amino acids at the same position of the tumor-associated antigen epitope sequence

[0100] Preferably, the at least one peptide is selected from the following group: SEQ ID No.91-209 or SEQ ID No.211-327 or SEQ ID No.329-507 or SEQ ID No.509-631; more preferably selected from the following group: SEQ ID No 91-197; preferably, the at least one peptide is selected from the following group: SEQ ID No 194, 195 or 196, preferably selected from the group consisting of SEQ ID No 99, 100, 102, 134, 137, 138, 160, 162, 164, 182, 183, 184.

[0101] In a preferred embodiment of the present invention, the dietary supplement or substitute of the present invention is used to treat and / or prevent cancer, wherein the cancer is characterized by increased expression of at least one of the following antigens: GnTV, LRPAP1, MAGE-A10, MAGE-A3, MAGE-C1, MAGE-C2, SSX-2, KM-HN-1, KM-HN-2, MAGE-A2, SAGE, preferably wherein the cancer is a solid tumor, preferably the solid tumor is selected from melanoma, lung cancer, bladder cancer, esophageal cancer and head and neck cancer, sarcoma, colorectal cancer, gastric cancer, cutaneous squamous cell carcinoma, undifferentiated pleomorphic sarcoma / myxofibrosarcoma, non-small cell lung cancer, diffuse large B-cell lymphoma, 1. hepatocellular carcinoma, breast cancer, pancreatic cancer, gynecological cancer.

[0102] A further object of the present invention is the non-therapeutic use of the dietary supplement of the present invention in the preparation of a nutraceutical composition.

[0103] As used herein, the expression "peptide derived from a microbiota" refers to a peptide sequence identified in a microbiota, and which can be obtained, isolated, extracted or purified from a microbiota, or can be synthesized, produced, expressed using methods and techniques known in the art.

[0104] According to the present invention, peptides derived from microbiota as sequence analogs of the identified TAAs can be advantageously used in anti-tumor vaccine therapy. In short, administration of a vaccine comprising one or more peptides according to the present invention will have the effect of stimulating the immune system against such peptides. Therefore, the present invention preferably provides a vaccine or immunogenic composition comprising a composition as defined above and a pharmaceutically acceptable carrier or excipient, and preferably an adjuvant. Preferably, the vaccine or immunogenic composition is used to treat or prevent cancer, preferably for the treatment or prevention of cancer as defined above.

[0105] In other embodiments, the present invention relates to an antibody coupled to one or more peptides and / or variants and / or salts, and wherein the antibody is capable of recognizing an antigen presenting cell (APC), preferably a dendritic cell.

[0106] The antibodies according to the invention are capable of recognizing C-type lectin receptors such as DC-SIGN (CD209) on dendritic cells. In this way, the share of peptides captured by dendritic cells is significantly increased and the peptides are presented more efficiently to T cells.

[0107] Advantageously, according to the present invention, peptides derived from the microbiota itself or in optimized form, such as peptides fused to antibodies capable of recognizing antigen presenting cells (APCs) (such as dendritic cells) can be used as vaccines. The peptides can be given in an alternative form (such as a nucleic acid encoding the peptide, or a vector comprising the nucleic acid) or directly given to cells (e.g. APCs) expressing the peptide.

[0108] Furthermore, according to the present invention, peptides derived from the microbiota can be advantageously used to stimulate T cells ex vivo, which are then reinfused into the patient after administration of other therapeutic agents or in the absence of any specific pretreatment.

[0109] The present invention further relates to an engineered cell comprising a recombinant protein or a polynucleotide encoding a recombinant protein, preferably, the recombinant protein is a recombinant receptor, more preferably a receptor expressed on the surface of an immune cell receptor, wherein the recombinant receptor specifically binds to at least one peptide of a 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 further relates to a T lymphocyte receptor capable of binding to one or more peptides as previously defined, wherein the receptor optionally includes one or more costimulatory domains. The receptor is, for example, a chimeric receptor (CAR) of an antigen.

[0110] In another embodiment, the present invention relates to a nucleotide sequence (DNA or RNA) encoding a peptide as described above or an antibody as described above.

[0111] In other embodiments, the invention relates to a nucleotide sequence encoding a T lymphocyte receptor capable of binding to one or more peptides as previously defined.

[0112] In other embodiments, the present invention relates to an expression vector comprising the nucleotide sequence previously defined.

[0113] It should be noted that, in the context of this discussion, the expression pharmaceutical composition or composition refers indiscriminately to an immunogenic composition or a vaccine composition.

[0114] The composition according to the present invention is used for treating cancer, preferably for treating or preventing cancer characterized by increased expression of at least one of the following antigens: GnTV, LRPAP1, MAGE-A10, MAGE-A3, MAGE-C1, MAGE-C2, SSX-2, KM-HN-1, KM-HN-2, MAGE-A2, SAGE.

[0115] As used herein, the expression "cancer characterized by increased expression of at least one of the following antigens: GnTV, LRPAP1, MAGE-A10, MAGE-A3, MAGE-C1, MAGE-C2, SSX-2, KM-HN-1, KM-HN-2, MAGE-A2, SAGE" refers to solid tumors. As used herein, solid tumors include melanoma, lung cancer, bladder cancer, esophageal cancer and head and neck cancer, as well as sarcoma, colorectal cancer, gastric cancer, squamous cell carcinoma of the skin, undifferentiated pleomorphic sarcoma / myxofibrosarcoma, non-small cell lung cancer and diffuse large B-cell lymphoma.

[0116] Preferably, the composition of the present invention can be administered to a patient in need thereof in combination with other treatment regimens. Also preferably, the composition of the present invention is administered to a subject in a therapeutically effective amount before, simultaneously or sequentially with other treatment regimens or co-agents (e.g., multiple drug regimens) that can be used to treat and / or stabilize cancer and / or prevent cancer recurrence. The composition according to the present invention can be administered in the same or different compositions and by the same or different administration routes as the co-agents.

[0117] The other treatment regimens or adjuvants may be selected from the following groups: radiotherapy, chemotherapy, surgery, targeted therapy (including small molecules, peptides and monoclonal antibodies) and anti-angiogenic therapy. Anti-angiogenic therapy is defined herein as administering an agent that directly or indirectly targets the tumor-associated vasculature. Preferred anticancer agents include chemotherapeutics, targeted drugs and / or immunotherapeutics, such as immune checkpoint regulators.

[0118] The composition of the invention may also be used as a dietary supplement or substitute, meaning for example a food or drink comprising the composition as defined herein.

[0119] According to the present invention, the expression vector for inducing peptide expression comprises a nucleic acid, DNA or RNA encoding the peptide. The vector may be an RNA vector, a DNA vector, a viral vector or a bacterial vector.

[0120] According to the present invention, "microbiota sequence analogs" refer to peptide sequences, and the term "peptide" includes peptide variants that retain the ability to bind to MHC class I or MHC class II molecules, such as peptides having one or two amino acids substituted by amino acids belonging to the same group.

[0121] As another example, the microbiota sequence analogs of TAA of the present invention have at least 80%, preferably at least 90% sequence homology with respect to the sequence of one or more peptides comprising an amino acid sequence selected from the group consisting of SEQ ID No. 1-12 or consisting of SEQ ID No. 1-12, and retain the ability to bind to MHC class I.

[0122] Preferably, the composition of the present invention comprises a peptide having a length of 9 to 30 amino acids, preferably 9 to 20 amino acids, more preferably 9 amino acids.

[0123] In detail, a peptide of 9 amino acids is optimal for binding to MHC class I, whereas in order to bind to MHC class II, a peptide must have at least 15 amino acids, preferably 20-30 amino acids.

[0124] Advantageously, when the peptide or peptides according to the invention are capable of binding to MHC class II, the latter have a length of at least 15 amino acids, preferably between 20 and 30 amino acids.

[0125] As used herein, MHC class II refers to HLA class II, preferably HLA-DR, more preferably HLA-DR1, HLA-DR3, HLA-DR4 and / or HLA-DR11.

[0126] As used herein, MHC class I refers to HLA class I, preferably HLA-A and / or HLA-B, more preferably HLA-A.

[0127] Specifically, HLA-A is selected from the following group: HLA-A*02:01, HLA-A*01:01, HLA-A*26:01, HLA-A*03:01 and / or HLA-A*24:02, preferably HLA-A*02:01 and / or HLA-A*24:02.

[0128] The peptide according to the invention or a peptide variant as defined above may comprise an additional portion of amino acids at the N-terminus or C-terminus which do not necessarily serve as part of the peptide portion of the MHC epitope.

[0129] However, these additional moieties may be important for the efficient introduction of the peptides according to the invention into cells.

[0130] In other embodiments of the invention, peptides derived from the microbiota are combined with antibodies or functional parts of the antibodies themselves, in particular peptides that can be inserted into the antibody sequence so as to be specifically carried by the antibody, or for example can be fused to an antibody, or inserted into an antibody that is specific for dendritic cells.

[0131] In addition, the peptide or variant derived from microbiota according to the present invention can be further modified or modified to improve stability and / or the combination with MHC molecules to obtain a stronger immune response. Methods for optimizing peptide sequences are well known in the art and include, for example, the introduction of reverse peptide bonds or non-peptide bonds.

[0132] In a reverse peptide bond, the amino acid residues are not joined by a peptide bond (-CO-NH-), but the peptide bond is reversed. Such retro-inverse peptide mimics (peptidomimetic) peptides can be prepared 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 method involves creating pseudopeptides containing changes involving the backbone rather than the side chain orientation. Meziere et al. (1997) showed that these pseudopeptides contribute to MHC binding and helper T cell responses.

[0133] Retro-inverse peptides contain NH-CO bonds instead of CO-NH peptide bonds and are more resistant to proteolysis.

[0134] The non-peptide bond can be, for example, one of the following: -CH2-NH, -CH2S-, -CH2CH2-, -CH═CH-, -COCH2-, -CH(OH)CH2-, and -CH2SO-. U.S. Pat. No. 4,897,445 provides a method for solid phase synthesis of non-peptide bonds (-CH2-NH) in polypeptide chains, which method involves using a polypeptide synthesized by a standard procedure and a non-peptide bond synthesized by reacting an aminoaldehyde and an amino acid in the presence of NaCNBH3.

[0135] The peptides comprising the above sequences can be synthesized with other chemical groups present at their amino and / or carboxyl terminal groups to improve the stability, bioavailability and / or affinity of the peptides. For example, a hydrophobic group such as benzyloxycarbonyl, dansyl or tert-butyloxycarbonyl can be added to the amino terminus of the peptide.

[0136] Similarly, an acetyl group or a 9-fluorenylmethoxycarbonyl group can be placed at the amino terminus of the peptide. In addition, a hydrophobic group, a tert-butoxycarbonyl group or an amide group can be added to the carboxyl terminus of the peptide.

[0137] In addition, peptides according to the present invention can be synthesized in a manner that changes their spatial configuration. For example, the D isomer of one or more amino acid residues of the peptide can be used, rather than the common L isomer. In addition, at least one amino acid residue of the peptide of the present invention can be substituted by non-naturally occurring, known amino acid residues. Changes such as these can be used to increase the stability, bioavailability and / or binding of the peptide of the present invention.

[0138] Similarly, the peptide or peptide variant according to the present invention can be chemically modified before or after peptide synthesis or modified by reacting specific amino acids. Examples of such modifications are well known in the art and are summarized in, for example, R. Lundblad, Chemical Reagents for Protein Modification, 3rd edition, CRC Press, 2005, which is incorporated herein by reference.

[0139] Chemical modifications of amino acids include, but are not limited to, pyridinium oxidation, acylation, amidation, reductive alkylation of lysine, trinitrobenzylation of amino groups with 2,4,6-trinitrobenzenesulfonic acid (TNBS), amide modification of carboxyl groups and sulfhydryl modification of cysteine ​​by oxidation of cysteine ​​with performic acid, formation of mercuric 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. At this point, methods of chemical modification of proteins are well known to those skilled in the art.

[0140] In brief, modification of arginyl residues in proteins is often based on the reaction of ortho-dicarbonyl compounds such as phenylglyoxal, 2,3-butanedione and 1,2-cyclohexanedione to form adducts. Another example is the reaction of methylglyoxal with arginine residues. Cysteine ​​can be modified without simultaneously modifying other nucleophilic sites (such as lysine and histidine).

[0141] Therefore, a large number of cysteine ​​modification reagents are available. Company websites such as Sigma-Aldrich (http: / / www.sigma-aldrich.com) provide information on specific reagents.

[0142] Selective reduction of disulfide bonds in proteins is also known. During thermal treatment of biopharmaceutical products, disulfide bonds may form and oxidize. Woodward's K reagent can be used to modify specific glutamic acid residues. N-(3-(dimethylamino)propyl)-N'-ethylcarbodiimide can be used to form intramolecular linkages between lysine residues and glutamic acid residues. For example, diethyl pyrocarbonate is a reagent used to modify histidyl residues in proteins. Histidine can also be modified using 4-hydroxy-2-nonenal. For example, reactions of lysine residues with other α-amino groups can be used for binding of peptides to surfaces or for cross-linking with proteins / peptides. Lysine is the attachment site for polyethylene glycol and is also the primary modification site for protein glycosylation. Methionine residues in proteins can be modified using, for example, iodoacetamide, bromoethylamine, and chloramine T.

[0143] Tetranitromethane and N-acetylimidazole can be used for modification of tyrosyl residues. Cross-linking through formation of dityrosine can be accomplished with hydrogen peroxide / copper ions.

[0144] N-bromosuccinimide, 2-hydroxy-5-nitrobenzyl bromide, or 3-bromo-3-methyl-2-(2-nitrobenzylthio)-3H-indole (BPNS-skatole) have been used in some tryptophan modification studies.

[0145] Successful modification of therapeutic proteins and peptides with PEG often results in increased circulation half-life, while cross-linking of proteins with glutaraldehyde, polyethylene glycol diacrylate, and formaldehyde is used to prepare hydrogels.

[0146] Chemical modification of allergens for immunotherapy is usually achieved by carbamylation with potassium cyanate.

[0147] In general, peptides and variants (at least those containing peptide bonds between amino acid residues) can be synthesized by the Fmoc-polyamide mode of solid phase peptide synthesis, as disclosed by Lukas et al. (Synthesis of the solid phase peptide under continuous flow conditions) Proc. Natl Acad Sci USA, 1981 May; 78(5): 2791-2795). Temporary protection of the N-amino group is provided by 9-fluorenylmethoxycarbonyl (Fmoc). BRIEF DESCRIPTION OF THE DRAWINGS

[0148] Figure 1. Affinity and stability of paired peptides. NetMHCstabpan predicted the affinity of each TAA and paired bacterial peptide to HLA*02:01 (A) and HLA*24:02 (B) molecules. (C) Represents the affinity of all bacterial peptides from Firmicutes and Bacteroidetes species to HLA molecules. Affinity values ​​(Aff) are expressed in nanomolar concentrations (nM).

[0149] Figure 2. Comparison of amino acid residues between paired peptides. The amino acid substitution patterns at each peptide position were evaluated by comparing paired TAAs with homologous peptides derived from microbiota. The substitution patterns at each position were expressed as a percentage of the total number of sequences.

[0150] Figure 3. Predicted conformations of the structures of MAGE-A10 and bacterial paired peptides. The conformations of the paired peptide bound to the HLA-A*02:01 molecule are shown. (A) Contact points on the molecular surface are shown. Black areas = contact points with HLA molecules; light gray areas = contact points with TCRα and β chains. (B) Hydrogen bonds between the peptide and the TCRα and β chains are shown as black dotted circles.

[0151] Figure 4. Structural prediction conformations of MAGE-A3 KVAELVHFL and bacterial paired peptides. The conformations of the paired peptide bound to the HLA-A*02:01 molecule are shown. (A) Contact points on the molecular surface are shown. Black areas = contact points with HLA molecules; light gray areas = contact points with TCRα and β chains. (B) Hydrogen bonds between the peptide and the TCRα and β chains are shown as black dotted circles.

[0152] Figure 5. Structural predicted conformations of MAGE-A3 FLWGPRALV and bacterial paired peptides. The conformations of the paired peptide bound to the HLA-A*02:01 molecule are shown. (A) Contact points on the molecular surface are shown. Black areas = contact points with HLA molecules; light gray areas = contact points with TCRα and β chains. (B) Hydrogen bonds between the peptide and the TCRα and β chains are shown as black dotted circles.

[0153] Materials and methods

[0154] Peptides from the Cancer Antigen Peptide Database (https: / / caped.icp.ucl.ac.be / Peptide / list) were selected if they were predicted to be strong binders (SB) restricted to the most common MHC class I alleles (26). Subsequently, they performed a global protein BLAST against bacterial sequences from the phyla Firmicutes and Bacteroidetes in the GeneBank nonredundant protein database. The search returned a large number of HLA-A*0201- and HLA-A*2402-restricted bacterial sequences with homology to the selected TAAs, and the majority of such homology was found to HLA-A*0201 (Tables 1 and 2). Specifically, the following TAAs were selected and reported in Tables 1 and 2: GnTv (PMID 8642259); LRPAP1 (PMID 30115740); MAGEA10 (PMID 10352307), MAGEA3 (PMID 28337438); MAGE A12m (PMID 7805731); MAGE C1 (PMID 21461886); MAGE C2 (PMID14999777); SSX-2 (PMID 11823502); KM-HN-1 (PMID 15447989); MAGE A2 (PMID 10473111); SAGE (PMID 16061876).

[0155]

[0156]

[0157]

[0158]

[0159]

[0160]

[0161]

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[0165]

[0166]

[0167]

[0168]

[0169]

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[0172]

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[0177]

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[0179]

[0180]

[0181]

[0182]

[0183]

[0184]

[0185]

[0186]

[0187]

[0188]

[0189]

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[0192]

[0193]

[0194]

[0195]

[0196]

[0197]

[0198]

[0199]

[0200]

[0201] Regarding tumor-specific TAAs, antigens of the MAGE family (melanoma-associated gene protein family), specifically MAGE-A10, MAGE-A3, MAGE-C1 and MAGE-C2, were found to have high levels of homology, among others. Interestingly, two different MAGE-A3 TAAs (FLWGPRALV and KVAELVHFL) were found to have homology with bacterial species from both phyla.

[0202] In general, for each TAA analyzed, several peptides from different species in the two phyla were found to have homology with very high affinities (<100 nM). Specifically, for peptides from Firmicutes and Bacteroidetes, the average affinities were 34.4 nM and 30.0 nM, respectively (Figures 1A and B). Interestingly, the average affinity values ​​for bacterial peptides restricted to HLA*02:01 (18.8 and 26.6 nM, respectively) were significantly higher than those for bacterial peptides restricted to HLA*24:02 (95.2 and 44.48 nM, respectively) (Figure 1C). The calculation of affinity values ​​is described in Ragone C et al., PMID: 34049932.

[0203] Alignment of representative TAAs with homologous bacterial peptides showed that the amino acid residues at each position were mostly identical or belonged to the same class (conservative substitutions) ( Table 3 ).

[0204] Table 3. Alignment of TAAs with homologous bacterial peptides. Phylum (Firmicutes or Bacteroidetes) is indicated at the top of each box; dots = identical amino acid residues; conservative amino acid substitutions are indicated in black; non-conservative amino acid substitutions are indicated in underline and italics.

[0205] Firmicutes

[0206]

[0207] Table 3 (Continued) Bacteroidetes

[0208]

[0209]

[0210] Firmicutes

[0211]

[0212] Bacteroidetes

[0213]

[0214] Table 3 (Continued) Firmicutes

[0215]

[0216]

[0217] Bacteroidetes

[0218]

[0219] Table 3 (Continued) Firmicutes

[0220]

[0221] Bacteroidetes

[0222]

[0223] Firmicutes

[0224]

[0225] Table 3 (Continued) Bacteroidetes

[0226]

[0227]

[0228] Firmicutes

[0229]

[0230] Bacteroidetes

[0231]

[0232] Firmicutes

[0233]

[0234] Table 3 (Continued) Bacteroidetes

[0235]

[0236] Firmicutes

[0237]

[0238]

[0239] Bacteroidetes

[0240]

[0241] Firmicutes

[0242]

[0243] Table 3 (Continued) Bacteroidetes

[0244]

[0245] Firmicutes

[0246]

[0247] Bacteroidetes

[0248]

[0249] Firmicutes

[0250]

[0251] Table 3 (continued)

[0252] Bacteroidetes

[0253]

[0254] Firmicutes

[0255]

[0256]

[0257] Bacteroidetes

[0258]

[0259] In fact, referring to the sequences reported in Table 3, the average percentage of identical residues at each position is 82.8%, ranging from 79.7% at position 3 to 89.5% at position 2. Summarizing conservative substitutions, the average percentage of identical residues at each position is 93.6%, ranging from 86.7% at position 7 to 98.3% at position 9. Thus, the average percentage of non-conservative substitutions at each position is only 6.39%, ranging from 1.6% at position 9 to 13.2% at position 7. The only exception is position 1, which seems to be more permissive to non-conservative substitutions, with an average of 30.9%, ranging from 12.5% ​​(MAGE-C2) to 52.6% (KM-HN-1) (Figure 2).

[0260] Strikingly, bacterial peptides identical to TAAs were identified. In fact, considering the HLA*02:01 restricted peptide, the VLPDVFIRV peptide (SEQ ID No 4) derived from the ACT domain-containing protein [Oscillospiraceae bacteria] is identical to the GnTV TAA; the KVVEFLAML peptide (SEQ ID No 6) derived from the helix-turn-helix transcription regulator [Clostridium bacteria] is identical to the MAGE-C1TAA. Similarly, considering the HLA*24:02 restricted peptide, the EYLSLSDKI peptide (SEQ ID No 10) derived from the SMI1 / KNR4 family protein Roseburia 1XD42-69 is identical to the KM-HN-1TAA (Tables 1 and 2).

[0261] To verify whether the predicted paired TAA and bacterial epitopes have similar contact residues with HLA molecules and TCRs, epitope modeling and molecular docking were performed (Ragone C et al., PMID: 34049932). Due to the lack of crystallized structures including HLA and TCR for other alleles deposited in the PDB, this is only applicable to HLA-A*0201 restricted epitopes. In addition, no epitopes crystallized with HLA-A*0201 and TCRs showing sequence homology with TAA peptides were found. Therefore, with full awareness of possible precautions, the 1AO7 crystallized complex containing the HTLV-I TAX epitope was used as a universal template for analysis (Garboczi, DN, Ghosh, P., Utz, U., Fan, QR, Biddison, WE, Wiley, DC (1996) Nature 384: 134-141).

[0262] Among the TAAs analyzed in this study, the inventors focused on MAGE-A3 and MAGE-A10, which have been identified in a variety of cancers of different histological origin, including non-small cell lung cancer (NSCLC), bladder cancer, esophageal cancer, and head and neck cancers and sarcomas (28). Specifically, MAGE-A3 is overexpressed in multiple tumor types, including melanoma (29) and lung cancer (30), and its presence is associated with poor prognosis in colorectal cancer (31), squamous cell carcinoma of the skin (32), and undifferentiated pleomorphic sarcoma / myxofibrosarcoma (33). Therefore, the structural and conformational homology of peptides derived from the microbiota to these TAAs may have a strong impact on a variety of cancers.

[0263] result

[0264] MAGE-A10 GLYDGMEHL TAA

[0265] Structural and conformational analysis confirmed that the MAGE-A10 GLYDGMEHL (SEQID No 1) peptide showed a very similar interaction pattern with HLA and TCR compared to the GLYDGMEYI (SEQ ID No 13), MLYDGMERL (SEQID No 24) and KLYDGIEHL (SEQ ID No 23) peptides of Firmicutes and the GLYDGMRHL (SEQ ID No 79), GLYDGMEKA (SEQ ID No 75) and ALYDGMEDL (SEQ ID No 76) peptides of Bacteroidetes (Figure 3A). In addition, the same hydrogen bonding pattern and the same distance were observed in the paired peptides between the residues at positions 4 and 8 of the peptide and the Ser100 of the α chain and Leu98 of the β chain of the TCR, respectively. This suggests that TCR clones targeting TAAs and microbial peptides will share the same α and β chains (Figure 3B).

[0266] MAGE-A3 KVAELVHFL TAA

[0267] Structural and conformational analysis confirmed that the MAGE-A3 KVAELVHFL (SEQ ID No 2) peptide showed a very similar interaction pattern with HLA and TCR compared to the KIAELVHFL (SEQ ID No 99), KIAEMVHFL (SEQ ID No 100) and AIAELVHFL (SEQ ID No 102) peptides from Firmicutes and the VLAELVHFL (SEQ ID No 134) peptide from Bacteroidetes. In contrast, the contact patterns of the KVAEFIHFL (SEQ ID No 137) and KVAELVHHV (SEQ ID No 138) peptides were significantly different (Figure 4A). This is also reflected in the hydrogen bonding pattern of the α and β chains of the TCR. In fact, in addition to the common bonds between the residues at positions 4 and 8 of the peptide and Ser100 of the α chain and Leu98 of the β chain of the TCR, the latter two peptides showed two additional hydrogen bonds between the Val2 and Glu4 residues and the Gln30 and Ser100 residues of the α chain. This indicated that TCR clones targeting the TAA and microbiota KVAEFIHFL (SEQ ID No 137) and KVAELVHHV (SEQ ID No 138) peptides would only share the β chain, but the α chain would be different ( FIG. 4B ).

[0268] MAGE-A3 FLWGPRALV TAA

[0269] Structural and conformational analysis confirmed that the MAGE-A3 FLWGPRALV (SEQ ID No 3) peptide showed the most similar interaction pattern with HLA and TCR compared to the FLWGGRALL (SEQ ID No 164) peptide of Firmicutes and the FLWGSIALV (SEQ ID No 182) peptide of Bacteroidetes. In contrast, the FLWGPFSLV (SEQ ID No 162) peptide of Firmicutes and the FLWGPHDLV (SEQ ID No 184) peptide of Bacteroidetes only shared the interaction pattern with the TCRβ chain; while the FLWAPIALV (SEQ ID No160) peptide of Firmicutes and the FLWESRALV (SEQ ID No 183) peptide of Bacteroidetes only shared the interaction pattern with the TCRα chain (Figure 5A).

[0270] Despite such differences, the same hydrogen bonding pattern as that of the α and β chains of TCR was observed between the residues at positions 4 and 8 of the peptide and Ser100 of the α chain and Leu98 of the β chain of TCR ( FIG. 5B ).

[0271] The data reported in this study demonstrate for the first time that TAAs share high homology in linear sequence as well as in structure and conformation with peptides derived from the Firmicutes and Bacteroidetes microbiota, which together account for 90% of the intestinal microbiota. Such high levels of homology (reaching 100% in some cases) strongly suggest that T cells cross-recognize TCRs that share similar or identical α and β chains. In support of this hypothesis, the inventors recently showed that CD8+ T cells cross-react with TAAs and peptides derived from viruses with the same level of homology as observed in this study (26).

[0272] Therefore, depending on the human life stage when an individual encounters a microbiota species, this homology may represent an advantageous or disadvantageous factor. Indeed, if the microbiota colonizes the gastrointestinal tract already during the first months of life, the immune system may recognize the derived peptides as self-antigens and specific T-cell clones will be eliminated. In this case, tumor lesions presenting the homologous TAAs have a selective advantage for the establishment and progression of a poor prognosis.

[0273] In contrast, if the microbiota colonizes the gastrointestinal tract later in life, the immune system can recognize the derived peptides as non-self antigens and specific memory T cell clones will be established. In this case, for preventive vaccines, tumor lesions presenting the cognate TAA will rapidly recall memory T cells that can eliminate or control tumor growth, thereby improving prognosis.

[0274] The interactions between the human microbiota and the immune response open up new horizons with potentially profound effects on tumor initiation and progression. Moreover, they provide a completely new class of antigens that can be used as anticancer preventive vaccinations or administered as food integrators.

[0275] References

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[0308] 33. Conley AP, Wang WL, Livingston JA, Ravi V, Tsai JW, Ali A, Ingram DR, Lowery CD, Roland CL, Somaiah N, Hwu P, Yee C, Subbiah V, Futreal A, Lazar AJ, Patel S, Roszik J. MAGE-A3 is a Clinically Relevant Target in Undifferentiated Pleomorphic Sarcoma / Myxofibrosarcoma. Cancers (Basel). 2019 May 15;11(5).doi:10.3390 / cancers11050677. PubMed PMID: 31096717; PubMed Central Article ID: PMC6562561.

Claims

1. A composition comprising at least one peptide derived from a human microbiota and at least one pharmaceutically acceptable excipient, wherein the at least one peptide comprises a core sequence of 9 amino acids, wherein the core sequence has 6, 7 or 8 amino acids that are identical to the tumor-associated antigen epitope sequence GLYDGMEHL (SEQ ID No 1) and in the same position, and the remaining amino acids are different from the amino acids in the same position of the epitope sequence.

2. The composition according to claim 1, wherein the at least one peptide is selected from the group consisting of SEQ ID No. 13-90.

3. The composition of any one of claims 1 or 2, wherein the at least one peptide is selected from the group consisting of SEQ ID No 13, 16, 21, 23, 24, 27, 28, 29, 30, 33, 36, 38, 39, 40, 41, 43, 44, 45, 46, 55, 66, 67, 72, 73, 74, 75, 76, 77, 78, 79, 82, 82, 84, 85, 86, 87 and 88, preferably selected from the group consisting of SEQ ID No 13, 23, 24, 75, 76 and 79.

4. A composition consisting of a peptide derived from human microbiota according to any one of the preceding claims and at least one pharmaceutically acceptable excipient.

5. The composition according to any one of the preceding claims, comprising at least one other peptide, wherein the at least one other peptide comprises a core sequence of 9 amino acids, wherein the core sequence has at least 6 amino acids that are identical and in the same position as a tumor-associated antigen epitope sequence selected from the following group: - KVAELVHFL (SEQ ID No. 2); or - FLWGPRALV (SEQ ID No 3); or - VLPDVFIRV (SEQ ID No 4); or - KVLEYVIKV (SEQ ID No 5); or - KVVEFLAML (SEQ ID No 6); or -ALKDVEERV (SEQ ID No 7); or -KASEKIFYV(SEQ ID No 8); or -NYNNFYRFL (SEQ ID No 9); or - EYLSLSDKI (SEQ ID No 10); or - EYLQLVFGI (SEQ ID No 11); or -LYATVIHDI (SEQ ID No 12).

6. The composition according to claim 5, wherein the at least one other peptide is selected from the group consisting of SEQ ID Nos. 91-631.

7. The composition according to claim 5, wherein the at least one other peptide is selected from the group consisting of SEQ ID No 91-197.

8. The composition of claim 7, wherein the at least one peptide is selected from the group consisting of SEQ ID No 134, 136, 137, 138, 142, 144, 146, 147, 150, 152, 153, 154, 155, 156, 160, 162, 163, 164, 166, 167, 169, 170, 274, 276, 177, 178, 282, 183, 184, 185, 186, 187, 188, 189, 190, 191, 194, 195 or 196, preferably selected from the group consisting of SEQ ID No 99, 100, 102, 134, 137, 138, 160, 162, 164, 182, 183, 184.

9. A composition comprising at least one peptide derived from a human microbiota and a pharmaceutically acceptable excipient, wherein the at least one peptide comprises a core sequence of 9 amino acids, wherein the core sequence has 6, 7 or 8 amino acids that are identical and in the same position as a tumor-associated antigen epitope sequence selected from the following group: - KVAELVHFL (SEQ ID No. 2); or - FLWGPRALV (SEQ ID No 3); or - VLPDVFIRV (SEQ ID No 4); or - KVLEYVIKV (SEQ ID No 5); or - KVVEFLAML (SEQ ID No 6); or -ALKDVEERV (SEQ ID No 7); or -KASEKIFYV(SEQ ID No 8); or -NYNNFYRFL (SEQ ID No 9); or - EYLSLSDKI (SEQ ID No 10); or - EYLQLVFGI (SEQ ID No 11); or -LYATVIHDI (SEQ ID No 12); The remaining amino acids are different from the amino acids at the same position in the tumor-associated antigen epitope sequence.

10. The composition according to claim 9, wherein the peptide is selected from the group consisting of SEQ ID No. 91-209 or SEQ ID No. 211-327 or SEQ ID No. 329-507 or SEQ ID No. 509-631.

11. The composition according to claim 10, wherein the at least one other peptide is selected from the group consisting of SEQ ID No 91-197.

12. The composition according to claim 11, wherein the at least one peptide is selected from the group consisting of SEQ ID No 134, 136, 137, 138, 142, 144, 146, 147, 150, 152, 153, 154, 155, 156, 160, 162, 163, 164, 166, 167, 169, 170, 274, 276, 177, 178, 282, 183, 184, 185, 186, 187, 188, 189, 190, 191, 194, 195 or 196, preferably selected from the group consisting of SEQ ID No 99, 100, 102, 134, 137, 138, 160, 162, 164, 182, 183, 184.

13. A composition according to any one of the preceding claims for use in the treatment and / or prevention of cancer, wherein the cancer is characterized by an increased expression of at least one of the following antigens: MAGE-A10, MAGE-A3, GnTV, LRPAP1, MAGE-C1, MAGE-C2, SSX-2, KM-HN-1, KM-HN-2, MAGE-A2, SAGE.

14. The composition for use according to claim 13, wherein the cancer is a solid tumor, preferably the solid tumor is selected from melanoma, lung cancer, bladder cancer, esophageal cancer and head and neck cancer, as well as sarcoma, colorectal cancer, gastric cancer, cutaneous squamous cell carcinoma, undifferentiated pleomorphic sarcoma / myxofibrosarcoma, non-small cell lung cancer, diffuse large B-cell lymphoma, hepatocellular carcinoma, breast cancer, pancreatic cancer, gynecological cancer.

15. The composition according to claim 13 or 14 for use in combination with other anti-cancer therapeutic agents.

16. A vaccine or immunogenic composition comprising the composition of any one of claims 1 to 12 and a pharmaceutically acceptable carrier or excipient, and preferably an adjuvant.

17. The vaccine or immunogenic composition according to claim 16 for use in the treatment and / or prevention of cancer, preferably for use in the treatment and / or prevention of cancer, characterized in that Increased expression of at least one of the following antigens: GnTV, LRPAP1, MAGE-A10, MAGE-A3, MAGE-C1, MAGE-C2, SSX-2, KM-HN-1, KM-HN-2, MAGE-A2, SAGE, more preferably for the treatment and / or prevention of solid tumors, preferably solid tumors selected from melanoma, lung cancer, bladder cancer, esophageal cancer and head and neck cancer, sarcoma, colorectal cancer, gastric cancer, skin squamous cell carcinoma, undifferentiated pleomorphic sarcoma / myxofibrosarcoma, non-small cell lung cancer, diffuse large B-cell lymphoma, hepatocellular carcinoma, breast cancer, pancreatic cancer, gynecological cancer.

18. A dietary supplement or substitute comprising at least one peptide derived from a human microbiota, wherein the at least one peptide comprises a core sequence of 9 amino acids, wherein the core sequence has 6, 7 or 8 amino acids that are identical to the tumor-associated antigen epitope sequence GLYDGMEHL (SEQ ID No 1) and in the same position, and the remaining amino acids are different from the amino acids in the same position of the epitope sequence.

19. The dietary supplement or substitute according to claim 18, wherein the at least one peptide is selected from the group consisting of SEQ ID No. 13-90.

20. A dietary supplement or substitute according to any one of claims 18 or 19, wherein the at least one peptide is selected from the group consisting of SEQ ID No 13, 16, 21, 23, 24, 27, 28, 29, 30, 33, 36, 38, 39, 40, 41, 43, 44, 45, 46, 55, 66, 67, 72, 73, 74, 75, 76, 77, 78, 79, 82, 82, 84, 85, 86, 87 and 88, preferably selected from the group consisting of SEQ ID No 13, 23, 24, 75, 76 and 79.

21. The dietary supplement or substitute according to any one of claims 18-20, comprising at least one other peptide derived from the human microbiota, wherein the at least one other peptide comprises a core sequence of 9 amino acids, wherein the core sequence has at least 6 amino acids identical to and in the same position as a tumor-associated antigen epitope sequence selected from the group consisting of: - KVAELVHFL (SEQ ID No. 2); or - FLWGPRALV (SEQ ID No 3); or - VLPDVFIRV (SEQ ID No 4); or - KVLEYVIKV (SEQ ID No 5); or - KVVEFLAML (SEQ ID No 6); or -ALKDVEERV (SEQ ID No 7); or -KASEKIFYV(SEQ ID No 8); or -NYNNFYRFL (SEQ ID No 9); or - EYLSLSDKI (SEQ ID No 10); or - EYLQLVFGI (SEQ ID No 11); or -LYATVIHDI (SEQ ID No 12); and pharmaceutically acceptable carriers or excipients.

22. The dietary supplement or substitute according to claim 21, wherein the at least one other peptide is selected from the group consisting of SEQ ID No. 91-631.

23. The dietary supplement or substitute according to claim 22, wherein the at least one other peptide is selected from the group consisting of SEQ ID Nos. 91-197.

24. The dietary supplement or substitute according to claim 23, wherein the at least one peptide is selected from the group consisting of SEQ ID No 134, 136, 137, 138, 142, 144, 146, 147, 150, 152, 153, 154, 155, 156, 160, 162, 163, 164, 166, 167, 169, 170, 274, 276, 177, 178, 282, 183, 184, 185, 186, 187, 188, 189, 190, 191, 194, 195 or 196, preferably selected from the group consisting of SEQ ID No 99, 100, 102, 134, 137, 138, 160, 162, 164, 182, 183, 184.

25. A dietary supplement or substitute comprising at least one peptide derived from a human microbiota, wherein the at least one peptide comprises a core sequence of 9 amino acids, wherein the core sequence has 6, 7 or 8 amino acids that are identical and in the same position as a tumor-associated antigen epitope sequence selected from the group consisting of: - KVAELVHFL (SEQ ID No. 2); or - FLWGPRALV (SEQ ID No 3); or - VLPDVFIRV (SEQ ID No 4); or - KVLEYVIKV (SEQ ID No 5); or - KVVEFLAML (SEQ ID No 6); or -ALKDVEERV (SEQ ID No 7); or -KASEKIFYV(SEQ ID No 8); or -NYNNFYRFL (SEQ ID No 9); or - EYLSLSDKI (SEQ ID No 10); or - EYLQLVFGI (SEQ ID No 11); or -LYATVIHDI (SEQ ID No 12); The remaining amino acids are different from the amino acids at the same position in the tumor-associated antigen epitope sequence.

26. The dietary supplement or substitute according to claim 25, wherein the at least one peptide is selected from the group consisting of SEQ ID No. 91-209 or SEQ ID No. 211-327 or SEQ ID No. 329-507 or SEQ ID No. 509-631.

27. A dietary supplement or substitute according to claim 26, wherein the at least one other peptide is selected from the group consisting of SEQ ID No 91-197, preferably the at least one peptide is selected from the group consisting of SEQ ID No 134, 136, 137, 138, 142, 144, 146, 147, 150, 152, 153, 154, 155, 156, 160, 162, 163, 164, 166, 167, 169, 170, 274, 276, 177, 178, 282, 183, 184, 185, 186, 187, 188, 189, 190, 191, 194, 195 or 196, preferably selected from the group consisting of SEQ ID No 99, 100, 102, 134, 137, 138, 160, 162, 164, 182, 183, 184.

28. A dietary supplement or substitute according to any one of claims 18 to 27 for use in the treatment and / or prevention of cancer, wherein the cancer is characterized by an increased expression of at least one of the following antigens: MAGE-A10, MAGE-A3, GnTV, LRPAP1, MAGE-C1, MAGE-C2, SSX-2, KM-HN-1, KM-HN-2, MAGE-A2, SAGE.

29. A dietary supplement or substitute for use according to claim 28, wherein the cancer is a solid tumor, preferably the solid tumor is selected from melanoma, lung cancer, bladder cancer, esophageal cancer and head and neck cancer, as well as sarcoma, colorectal cancer, gastric cancer, cutaneous squamous cell carcinoma, undifferentiated pleomorphic sarcoma / myxofibrosarcoma, non-small cell lung cancer, diffuse large B-cell lymphoma, hepatocellular carcinoma, breast cancer, pancreatic cancer, gynecological cancer.

30. Non-therapeutic use of a dietary supplement according to any one of claims 18 to 27 in the preparation of a nutraceutical composition.

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