Antigenic peptides for preventing and treating cancer

Abstract

The present invention relates to antigen-based immunotherapy, specifically cancer immunotherapy. Specifically, the present invention provides antigenic peptides that are different from human tumor antigen fragments but have amino acid similarity. The present invention further provides immunogenic compounds, nanoparticles, cells, and pharmaceutical compositions comprising such antigenic peptides, as well as nucleic acids encoding such antigenic peptides.

Description

Technical Field

[0001] The present invention relates to the field of cancer treatment, more particularly to immunotherapy. Specifically, the present invention provides various peptides that can be used for cancer immunotherapy. Background Art

[0002] Cancer is one of the leading causes of death worldwide. According to the World Health Organization (WHO), in 2012 alone, 14 million new cases and 8.2 million cancer-related deaths were reported worldwide, and the number of new cancer cases is expected to increase by approximately 70% over the next two decades. So far, more than 60% of the world's new cases each year occur in Africa, Asia, and Central and South America. These regions also account for 70% of the world's cancer deaths. In men, the five most common cancer sites are lung, prostate, colorectum, stomach, and liver. In women, the five most common cancer sites are breast, colorectum, lung, cervix, and stomach.

[0003] Cancer has long been managed with surgery, radiotherapy, cytotoxic chemotherapy, and endocrine manipulation, which are often combined sequentially to best control the disease. However, the main limitation to the actual efficacy of these standard therapies is their imprecise specificity, which leads to collateral damage to normal tissues caused by treatment, low cure rates, and inherent drug resistance.

[0004] The development of cancer therapies has increased tremendously in recent years, particularly due to the tremendous progress in the expression profiling of tumor and normal cells, and recent studies and the first clinical results of immunotherapy or molecular targeted therapies have begun to change our understanding of this disease.

[0005] Promising anticancer immunotherapies are now a reality, and evidence that the host immune system can recognize tumor antigens has led to the development of anticancer drugs that have now been approved by regulatory agencies such as the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Various treatment approaches include adoptive transfer of ex vivo expanded tumor-infiltrating lymphocytes (TILs), cancer cell vaccines, immunostimulatory cytokines and their variants, pattern recognition receptor (PRR) agonists, and immunomodulatory monoclonal antibodies targeting tumor antigens or immune checkpoints (Galuzzi et al., Classification of current anticancer immunotherapies. Oncotarget. 2014 Dec 30; 5(24): 12472-508).

[0006] Unfortunately, a significant percentage of patients may still develop intrinsic resistance, or even acquired resistance, to some of these immunotherapies during the course of treatment. For example, the three-year survival rate with the anti-CTLA-4 antibody ipilimumab in unresectable or metastatic melanoma has been reported to be approximately 20% (Snyder et al., Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med. 2014 Dec 4;371(23):2189-2199; Schadendorf et al., Pooled Analysis of Long-Term Survival Data From Phase II and Phase III Trials of Ipilimumab in Unresectable or Metastatic Melanoma. J Clin Oncol. 2015 Jun 10;33(17):1889-94), whereas the three-year survival rate with another checkpoint inhibitor, nivolumab, which targets PD-1, has been reported to be 44% in renal cell carcinoma (RCC) and 18% in non-small cell lung cancer (NSCLC) (Mc Dermott et al., Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med. 2014 Dec 4;371(23):2189-2199; Schadendorf et al., Pooled Analysis of Long-Term Survival Data From Phase II and Phase III Trials of Ipilimumab in Unresectable or Metastatic Melanoma. J Clin Oncol. 2015 Jun 10;33(17):1889-94). al., Survival, Durable Response, and Long-Term Safety in Patients With Previously Treated Advanced Renal Cell Carcinoma Receiving Nivolumab. J Clin Oncol. 2015 Jun 20; 33(18): 2013-20; Gettinger et al., Overall Survival and Long-Term Safety of Nivolumab (Anti-Programmed Death 1 Antibody, BMS-936558, ONO-4538) in Patients With Previously Treated Advanced Non-Small-Cell Lung Cancer. J Clin Oncol. 2015 Jun 20; 33(18): 2004-12). Therefore, fundamental drug resistance represents a fixed efficacy barrier for these immunotherapies. Therefore, it is clear that different cancer treatment approaches are needed to break this barrier.

[0007] The lack of response in many subjects treated with these immunotherapies may be related to defects in the anti-tumor immune response (e.g., defects in antigen presentation by antigen presenting cells (APCs) or defects in antigen recognition by T cells). In other words, a positive response to immunotherapy is associated with the ability of the immune system to generate specific lymphocyte subsets that can recognize MHC class I restricted antigens expressed by human cancer cells (Kvistborg et al., Human cancer regression antigens. Curr Opin Immunol. 2013 Apr; 25(2): 284-90). This hypothesis is strongly supported by data showing that the response to adoptive transfer of tumor infiltrating lymphocytes (TILs) is associated with a decrease in the number of CD8 + The number of T cells is directly related to the number of T cells (Besser et al., Adoptive transfer of tumor-infiltrating lymphocytes in patients with metastatic melanoma: intent-to-treat analysis and efficacy after failure to prior immunotherapies. Clin Cancer Res. 2013 Sep 1; 19(17): 4792-800). Therefore, an effective anti-tumor response will depend on the presentation of immunoreactive peptides and the presence of sufficient reactive cells that are "trained" to recognize these antigens.

[0008] Vaccination based on tumor antigens represents a unique cancer treatment method that has attracted considerable attention because it can recruit the patient's own immune system to recognize, attack and eliminate tumors in a specific and lasting manner. In fact, it is known that tumor cells express a large number of peptide antigens that are easily recognized by the immune system. Therefore, vaccines based on such antigens, due to their low toxicity and low molecular weight, provide great opportunities not only for improving the overall survival rate of patients but also for monitoring immune responses and preparing GMP-grade products. Examples of tumor antigens include byproducts of proteins transcribed from normally silent genes or overexpressed genes and proteins expressed by cancer viruses (Kvistborg et al., Human cancer regression antigens. Curr Opin Immunol. April 2013; 25(2): 284-90) and new antigens generated by point mutations of cellular proteins. The latter is of particular interest as it has been shown to be directly associated with increased overall survival in patients treated with CTLA-4 inhibitors (Snyder et al., Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med. 2014 Dec 4;371(23):2189-2199; Brown et al., Neo-antigens predicted by tumor genome meta-analysis correlate within increased patient survival. Genome Res. 2014 May;24(5):743-50).

[0009] However, the number of human tumor antigens on which cancer vaccines can be developed is limited. In particular, antigens derived from mutated or modified self-proteins can induce immune tolerance and / or undesirable autoimmune side effects.

[0010] Therefore, there is a need in the art to identify alternative cancer therapies that can overcome the limitations encountered in this field.

[0011] The object of the present invention is to meet the above needs. This object is achieved by the subject matter presented below, in particular the present invention and the items provided in the appended claims. Summary of the Invention

[0012] The present invention specifically provides the following items:

[0013] 1. An antigenic peptide comprising or consisting of the following: an amino acid sequence shown in any one of SEQ ID NOs: 1-580 and 861-887.

[0014] 2. The antigenic peptide according to item 1, comprising or consisting of the amino acid sequence shown in any one of SEQ ID NOs: 1-580.

[0015] 3. The antigenic peptide according to item 1, comprising or consisting of the amino acid sequence shown in any one of SEQ ID NOs: 861-887.

[0016] 4. The antigenic peptide according to item 1 or 2, comprising or consisting of the amino acid sequence shown in any one of SEQ ID NOs: 1-160, 162-253, and 255-580.

[0017] 5. The antigenic peptide according to item 2 or 4, wherein the antigenic peptide comprises or consists of the amino acid sequence shown in any one of SEQ ID NOs: 30, 31, 32, 87, 97, 145, 193, 194, 220, 221, 255, 521 and 524.

[0018] 6. The antigenic peptide according to any one of items 1 to 5, wherein the antigenic peptide comprises or consists of the amino acid sequence shown in any one of SEQ ID NOs: 30, 31, 32, 87, 97, 193, 194, 220, 255, 521 and 524.

[0019] 7. The antigenic peptide according to any one of items 1 to 6, wherein the antigenic peptide comprises or consists of the amino acid sequence shown in any one of SEQ ID NOs: 30, 31, 32, 87, 97, 194, 220, 255, 521 and 524.

[0020] 8. The antigenic peptide according to any one of items 1 to 7, wherein the antigenic peptide comprises or consists of the amino acid sequence shown in any one of SEQ ID NOs: 30, 32, 87, 97 and 194.

[0021] 9. The antigenic peptide according to item 1 or 2, wherein the antigenic peptide comprises or consists of the following: the amino acid sequence shown in any one of SEQ ID NO: 30, 32, 194, 220, 254 or 255.

[0022] 10. An immunogenic compound comprising the antigenic peptide according to any one of items 1 to 9.

[0023] 11. The immunogenic compound according to item 10, wherein the antigenic peptide is linked to a carrier molecule.

[0024] 12. The immunogenic compound according to item 11, wherein the carrier molecule is a carrier protein or a carrier peptide.

[0025] 13. The immunogenic compound according to any one of items 10-12, comprising or consisting of: a polypeptide of formula (I)

[0026] PepNt-CORE-PepCt (I)

[0027] in:

[0028] - "PepNt" consists of a polypeptide whose length varies between 0 and 500 amino acid residues and is located at the N-terminus of the polypeptide of formula (I);

[0029] - CORE consists of the antigenic peptide defined in any one of items 1 to 6; and

[0030] - "PepCt" consists of a polypeptide whose length varies between 0 and 500 amino acid residues and is located at the C-terminus of the polypeptide of formula (I).

[0031] 14. Nanoparticles loaded with

[0032] - at least one of the antigenic peptides according to any one of items 1 to 9, or

[0033] - at least one of the immunogenic compounds according to any one of items 10 to 13;

[0034] and optionally loaded with an adjuvant.

[0035] 15. A cell loaded with the antigenic peptide according to any one of items 1 to 9 or the immunogenic compound according to any one of items 10 to 13.

[0036] 16. The cell according to item 15, wherein the cell is an antigen presenting cell (APC), preferably a dendritic cell.

[0037] 17. A nucleic acid encoding an antigenic peptide according to any one of items 1 to 9, a polypeptide of formula (I) as defined in item 13, or an immunogenic compound according to any one of items 10 to 13, wherein the immunogenic compound is a peptide or a protein.

[0038] 18. The nucleic acid according to item 17, wherein the nucleic acid is a DNA molecule or an RNA molecule; preferably selected from genomic DNA; cDNA; siRNA; rRNA; mRNA; antisense DNA; antisense RNA; ribozymes; complementary RNA and / or DNA sequences; RNA and / or DNA sequences with or without expression elements, regulatory elements and / or promoters; vectors; and combinations thereof.

[0039] 19. A host cell comprising the nucleic acid according to item 17 or 18.

[0040] 20. The host cell according to item 19, wherein the nucleic acid is a vector.

[0041] 21. The host cell according to item 19 or 20, wherein the host cell is a bacterial cell, preferably an enteric bacterial cell.

[0042] 22. A pharmaceutical composition comprising

[0043] - the antigenic peptide according to any one of items 1 to 9,

[0044] - the immunogenic compound according to any one of items 10 to 13,

[0045] - the nanoparticles according to item 14,

[0046] - the cell according to item 15 or 16,

[0047] - a nucleic acid according to item 17 or 18, and / or

[0048] - a host cell according to any one of items 19 to 21,

[0049] and optionally one or more pharmaceutically acceptable excipients or carriers.

[0050] 23. The pharmaceutical composition according to item 22, further comprising one or more immunostimulants.

[0051] 24. The pharmaceutical composition according to item 23, wherein the immunostimulant is selected from immune adjuvants and antigen-presenting cells.

[0052] 25. The pharmaceutical composition according to item 24, wherein the antigen-presenting cells are dendritic cells.

[0053] 26. The pharmaceutical composition according to any one of items 22-25, wherein the composition comprises

[0054] (i) at least two different antigenic peptides according to any one of items 1 to 9;

[0055] (ii) at least two different immunogenic compounds according to any one of items 10-13;

[0056] (iii) at least two different nanoparticles according to item 14; and / or

[0057] (iv) at least two different nucleic acids according to item 17 or 18.

[0058] 27. Kit, including

[0059] - the antigenic peptide according to any one of items 1 to 9,

[0060] - the immunogenic compound according to any one of items 10 to 13,

[0061] - the nanoparticles according to item 14,

[0062] - the cell according to item 15 or 16,

[0063] - the nucleic acid according to item 17 or 18,

[0064] - a host cell according to any one of items 19-21, and / or

[0065] - The pharmaceutical composition according to any one of items 22-26.

[0066] 28. The kit according to item 27, further comprising a package insert or instructions with instructions for preventing or treating cancer using the antigenic peptide, the immunogenic compound, the nanoparticle, the cell, the nucleic acid, the host cell and / or the pharmaceutical composition.

[0067] 29. The kit according to item 27 or 28, wherein the kit comprises at least two different antigenic peptides according to any one of items 1 to 9.

[0068] 30. Kit item according to item 27 or 28, wherein the kit comprises at least two different immunogenic compounds according to any one of items 10-13.

[0069] 31. The kit according to item 27 or 28, wherein the kit comprises at least two different nanoparticles according to item 14.

[0070] 32. The kit according to item 27 or 28, wherein the kit comprises at least two different nucleic acids according to item 15 or 16.

[0071] 33. The antigenic peptide according to any one of items 1 to 9,

[0072] The immunogenic compound according to any one of items 10 to 13,

[0073] The nanoparticle according to item 14,

[0074] The cell according to item 15 or 16,

[0075] The nucleic acid according to item 17 or 18,

[0076] The host cell according to any one of items 19 to 21,

[0077] The pharmaceutical composition according to any one of items 22 to 26, or

[0078] The kit according to any one of items 27-32

[0079] For the prevention and / or treatment of cancer.

[0080] 34. The antigenic peptide, immunogenic compound, nanoparticle, cell, nucleic acid, host cell, pharmaceutical composition or kit for use according to item 33, wherein the cancer is selected from glioma, renal cancer, skin cancer, in particular melanoma, lung cancer, ovarian cancer, breast cancer, colorectal cancer, liver cancer, pancreatic cancer, head and neck cancer, urothelial carcinoma and prostate cancer.

[0081] 35. A combination of at least two different antigenic peptides according to any one of items 1 to 9 for use in preventing and / or treating cancer.

[0082] 36. A combination of at least two different immunogenic compounds according to any one of items 10 to 13 for use in preventing and / or treating cancer.

[0083] 37. A combination of at least two different nanoparticles according to item 14, for use in preventing and / or treating cancer.

[0084] 38. A combination of at least two different nucleic acids according to item 17 or 18 for use in preventing and / or treating cancer.

[0085] 39. Combination for use according to any one of items 35 to 38, wherein the at least two different components are comprised in different compositions.

[0086] 40. Combination for use according to any one of items 35 to 38, wherein the at least two different components are comprised in the same composition.

[0087] 41. The combination for use according to any one of items 35-39, wherein the at least two different components are administered by different routes of administration.

[0088] 42. The combination for use according to any one of items 35-40, wherein the at least two different components are administered by the same route of administration.

[0089] 43. Combination for use according to any one of items 35-39, 41 and 42, wherein the at least two different components are administered sequentially.

[0090] 44. The combination for use according to any one of items 35-42, wherein the at least two different components are administered at about the same time.

[0091] 45. A method for preventing and / or treating cancer or inducing, enhancing or prolonging an anti-tumor response in a subject in need thereof, comprising administering to said subject

[0092] - the antigenic peptide according to any one of items 1 to 9,

[0093] - the immunogenic compound according to any one of items 10 to 13,

[0094] - the nanoparticles according to item 14,

[0095] - the cell according to item 15 or 16,

[0096] - the nucleic acid according to item 17 or 18,

[0097] - a host cell according to any one of items 19 to 21,

[0098] - a pharmaceutical composition according to any one of items 22-26, and / or

[0099] - A combination as defined in any of items 35-44.

[0100] 46. ​​The method according to item 45, wherein the cancer is selected from glioma, renal cancer, skin cancer, in particular melanoma, lung cancer, ovarian cancer, breast cancer, colorectal cancer, liver cancer, pancreatic cancer, head and neck cancer, urothelial carcinoma and prostate cancer.

[0101] 47. A peptide-MHC (pMHC) multimer comprising the antigenic peptide according to any one of items 1 to 9.

[0102] The present invention and in particular the above-mentioned items are described in more detail below.

[0103] definition

[0104] Unless otherwise defined herein, the scientific and technical terms used in this application will have the meanings commonly understood by those of ordinary skill in the art. In addition, unless the context requires otherwise, nomenclature used herein and cell and tissue culture techniques are well known and commonly used in the art.

[0105] Such technology is widely used in the literature such as Owen et al. (Kuby Immunology, 7 th, edition, 2013–WH Freeman) and Sambrook et al. (Molecular cloning: A laboratory manual 4th edition, Cold Spring Harbor Laboratory Press-Cold Spring Harbor, NY, USA, 2012) are fully described.

[0106] However, with respect to the usage of various terms throughout this specification, the following definitions more particularly apply.

[0107] The terms "peptide", "polypeptide", "protein" and variations of these terms refer to peptides, oligopeptides, polypeptides or proteins comprising at least two amino acids, which are linked to each other, preferably by ordinary peptide bonds or alternatively by modified peptide bonds, as, for example, in the case of isopeptides. The term "(poly)peptide" refers to peptides and / or polypeptides. Specifically, the terms "peptide", "polypeptide" and "protein" refer to sequential chains of amino acids of any length linked together by peptide bonds (-NHCO-). Peptides, polypeptides and proteins can play structural and / or functional roles in cells in vitro and / or in vivo. The terms "peptide", "polypeptide" and "protein" preferably include amino acid chains with a size ranging from 2 to at least about 1000 amino acid residues. The term "peptide" preferably includes amino acid chains with a size of less than about 30 amino acids in this article, while the terms "polypeptide" and "protein" preferably include amino acid chains with a size of at least 30 amino acids. The terms "polypeptide" and "protein" are used interchangeably herein. In a preferred embodiment, the terms "peptide", "polypeptide" and "protein" also include "peptoids", which are defined as peptide analogs containing non-peptide structural elements that can mimic or antagonize the biological effects (one or more) of the natural parent peptide. Peptoids lack typical peptide features, such as enzymatically cleaved peptide bonds. Specifically, peptides, polypeptides or proteins can contain amino acids other than the 20 amino acids defined by the genetic code in addition to these amino acids, or they can be composed of amino acids other than the 20 amino acids defined by the genetic code. Specifically, in the context of the present invention, peptides, polypeptides or proteins can be equivalent to amino acids modified by natural processes well known to those skilled in the art, such as post-translational maturation processes or chemical processes. Such modifications are described in detail in the literature. These modifications can occur at any position in the polypeptide: in the peptide backbone, in the amino acid chain or even at the carboxyl or amino terminus. Specifically, the peptide or polypeptide can be branched after ubiquitination, or cyclic with or without branches. This type of modification can be the result of a natural or synthetic post-translational process well known to those skilled in the art. In the context of the present invention, the terms "peptide", "polypeptide" and "protein" specifically also include modified peptides, polypeptides and proteins. For example, peptide, polypeptide or protein modifications may include acetylation, acylation, ADP-ribosylation, amidation, covalent immobilization of nucleotides or nucleotide derivatives, covalent immobilization of lipids or lipid derivatives, covalent immobilization of phosphatidylinositols, covalent or non-covalent cross-linking, cyclization, disulfide bond formation, demethylation, glycosylation including PEGylation, hydroxylation, iodination, methylation, myristoylation, oxidation, proteolytic processing, phosphorylation, prenylation, racemization, seneloylation, sulfation, amino acid addition such as arginylation or ubiquitination.Such modifications are described in detail in the literature (Proteins Structure and Molecular Properties (1993) 2nd Ed., E. C. Creighton, New York; Post-translational Covalent Modifications of Proteins (1983) B. C. Johnson, Ed., Academic Press, New York; Seifter et al. (1990) Analysis for protein modifications and nonprotein cofactors, Meth. Enzymol. 182: 626-646; and Rattan et al., (1992) Protein Synthesis: Post-translational Modifications and Aging, Ann NY Acad Sci, 663: 48-62). Therefore, the terms "peptide", "polypeptide" and "protein" preferably include, for example, lipopeptides, lipoproteins, glycopeptides, glycoproteins and the like.

[0108] In a preferred embodiment, the (poly)peptide or protein is a "typical" (poly)peptide or protein, wherein a "typical" (poly)peptide or protein is typically composed of amino acids selected from the 20 amino acids defined by the genetic code, which amino acids are linked to each other by common peptide bonds.

[0109] As is well known in the art, peptides, polypeptides and proteins can be encoded by nucleic acids. The terms "nucleic acid", "nucleic acid molecule", "nucleic acid sequence", "polynucleotide", "nucleotide sequence" are used interchangeably herein and refer to precisely linked natural nucleotides (e.g., A, T, G, C and U) or synthetic nucleotides, i.e., a chain of at least two nucleotides. In particular, the terms "nucleic acid", "nucleic acid molecule", "nucleic acid sequence", "polynucleotide", "nucleotide sequence" refer to DNA or RNA. The nucleic acid preferably comprises single-stranded, double-stranded or partially double-stranded DNA or RNA, preferably selected from genomic DNA (gDNA), complementary DNA (cDNA), ribosomal DNA (rDNA) and transcription products of said DNA, such as RNA. Preferred examples of nucleic acids include ribosomal RNA (rRNA), messenger RNA (mRNA); antisense DNA, antisense RNA; complementary RNA and / or DNA sequences, ribozymes, (complementary) RNA / DNA sequences with or without expression elements, vectors; minigenes, gene fragments, regulatory elements, promoters and combinations thereof. Further preferred examples of nucleic acids (molecules) and / or polynucleotides include, for example, recombinant polynucleotides, vectors, oligonucleotides, RNA molecules such as rRNA, mRNA, or transfer RNA (tRNA), or the aforementioned DNA molecules. Thus, preferably, the nucleic acid (molecule) is a DNA molecule or an RNA molecule; preferably selected from gDNA; cDNA; rRNA; mRNA; antisense DNA; antisense RNA; complementary RNA and / or DNA sequences; RNA and / or DNA sequences with or without expression elements, regulatory elements, and / or promoters; vectors; and combinations thereof. It is within the capabilities of those skilled in the art to determine a nucleotide sequence that can encode a specific amino acid sequence.

[0110] The (poly)peptides and / or nucleic acids according to the present invention can be prepared by any method known in the art, including but not limited to any synthetic method, any recombinant method, any in vitro generation method, etc. and any combination thereof. Such technology is fully described in the above-mentioned literature.

[0111] As used herein, the term "antigenic peptide" refers to a peptide that easily induces / triggers, increases, prolongs or maintains an immune response in a subject to which it is administered. Specifically, the antigenic peptide is a sequence variant of (a fragment / epitope of) a (human) tumor antigen. In other words, the antigenic peptide is preferably different from (a fragment / epitope of) a (human) tumor antigen, but it preferably has amino acid similarity to (a fragment / epitope of) a (human) tumor antigen. Preferably, the immune response induced / triggered, increased, prolonged or maintained by the antigenic peptide is (also) directed against (a fragment / epitope of) the corresponding (human) tumor antigen.

[0112] As used herein, the term "tumor antigen" includes tumor-specific antigens and tumor-associated antigens. In general, the term "tumor antigen" or "tumor protein" refers to an antigenic substance produced in tumor cells and sometimes in normal cells in this article, and can trigger an immune response after being administered to a subject. In humans, those (tumor antigens) have been classified according to their expression pattern, function or genetic origin, and include, but are not limited to, overexpressed self-antigens (such as HER2 / neu and its variants dHER2, p53, Wilm's tumor 1, Ephrin receptor, proteinase 3, mucin-1, mesothelin, EGFR, CD20); testicular cancer (CT) antigens (such as MAGE-1, BAGE, GAGE, NY-ESO-1); mutant antigens, also called new antigens (such as mutants of MUM-1, bcr-abl, ras, b-raf, p53, CDK-4, CDC27, β-catenin, α-actin-4 (α-actenin-4)); tissue-specific differentiation antigens (such as melanoma antigen Melanoma); A / MART-1, tyrosinase, TRP1 / pg75, TRP2, gp100 and gangliosides GM3, GM2, GD2 and GD3; prostate cancer antigens PSMA, PSA and PAP); viral antigens expressed by oncoviruses (such as HPV, EBV); fetal antigens (such as α-fetoprotein AFP and carcinoembryonic antigen CEA); and universal antigens (terminal enzyme, hTERT, survivin, mdm-2, CYP-1B1) (Srinivasan and Wolchok, Tumor antigens for cancer immunotherapy: therapeutic potential of xenogeneic DNA vaccines. J Transl Med. 2004 Apr 16; 2(1): 12). Thus, human tumor antigens are well known in the art. For example, interleukin 13 receptor subunit α-2 (IL-13Ra2 or IL13RA2) is a membrane-bound protein encoded by the IL13RA2 gene in humans. As a non-exhaustive list, IL13RA2 has been reported as a potential immunotherapy target (see Beard et al.; Clin Cancer Res; 72(11); 2012). High expression of IL13RA2 is also associated with invasion, liver metastasis, and poor prognosis in colorectal cancer (Barderas et al.; Cancer Res; 72(11); 2012). Specifically, the antigenic peptides according to the present invention are preferably sequence variants of (epitopes / fragments of) the tumor antigens shown in Table 1B, and can be used in particular in the diseases outlined in Table 1B for the corresponding tumor antigens.

[0113] As used herein, the term "microbiota" refers to the symbiotic microorganisms found in and on all multicellular organisms studied to date, from plants to animals. Specifically, the microbiota has been found to be crucial for its host's immune system, hormones, and metabolic homeostasis. The microbiota includes bacteria, archaea, protists, fungi, and viruses. Thus, a "microbiota sequence variant" is a sequence variant of a reference sequence (specifically, an epitope / fragment of a human tumor antigen) present in the microbiota (e.g., which may be contained in a microbiota protein). A "sequence variant" generally has at least 50% sequence identity with the reference sequence (i.e., a fragment / epitope of a (reference) tumor antigen), particularly over the full length of the sequence. Preferably, the sequence variant has at least 60%, preferably at least 70%, preferably at least 75%, more preferably at least 80%, even more preferably at least 85%, still more preferably at least 90%, particularly preferably at least 95%, and most preferably at least 99% sequence identity with the reference sequence (i.e., a fragment / epitope of a (reference) tumor antigen). Sequence identity can be calculated as known in the art, specifically as described below. Preferably, the sequence variant retains a specific function of the reference sequence, such as its function as a tumor epitope and / or its ability to elicit or maintain an immune response. The microbial biota sequence variant is preferably selected from bacterial sequence variants, archaeal sequence variants, protist sequence variants, fungal sequence variants, and viral sequence variants. More preferably, the microbial biota sequence variant is a bacterial sequence variant.

[0114] Anatomically, the microbiota resides on or in a variety of tissues and biological fluids, including the skin, conjunctiva, breast, vagina, placenta, semen, uterus, ovarian follicles, lungs, saliva, oral cavity (particularly oral mucosa), and gastrointestinal tract, particularly the intestinal tract. In the context of the present invention, the microbiota sequence variants are preferably sequence variants of the gastrointestinal microbiota (microorganisms residing in the gastrointestinal tract), more preferably sequence variants of the intestinal microbiota (microorganisms residing in the intestinal tract). Thus, most preferably, the microbiota sequence variants are (human) enterobacterial sequence variants (i.e., sequence variants of bacteria residing in the (human) intestinal tract).

[0115] Although microbial biota can be found in and on many multicellular organisms (all multicellular organisms studied so far, from plants to animals), microbial biota found in and on the human body are preferred. Such microbial biota is referred to herein as "human microbial biota" (wherein the term "human" specifically refers to the location / residence of the microbial biota). In the context of the present invention, microbial biota sequence variants are human microbial biota sequence variants.

[0116] The term "immunogenic compound" refers to a compound comprising an antigenic peptide according to the present invention. An "immunogenic compound" is capable of inducing / eliciting, increasing, prolonging or maintaining an immune response to the antigenic peptide in a subject to which it is administered. In some embodiments, the immunogenic compound comprises at least one antigenic peptide, or alternatively at least one compound comprising such an antigenic peptide, linked to a protein, such as a carrier protein.

[0117] A "carrier protein" is generally a protein capable of transporting a cargo, such as an antigenic peptide according to the present invention. For example, a carrier protein can transport its cargo across a membrane. In the context of the present invention, a carrier protein specifically (also) includes a peptide or polypeptide capable of eliciting an immune response against the antigenic peptide to which it is attached. Carrier proteins are known in the art.

[0118] Alternatively, such a carrier peptide or polypeptide may be co-administered in the form of an immunoadjuvant.

[0119] Preferably, the antigenic peptides described herein can be co-administered or, for example, linked to proteins / peptides with immune adjuvant properties by covalent or non-covalent bonds, such as providing stimulation of CD4+ Th1 cells. Although the antigenic peptides described herein are preferably bound to MHC class I, CD4+ helper (cells) can be used in addition to provide an effective immune response. Th1 helper cells can maintain effective dendritic cell (DC) activation and specific CTL activation by secreting interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α) and interleukin-2 (IL-2) and enhancing the expression of costimulatory signals on DC and T cells (Galaine et al., Interest of Tumor-Specific CD4 T Helper 1 Cells for Therapeutic Anticancer Vaccine. Vaccines (Basel). 2015 Jun 30; 3 (3): 490-502).

[0120] For example, the adjuvant peptide / protein may preferably be different from the antigenic peptide of the present invention. Preferably, the adjuvant peptide / protein can restore immune memory or provide nonspecific assistance, or it can be a specific helper peptide. Several helper peptides have been described in the literature for providing nonspecific T cell assistance, such as tetanus helper peptide, spike-shaped shellfish hemocyanin peptide or PADRE peptide (Adotévi et al., Targeting antitumor CD4 helper T cells with universal tumor-reactive helper peptides derived from telomerase for cancer vaccine. Hum Vaccin Immunother. 2013 May; 9 (5): 1073-7, Slingluff CL, The present and future ofpeptide vaccines for cancer: single or multiple, long or short, alone or incombination? Cancer J. 2011 September-October; 17 (5): 343-50). Therefore, tetanus helper peptide, spike-shaped shellfish hemocyanin peptide and PADRE peptide are preferred examples of such adjuvant peptides / proteins. Specifically, the antigenic peptides described herein or polypeptides comprising the antigenic peptides can be linked, for example, via a covalent or non-covalent bond, to an HHD-DR3 peptide of the sequence MAKTIAYDEEARRGLERGLN (SEQ ID NO: 856). This peptide represents another example of an adjuvant peptide (having immunoadjuvant properties), which is preferred in the context of the present invention. Another preferred example is h-pAg T13L (sequence: TPPAYRPPNAPIL; SEQ ID NO: 860; Bhasin M, Singh H, Raghava GP (2003) MHCBN: a comprehensive database of MHC binding and non-binding peptides. Bioinformatics 19: 665–666).Other examples of preferred helper peptides include UCP2 peptides (e.g., as described in WO 2013 / 135553 A1 or Dosset M, Godet Y, Vauchy C, Beziaud L, Lone YC, Sedlik C, Liard C, Levionnois E, Clerc B, Sandoval F, Daguindau E, Wain-Hobson S, Tartour E, Langlade-Demoyen P, Borg C, Adotévi O: Universal cancer peptide-based therapeutic vaccine breaks down lerance against telomerase and eradicates established tumor. Clin Cancer Res. 2012 Nov 15; 18(22): 6284-95. doi: 10.1158 / 1078-0432. CCR-12-0896. Epub 2012 2012) and BIRC5 peptides (eg as described in EP2119726A1 or Widenmeyer M, Griesemann H,. S, Feyerabend S, Klein R, Attig S, Hennenlotter J, Wernet D, Kuprash DV, Sazykin AY, Pascolo S, Stenzl A, Gouttefangeas C, Rammensee HG: Promiscuous survivin peptide induces robust CD4+ T-cell responses in the majority of vaccinated cancer patients. Int J Cancer. 2012 Jul 1;131(1):140-9. doi:10.1002 / ijc.26365. Epub 2011 Sep 14. The most preferred helper peptide is the UCP2 peptide (amino acid sequence: KSVWSKLQSIGIRQH; SEQ ID NO: 859, e.g. as described in WO 2013 / 135553 A1 or Dosset et al., Clin Cancer Res. 2012 Nov 15; 18(22): 6284-95.

[0121] As used herein, the term "immunogenic composition" refers to a composition that can elicit, induce, increase, prolong or maintain an immune response, particularly a composition that elicits, induces, increases, prolong or maintains an immune response when administered to a mammal, especially a composition that elicits, induces, increases, prolongs or maintains an immune response when administered to a human subject. Preferably, the immunogenic composition further comprises one or more immune adjuvant substances.

[0122] "Pharmaceutically acceptable excipient or carrier" means in this article a pharmaceutical grade compound that improves the delivery, stability or bioavailability of the active agent and can be metabolized by the subject to which it is administered and is non-toxic to the subject to which it is administered. Preferred excipients and carriers according to the present invention include any excipient or carrier commonly used in pharmaceutical products, such as, for example, water, saline, phosphate buffered saline, dextrose, glycerol, ethanol, etc. and combinations thereof. In many cases, it is preferred to include an isotonic agent in the composition, such as a sugar, a polyol such as mannitol, sorbitol, or sodium chloride. Pharmaceutically acceptable excipients or carriers may further include a small amount of auxiliary substances, such as a wetting agent or an emulsifier or a preservative.

[0123] "Vaccine" in this context means a composition that is capable of stimulating the immune system of a living organism to provide protection against harmful antigens by prophylaxis or treatment. Preventive vaccines are preferred. Preferably, the vaccine or vaccine composition also contains one or more immunoadjuvant substances.

[0124] According to the various aspects and embodiments of the invention described herein, a "subject" or "host" preferably refers to a mammal, most preferably a human. The subject may have cancer, be suspected of having cancer, or be at risk of having cancer.

[0125] As used herein, the term "cancer" refers to a malignant tumor. Specifically, the term "cancer" refers herein to any member of a class of diseases or disorders characterized by the uncontrolled division of cells and the ability of these cells to invade other tissues, either by growing directly into adjacent tissues via invasion or by implanting into distant sites via metastasis. Metastasis is defined as the stage at which cancer cells are transported through the bloodstream or lymphatic system. It includes esophageal cancer, stomach cancer, duodenum cancer, small intestine cancer, appendix cancer, large intestine cancer, colon cancer, rectal cancer, colorectal cancer, anal cancer, pancreatic cancer, liver cancer, gallbladder cancer, spleen cancer, kidney cancer, bladder cancer, prostate cancer, testicular cancer, uterine cancer, endometrial cancer, ovarian cancer, vaginal cancer, vulvar cancer, breast cancer, lung cancer, thyroid cancer, thymus cancer, brain cancer, nervous system cancer, glioma, oral cancer, skin cancer, blood cancer, lymphoma, eye cancer, bone cancer, bone marrow cancer, muscle cancer... In the context of the present invention, melanoma, head and neck cancer, breast cancer, colorectal cancer or kidney cancer (such as clear cell renal cell carcinoma) are preferred.

[0126] As used herein, the terms "preventing," "prevention," "prophylaxis," or "prevent" generally mean avoiding or minimizing the onset or development of a disease or condition before it occurs, while the terms "treating," "treatment," or "treat" include alleviating, ameliorating, or curing a disease or condition (or symptoms of a disease or condition) after it has occurred. The term "prevent" includes "reducing the likelihood of occurrence" or "reducing the likelihood of recurrence."

[0127] As used herein, an "effective amount" or "effective dose" is an amount that provides a desired effect. For therapeutic purposes, an effective amount is an amount sufficient to provide a beneficial or desired clinical result. The preferred effective amount for a given application can be readily determined by a skilled artisan taking into account, for example, the subject's size, age, weight, the type of disease / disorder to be prevented or treated, and the amount of time since the onset of the disease / disorder. In the context of the present invention, an effective amount of a composition, with respect to prevention or treatment, is an amount sufficient to induce a humoral and / or cell-mediated immune response to the disease / disorder.

[0128] Throughout the specification and appended claims, unless the context indicates otherwise, the term "comprise" and variations such as "comprising" and "containing" will be understood to mean the inclusion of stated members, integers or steps, but not the exclusion of any other unstated members, integers or steps. The term "consisting of is a specific embodiment of the term "comprising", in which any other unstated members, integers or steps are excluded. In the context of the present invention, the term "comprising" encompasses the term "consisting of". Thus, the term "comprising" encompasses "including" as well as "consisting of", for example, a composition "comprising" X may consist of X only, or may include other contents, such as X+Y.

[0129] The terms "a" and "an" and "the" and similar references used in the context of describing the present invention (especially in the context of the claims) should be interpreted to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by the context. The recitation of numerical ranges herein is intended merely to serve as a shorthand method of individually referring to each individual value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually referred to herein. No language in the specification should be construed as indicating that any unclaimed element is essential to the practice of the present invention.

[0130] The word "substantially" does not exclude "completely", for example, a composition that is "substantially free" of Y may be completely free of Y. Where necessary, the word "substantially" may be omitted from the definition of the present invention.

[0131] The term "about" in connection with a value x refers to x ± 10%.

[0132] Additional definitions are provided throughout the specification.

[0133] The present invention can be understood more readily by reference to the following detailed description, including preferred embodiments of the invention, and the Examples included therein.

[0134] Detailed description

[0135] Although the present invention is described in detail below, it should be understood that the present invention is not limited to the specific methods, protocols and reagents described herein, as these may vary. It should also be understood that the terminology used herein is not intended to limit the scope of the present invention, which is limited only by the appended claims. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art.

[0136] Hereinafter, the elements of the present invention will be described. These elements are listed together with the specific embodiments, but it should be understood that they can be combined in any way and in any number to establish other embodiments. The examples and preferred embodiments of the various descriptions should not be interpreted as limiting the present invention to only the embodiments clearly described. This description should be understood to support and encompass embodiments that combine the embodiments clearly described with any number of disclosed and / or preferred elements. In addition, unless the context indicates otherwise, the description of the present application should be considered to disclose any arrangement and combination of all the elements described in the present application.

[0137] The present inventors have identified a group of antigenic peptides that can be used to induce a specific immune response against tumor cells. Those antigenic peptides are different from (fragments of) the human tumor antigens shown in Table 1A and Table 1B, but have amino acid similarity thereto.

[0138] Specifically, the antigenic peptides according to the present invention are contained in the polypeptides and proteins produced by the symbiotic bacteria from the human intestinal tract. Therefore, the antigenic peptides according to the present invention are not human sequences, but bacterial sequences. Without wishing to be bound by any specific theory, the inventors believe that the human immune repertoire (repertoire) comprises T cell clones with responsiveness to bacterial peptides (contained in the proteins produced by the symbiotic bacteria from the intestinal tract), and the fragments of the peptides and human tumor antigens have amino acid similarity. Specifically, the antigenic peptides according to the present invention can cause a stronger immune response than the corresponding human peptides, because the T cells that can strictly identify human peptides have been exhausted when identifying autoantigens during maturation, and there is no such situation according to the antigenic peptides of the present invention. This can explain why the antigenic peptides as described herein can induce an immune response, and especially T cell response---when these peptides are given to (people) individuals.

[0139] Therefore, the inventors believe that proteins produced by commensal bacteria from the intestine can "mimic" tumor antigens and can be used to elicit a specific immune response against tumor cells. These findings provide further evidence that commensal bacteria may contribute to the elimination of tumor cells.

[0140] The antigenic peptides disclosed herein can be prepared using well-known techniques. For example, the peptides can be prepared synthetically by recombinant DNA technology or chemical synthesis. The peptides disclosed herein can be synthesized individually or as longer polypeptides comprising two or more peptides (e.g., two or more peptides, or peptides and non-peptides). The antigenic peptides can be isolated, i.e., purified to be substantially free of other naturally occurring host cell proteins and fragments thereof, for example, at least about 70%, 80% or 90% purified. Preferably, the antigenic peptides according to the present invention are isolated antigenic peptides.

[0141] Antigenic peptides according to the present invention

[0142] In a first aspect, the present invention provides an antigenic peptide comprising or consisting of an amino acid sequence as set forth in any one of SEQ ID NOs: 1-580 and 861-887. Preferably, the antigenic peptide comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 1-580. Preferably, the antigenic peptide comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 861-887.

[0143] Thus, the present invention relates to antigenic peptides that have amino acid similarity to tumor antigens. As used herein, the expression "having amino acid similarity to a tumor antigen" refers specifically to sequence variants of fragments of a (reference) human tumor antigen, such as IL13RA2, or other exemplary human tumor antigens described in Tables 1A and 1B below. A "sequence variant" generally has at least 50% sequence identity with the reference sequence, i.e., a fragment of a (reference) tumor antigen, in particular over the entire length of the sequence. Preferably, the sequence variant has at least 60%, preferably at least 70%, preferably at least 75%, more preferably at least 80%, even more preferably at least 85%, still more preferably at least 90%, particularly preferably at least 95%, and most preferably at least 99% sequence identity with the reference sequence, i.e., a fragment of a (reference) tumor antigen. Sequence identity can be calculated as known in the art, in particular as described below. Preferably, the sequence variant retains a specific function of the reference sequence, such as its function as a tumor epitope and / or its ability to elicit or maintain an immune response. Specifically, amino acid sequence variants have altered sequences in which one or more of the amino acids in the reference sequence are mutated, e.g., deleted or substituted, or one or more amino acids are inserted into the sequence of the reference amino acid sequence. For example, a variant sequence having at least 90% identity has no more than 10 alterations per 100 amino acids of the reference sequence, i.e., any combination of deletions, insertions, or substitutions.

[0144] Methods for comparing the identity (similarity) of two or more sequences are well known in the art. The percent identity of two sequences can be determined, for example, using a mathematical algorithm. A preferred but non-limiting example of a useful mathematical algorithm is the algorithm of Karlin et al. (1993), PNAS USA, 90: 5873-5877. Such algorithms are integrated into the BLAST family of programs, such as BLAST or NBLAST (see also Altschul et al., 1990, J. Mol. Biol. 215, 403-410 or Altschul et al. (1997), Nucleic Acids Res, 25: 3389-3402) - accessible through the NCBI World Wide Web homepage ncbi.nlm.nih.gov, and FASTA (Pearson (1990), Methods Enzymol. 183, 63-98; Pearson and Lipman (1988), Proc. Natl. Acad. Sci. USA 85, 2444-2448). These programs can identify sequences that have a certain degree of identity with other sequences. In addition, the programs available in the Wisconsin Sequence Analysis Software Package Version 9.1 (Devereux et al., 1984, Nucleic Acids Res., 387-395), such as the programs BESTFIT and GAP, can also be used to determine the percent identity between two polynucleotides and the percent identity between two (poly)peptide sequences. BESTFIT utilizes the "local homology" algorithm of Smith and Waterman (1981), J. Mol. Biol. 147, 195-197, and finds the best single region of similarity between two sequences.

[0145] Generally, a "fragment" of a (reference) tumor antigen, which serves as a reference sequence, preferably comprises at least 7, more preferably at least 8, and most preferably (at least) 9 or 10 amino acids. It is to be understood that a "fragment" of a (reference) tumor antigen (protein) is not the full-length tumor antigen (protein). Thus, the maximum length of a "fragment" of a (reference) tumor antigen may be 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1% of the full-length (reference) tumor antigen. In some embodiments, the length of a fragment of a (reference) tumor antigen does not exceed 50% of the length of the (full-length) (reference) tumor antigen. In other embodiments, the length of the fragment of the (reference) tumor antigen does not exceed 20% or 10% of the length of the (full-length) (reference) tumor antigen.

[0146] In some embodiments, the present invention provides the antigenic peptide of the present invention.In some embodiments, the antigenic peptide of the present invention has a length of at least 350 amino acids. In some embodiments, the antigenic peptide of the present invention has a length of at least 350 amino acids. In some embodiments, the antigenic peptide of the present invention has a length of at least 350 amino acids. In some embodiments, the antigenic peptide of the present invention has a length of at least 350 amino acids. In some embodiments, the antigenic peptide of the present invention has a length of at least 350 amino acids. In some embodiments, the antigenic peptide of the present invention has a length of at least 350 amino acids. In some embodiments, the antigenic peptide of the present invention has a length of at least 350 amino acids. In some embodiments, the antigenic peptide of the present invention has a length of at least 350 amino acids. In some embodiments, the antigenic peptide of the present invention has a length of at least 350 amino acids. In some embodiments, the antigenic peptide of the present invention has a length of at least 350 amino acids. In some embodiments, the antigenic peptide of the present invention has a length of at least 350 amino acids. In some embodiments, the antigenic peptide of the present invention has a length of at least 350 amino acids. In some embodiments, the antigenic peptide of the present invention has a length of at least 350 amino acids. In some embodiments, the antigenic peptide of the present invention has a length of at least 350 amino acids. In some embodiments, the antigenic peptide of the present invention has a length of at least 350 amino acids. Specifically, the antigenic peptide is not a full-length protein produced by commensal bacteria from the intestine, from which the antigenic peptide is derived.

[0147] More generally, the present invention provides antigenic peptides comprising or consisting of: microbiota sequence variants of human tumor antigen fragments. The human tumor antigen can be selected from ACPP, ANKRD30A, AREG, ASCL1, ASCL2, BIRC5, CA9, CCNA1, CCND1, CDH17, CDH6, CDKN2A, CEACAM5, CHI3L1, CHI3L2, COL11A1, CT83, CTCFL, DCT, DMRTA2, EGFR, ERBB2, ERG, ESR1, EZH2, FAP, FLT1, FOXM1, FSIP1, GAL3ST1, GPR143, HES6, IL13RA2, KISS1R, KLHDC8A, KLHL14, KLK4, KRT81, LEMD 1. LRRC15, MAGEA1, MAGEA10, MAGEA11, MAGEA12, MAGEA4, MLANA, NKX2-1, NPTX2, PAGE3, PAX2, PCDHB16, PIWIL1, PMEL, PRAME, PTHLH, SEMG1, SERHL2 , SLC45A3, SLC6A3, SNX31, SOX11, SPINK1, STEAP1, TBL1Y, TDRD1, TOP2A, TPTE, TRPM8, TYMS, TYR, UPK2, VCAM1, WFDC2, WT1, ZEB1, ZNF165 and ZNF280A.

[0148] Specifically, the present invention provides antigenic peptides that are microbial sequence variants of human tumor antigen fragments, wherein the human tumor antigen fragments may comprise or consist of any one of SEQ ID NOs: 580-858 and 888-895. Table 1A below provides an overview of the antigenic peptides according to the present invention, their amino acid sequences and SEQ ID NOs, and corresponding fragments / epitopes of human tumor antigens (also referred to herein as "human reference peptides"). Table 1A also provides information on the tumor antigens to which each antigenic peptide according to the present invention relates. SEQ ID NOs 1 to 580 and 861 to 887 refer to the antigenic peptides according to the present invention.

[0149] Table 1A. Antigenic peptides according to the present invention

[0150]

[0151]

[0152]

[0153]

[0154]

[0155]

[0156]

[0157]

[0158]

[0159]

[0160]

[0161]

[0162]

[0163]

[0164]

[0165]

[0166] As can be seen from Table 1A, the antigenic peptides according to the present invention can be classified according to the corresponding "human reference peptide" and according to the corresponding tumor antigen.

[0167] In one embodiment, the antigenic peptide according to the present invention is a microbial sequence variant of a fragment of the tumor antigen ACPP (human reference peptide), such as "FLFLLFFWL" (SEQ ID NO: 581), "SLSLGFLFL" (SEQ ID NO: 582) or "LSLGFLFLL" (SEQ ID NO: 583). In a preferred embodiment, the antigenic peptide according to the present invention is a sequence variant of a fragment of the tumor antigen ACPP, such as an antigenic peptide comprising or consisting of the amino acid sequence shown in any one of SEQ ID NOs: 1-4. More preferably, the antigenic peptide according to the present invention is a sequence variant of the ACPP fragment (human reference peptide) "FLFLLFFWL" (SEQ ID NO: 581), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 1. Even more preferably, the antigenic peptide according to the present invention is a sequence variant of the ACPP fragment (human reference peptide) "SLSLGFLFL" (SEQ ID NO: 582), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 2 or 3. And more preferably, the antigenic peptide according to the present invention is a sequence variant of the ACPP fragment (human reference peptide) "LSLGFLFLL" (SEQ ID NO: 583), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 4.

[0168] In another embodiment, the antigenic peptide according to the present invention is a fragment of the tumor antigen ANKRD30A (human reference peptide), such as a microbial sequence variant of "YTSNDSYIV" (SEQ ID NO: 584), "ILIDSGADI" (SEQ ID NO: 585), "SLFESSAKI" (SEQ ID NO: 586) or "SLTPLLLSI" (SEQ ID NO: 587). In another preferred embodiment, the antigenic peptide according to the present invention is a sequence variant of a fragment of the tumor antigen ANKRD30A, such as an antigenic peptide comprising or consisting of the amino acid sequence shown in any one of SEQ ID NOs: 5-15. More preferably, the antigenic peptide according to the present invention is a sequence variant of the ANKRD30A fragment (human reference peptide) "YTSNDSYIV" (SEQ ID NO: 584), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 5. More preferably, the antigenic peptide according to the present invention is a sequence variant of the ANKRD30A fragment (human reference peptide) "ILIDSGADI" (SEQ ID NO: 585), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 6, 7 or 8. More preferably, the antigenic peptide according to the present invention is a sequence variant of the ANKRD30A fragment (human reference peptide) "SLFESSAKI" (SEQ ID NO: 586), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 9 or 10. More preferably, the antigenic peptide according to the present invention is a sequence variant of the ANKRD30A fragment (human reference peptide) "SLTPLLLSI" (SEQ ID NO: 587), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 11, 12, 13, 14 or 15.

[0169] In another embodiment, the antigenic peptide according to the present invention is a microbial sequence variant of a fragment of the tumor antigen AREG (human reference peptide), such as "MSAVILTAV" (SEQ ID NO: 588) or "ALAAIAAFM" (SEQ ID NO: 589). In another preferred embodiment, the antigenic peptide according to the present invention is a sequence variant of a fragment of the tumor antigen AREG, such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in any one of SEQ ID NOs: 16-24. More preferably, the antigenic peptide according to the present invention is a sequence variant of the AREG fragment (human reference peptide) "MSAVILTAV" (SEQ ID NO: 588), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NOs: 16 or 17. Even more preferably, the antigenic peptide according to the present invention is a sequence variant of the AREG fragment (human reference peptide) "ALAAIAAFM" (SEQ ID NO: 589), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NOs: 18, 19, 20, 21, 22, 23, or 24.

[0170] In another embodiment, the antigenic peptide according to the present invention is a fragment of the tumor antigen ASCL1 (human reference peptide), such as a microbial sequence variant of "VSAAFQAGV" (SEQ ID NO: 590). In another preferred embodiment, the antigenic peptide according to the present invention is a sequence variant of a fragment of the tumor antigen ASCL1, such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 25. That is, the antigenic peptide according to the present invention comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 25 is a sequence variant of the ASCL1 fragment (human reference peptide) "VSAAFQAGV" (SEQ ID NO: 590).

[0171] In another embodiment, the antigenic peptide according to the present invention is a microbial sequence variant of a fragment of the tumor antigen ASCL2 (human reference peptide), such as "KLVNLGFQA" (SEQ ID NO: 591) or "ELLDFSSWL" (SEQ ID NO: 592). In another preferred embodiment, the antigenic peptide according to the present invention is a sequence variant of a fragment of the tumor antigen ASCL2, such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in any one of SEQ ID NOs: 26-29. More preferably, the antigenic peptide according to the present invention is a sequence variant of the ASCL2 fragment (human reference peptide) "KLVNLGFQA" (SEQ ID NO: 591), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NOs: 26 or 27. Even more preferably, the antigenic peptide according to the present invention is a sequence variant of the ASCL2 fragment (human reference peptide) "ELLDFSSWL" (SEQ ID NO: 592), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NOs: 28 or 29.

[0172] In another embodiment, the antigenic peptide according to the present invention is a microbial sequence variant of a fragment of the tumor antigen BIRC5 (human reference peptide), such as "LTLGEFLKL" (SEQ ID NO: 593). In another preferred embodiment, the antigenic peptide according to the present invention is a sequence variant of a fragment of the tumor antigen BIRC5, such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in any one of SEQ ID NOs: 30-32. More preferably, the antigenic peptide according to the present invention is a sequence variant of the BIRC5 fragment (human reference peptide) "LTLGEFLKL" (SEQ ID NO: 593), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NOs: 30, 31, or 32. Even more preferably, the antigenic peptide comprises or consists of SEQ ID NO: 32.

[0173] In another embodiment, the antigenic peptide according to the present invention is a fragment of the tumor antigen CA9 (human reference peptide), such as a microbial sequence variant of "AAGDILALV" (SEQ ID NO: 594), "ALVFGLLFA" (SEQ ID NO: 595), "FQYEGSLTT" (SEQ ID NO: 596), "HLSTAFARV" (SEQ ID NO: 597), "LSLLLLVPV" (SEQ ID NO: 598), "QLLLSLLLL" (SEQ ID NO: 599), or "VQLLLSLLL" (SEQ ID NO: 600). In another preferred embodiment, the antigenic peptide according to the present invention is a sequence variant of a fragment of the tumor antigen CA9, such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in any one of SEQ ID NOs: 33-50. More preferably, the antigenic peptide according to the present invention is a sequence variant of the CA9 fragment (human reference peptide) "AAGDILALV" (SEQ ID NO: 594), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NOs: 33 or 34. More preferably, the antigenic peptide according to the present invention is a sequence variant of the CA9 fragment (human reference peptide) "ALVFGLLFA" (SEQ ID NO: 595), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 35, 36, or 37. More preferably, the antigenic peptide according to the present invention is a sequence variant of the CA9 fragment (human reference peptide) "FQYEGSLTT" (SEQ ID NO: 596), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 38. More preferably, the antigenic peptide according to the present invention is a sequence variant of the CA9 fragment (human reference peptide) "HLSTAFARV" (SEQ ID NO: 597), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 39, 40, or 41. More preferably, the antigenic peptide according to the present invention is a sequence variant of the CA9 fragment (human reference peptide) "LSLLLLVPV" (SEQ ID NO: 598), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 42, 43, or 44. And more preferably, the antigenic peptide according to the present invention is a sequence variant of the CA9 fragment (human reference peptide) "QLLLSLLLL" (SEQ ID NO: 599), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 45, 46 or 47.And more preferably, the antigenic peptide according to the present invention is a sequence variant of the CA9 fragment (human reference peptide) "VQLLLSLLL" (SEQ ID NO: 600), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 48, 49 or 50.

[0174] In another embodiment, the antigenic peptide according to the present invention is a microbial sequence variant of a fragment of the tumor antigen CCNA1 (human reference peptide), such as "NLAKYVAEL" (SEQ ID NO: 601) or "LIAAAAFCL" (SEQ ID NO: 602). In another preferred embodiment, the antigenic peptide according to the present invention is a sequence variant of a fragment of the tumor antigen CCNA1, such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in any one of SEQ ID NOs: 51-55. More preferably, the antigenic peptide according to the present invention is a sequence variant of the CCNA1 fragment (human reference peptide) "NLAKYVAEL" (SEQ ID NO: 601), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 51. Even more preferably, the antigenic peptide according to the present invention is a sequence variant of the CCNA1 fragment (human reference peptide) "LIAAAAFCL" (SEQ ID NO: 602), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NOs: 52, 53, 54, or 55.

[0175] In another embodiment, the antigenic peptide according to the present invention is a fragment of the tumor antigen CCND1 (human reference peptide), such as a microbial sequence variant of "LLNDRVLRA" (SEQ ID NO: 603). In another preferred embodiment, the antigenic peptide according to the present invention is a sequence variant of a fragment of the tumor antigen CCND1, such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 56. That is, the antigenic peptide according to the present invention comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 56 is a sequence variant of the CCND1 fragment (human reference peptide) "LLNDRVLRA" (SEQ ID NO: 603).

[0176] In another embodiment, the antigenic peptide according to the present invention is a fragment of the tumor antigen CDH17 (human reference peptide), such as a microbial sequence variant of "GILLTTLLV" (SEQ ID NO: 604), "ILAVVFIRI" (SEQ ID NO: 605), "ILLTTLLVI" (SEQ ID NO: 606) or "LVIGIILAV" (SEQ ID NO: 607). In another preferred embodiment, the antigenic peptide according to the present invention is a sequence variant of a fragment of the tumor antigen CDH17, such as an antigenic peptide comprising or consisting of the amino acid sequence shown in any one of SEQ ID NOs: 57-63. More preferably, the antigenic peptide according to the present invention is a sequence variant of the CDH17 fragment (human reference peptide) "GILLTTLLV" (SEQ ID NO: 604), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 57. More preferably, the antigenic peptide according to the present invention is a sequence variant of the CDH17 fragment (human reference peptide) "ILAVVFIRI" (SEQ ID NO: 605), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 58 or 59. More preferably, the antigenic peptide according to the present invention is a sequence variant of the CDH17 fragment (human reference peptide) "ILLTTLLVI" (SEQ ID NO: 606), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 60, 61 or 62. More preferably, the antigenic peptide according to the present invention is a sequence variant of the CDH17 fragment (human reference peptide) "LVIGIILAV" (SEQ ID NO: 607), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 63.

[0177] In another embodiment, the antigenic peptide according to the present invention is a fragment of the tumor antigen CDH6 (human reference peptide), such as a microbial sequence variant of "ALVAILLCI" (SEQ ID NO: 608), "EMSDVGTFV" (SEQ ID NO: 609), "EMSTYLLPV" (SEQ ID NO: 610), "FLLEEYTGS" (SEQ ID NO: 611), "ILLCIVILL" (SEQ ID NO: 612), or "LLVTVVLFA" (SEQ ID NO: 613). In another preferred embodiment, the antigenic peptide according to the present invention is a sequence variant of a fragment of the tumor antigen CDH6, such as an antigenic peptide comprising or consisting of the amino acid sequence shown in any one of SEQ ID NOs: 64-81. More preferably, the antigenic peptide according to the present invention is a sequence variant of the CDH6 fragment (human reference peptide) "ALVAILLCI" (SEQ ID NO: 608), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NOs: 64, 65, 66, 67, 68, 69 or 70. More preferably, the antigenic peptide according to the present invention is a sequence variant of the CDH6 fragment (human reference peptide) "EMSDVGTFV" (SEQ ID NO: 609), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 71. More preferably, the antigenic peptide according to the present invention is a sequence variant of the CDH6 fragment (human reference peptide) "EMSTYLLPV" (SEQ ID NO: 610), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 72. More preferably, the antigenic peptide according to the present invention is a sequence variant of the CDH6 fragment (human reference peptide) "FLLEEYTGS" (SEQ ID NO: 611), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 73. More preferably, the antigenic peptide according to the present invention is a sequence variant of the CDH6 fragment (human reference peptide) "ILLCIVILL" (SEQ ID NO: 612), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 74 or 75. And more preferably, the antigenic peptide according to the present invention is a sequence variant of the CDH6 fragment (human reference peptide) "LLVTVVLFA" (SEQ ID NO: 613), such as an antigenic peptide comprising or consisting of the following amino acid sequence: SEQ ID NO: 76, 77, 78, 79, 80 or 81.

[0178] In another embodiment, the antigenic peptide according to the present invention is a fragment of the tumor antigen CDKN2A (human reference peptide), such as a microbial sequence variant of "AVALVLMLL" (SEQ ID NO: 614). In another preferred embodiment, the antigenic peptide according to the present invention is a sequence variant of a fragment of the tumor antigen CDKN2A, such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 82. That is, the antigenic peptide according to the present invention comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 82 is a sequence variant of the CDKN2A fragment (human reference peptide) "AVALVLMLL" (SEQ ID NO: 614).

[0179] In another embodiment, the antigenic peptide according to the present invention is a fragment of the tumor antigen CEACAM5 (human reference peptide), such as a microbial sequence variant of "LLTFWNPPT" (SEQ ID NO: 615). In another preferred embodiment, the antigenic peptide according to the present invention is a sequence variant of a fragment of the tumor antigen CEACAM5, such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 83. That is, the antigenic peptide according to the present invention comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 83 is a sequence variant of the CEACAM5 fragment (human reference peptide) "LLTFWNPPT" (SEQ ID NO: 615).

[0180] In another embodiment, the antigenic peptide according to the present invention is a fragment of the tumor antigen CHI3L1 (human reference peptide), such as a microbial sequence variant of "KQLLLSAAL" (SEQ ID NO: 616), "LLLSAALSA" (SEQ ID NO: 617), "QLAGAMVWA" (SEQ ID NO: 618), "SQTGFVVLV" (SEQ ID NO: 619) or "TLASSETGV" (SEQ ID NO: 620). In another preferred embodiment, the antigenic peptide according to the present invention is a sequence variant of a fragment of the tumor antigen CHI3L1, such as an antigenic peptide comprising or consisting of the amino acid sequence shown in any one of SEQ ID NOs: 84-114. More preferably, the antigenic peptide according to the present invention is a sequence variant of the CHI3L1 fragment (human reference peptide) "KQLLLSAAL" (SEQ ID NO: 616), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 84 or 85. More preferably, the antigenic peptide according to the present invention is a sequence variant of the CHI3L1 fragment (human reference peptide) "LLLSAALSA" (SEQ ID NO: 617), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, or 109. More preferably, the antigenic peptide according to the present invention is a sequence variant of the CHI3L1 fragment (human reference peptide) "QLAGAMVWA" (SEQ ID NO: 618), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 110, 111 or 112. More preferably, the antigenic peptide according to the present invention is a sequence variant of the CHI3L1 fragment (human reference peptide) "SQTGFVVLV" (SEQ ID NO: 619), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 113. Still more preferably, the antigenic peptide according to the present invention is a sequence variant of the CHI3L1 fragment (human reference peptide) "TLASSETGV" (SEQ ID NO: 620), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 114.

[0181] In another embodiment, the antigenic peptide according to the present invention is a fragment of the tumor antigen CHI3L2 (human reference peptide), such as a microbial sequence variant of "ILLSIGGYL" (SEQ ID NO: 621), "HLIYSFASI" (SEQ ID NO: 622), "VLIHELAEA" (SEQ ID NO: 623), or "SLWAGVVVL" (SEQ ID NO: 624). In another preferred embodiment, the antigenic peptide according to the present invention is a sequence variant of a fragment of the tumor antigen CHI3L2, such as an antigenic peptide comprising or consisting of the amino acid sequence shown in any one of SEQ ID NOs: 115–119. More preferably, the antigenic peptide according to the present invention is a sequence variant of the CHI3L2 fragment (human reference peptide) "ILLSIGGYL" (SEQ ID NO: 621), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 115. More preferably, the antigenic peptide according to the present invention is a sequence variant of the CHI3L2 fragment (human reference peptide) "HLIYSFASI" (SEQ ID NO: 622), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 116. More preferably, the antigenic peptide according to the present invention is a sequence variant of the CHI3L2 fragment (human reference peptide) "VLIHELAEA" (SEQ ID NO: 623), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 117 or 118. More preferably, the antigenic peptide according to the present invention is a sequence variant of the CHI3L2 fragment (human reference peptide) "SLWAGVVVL" (SEQ ID NO: 624), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 119.

[0182] In another embodiment, the antigenic peptide according to the present invention is a fragment of the tumor antigen COL11A1 (human reference peptide), such as a microbial sequence variant of "WLWDFTVTT" (SEQ ID NO: 625). In another preferred embodiment, the antigenic peptide according to the present invention is a sequence variant of a fragment of the tumor antigen COL11A1, such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 120. That is, the antigenic peptide according to the present invention comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 120 is a sequence variant of the COL11A1 fragment (human reference peptide) "WLWDFTVTT" (SEQ ID NO: 625).

[0183] In another embodiment, the antigenic peptide according to the present invention is a fragment of the tumor antigen CT83 (human reference peptide), such as a microbial sequence variant of "LLASSILCA" (SEQ ID NO: 626). In another preferred embodiment, the antigenic peptide according to the present invention is a sequence variant of a fragment of the tumor antigen CT83, such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in any one of SEQ ID NOs: 121-123. More preferably, the antigenic peptide according to the present invention is a sequence variant of the CT83 fragment (human reference peptide) "LLASSILCA" (SEQ ID NO: 626), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NOs: 121, 122, or 123.

[0184] In another embodiment, the antigenic peptide according to the present invention is a fragment of the tumor antigen CTCFL (human reference peptide), such as a microbial sequence variant of "KLAVSLAET" (SEQ ID NO: 627). In another preferred embodiment, the antigenic peptide according to the present invention is a sequence variant of a fragment of the tumor antigen CTCFL, such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 124. That is, the antigenic peptide according to the present invention comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 124 is a sequence variant of the CTCFL fragment (human reference peptide) "KLAVSLAET" (SEQ ID NO: 627).

[0185] In another embodiment, the antigenic peptide according to the present invention is a microbial sequence variant of a fragment of the tumor antigen DCT (human reference peptide), such as "ALVGLFVLL" (SEQ ID NO: 628), "GLFVLLAFL" (SEQ ID NO: 629), "SVYDFFVWL" (SEQ ID NO: 630), or "VVMGTLVAL" (SEQ ID NO: 631). In another preferred embodiment, the antigenic peptide according to the present invention is a sequence variant of a fragment of the tumor antigen DCT, such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in any one of SEQ ID NOs: 125-132. More preferably, the antigenic peptide according to the present invention is a sequence variant of the DCT fragment (human reference peptide) "ALVGLFVLL" (SEQ ID NO: 628), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NOs: 125 or 126. More preferably, the antigenic peptide according to the present invention is a sequence variant of the DCT fragment (human reference peptide) "GLFVLLAFL" (SEQ ID NO: 629), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 127, 128, or 129. More preferably, the antigenic peptide according to the present invention is a sequence variant of the DCT fragment (human reference peptide) "SVYDFFVWL" (SEQ ID NO: 630), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 130. More preferably, the antigenic peptide according to the present invention is a sequence variant of the DCT fragment (human reference peptide) "VVMGTLVAL" (SEQ ID NO: 631), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 131 or 132.

[0186] In another embodiment, the antigenic peptide according to the present invention is a microbial sequence variant of a fragment of the tumor antigen DMRTA2 (human reference peptide), such as "GTAEGLALA" (SEQ ID NO: 632) or "GLAAGLGPA" (SEQ ID NO: 633). In another preferred embodiment, the antigenic peptide according to the present invention is a sequence variant of a fragment of the tumor antigen DMRTA2, such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in any one of SEQ ID NOs: 133–134. More preferably, the antigenic peptide according to the present invention is a sequence variant of the DMRTA2 fragment (human reference peptide) "GTAEGLALA" (SEQ ID NO: 632), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 133. Even more preferably, the antigenic peptide according to the present invention is a sequence variant of the DMRTA2 fragment (human reference peptide) "GLAAGLGPA" (SEQ ID NO: 633), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 134.

[0187] In another embodiment, the antigenic peptide according to the present invention is a fragment of the tumor antigen EGFR (human reference peptide), such as a microbial sequence variant of "ALESILHRI" (SEQ ID NO: 634), "ALLAALCPA" (SEQ ID NO: 635), "ALLALLAAL" (SEQ ID NO: 636), "ILDEAYVMA" (SEQ ID NO: 637), "LLLLLVVAL" (SEQ ID NO: 638), "MVGALLLLL" (SEQ ID NO: 639), "NLQEILHGA" (SEQ ID NO: 640) or "SLAVVSLNI" (SEQ ID NO: 641). In another preferred embodiment, the antigenic peptide according to the present invention is a sequence variant of a fragment of the tumor antigen EGFR, such as an antigenic peptide comprising or consisting of the amino acid sequence shown in any one of SEQ ID NOs: 135-150. More preferably, the antigenic peptide according to the present invention is a sequence variant of the EGFR fragment (human reference peptide) "ALESILHRI" (SEQ ID NO: 634), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 135 or 136. Still more preferably, the antigenic peptide according to the present invention is a sequence variant of the EGFR fragment (human reference peptide) "ALLAALCPA" (SEQ ID NO: 635), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 137. Still more preferably, the antigenic peptide according to the present invention is a sequence variant of the EGFR fragment (human reference peptide) "ALLALLAAL" (SEQ ID NO: 636), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 138, 139, 140, 141, 142, 143 or 144. More preferably, the antigenic peptide according to the present invention is a sequence variant of the EGFR fragment (human reference peptide) "ILDEAYVMA" (SEQ ID NO: 637), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 145. More preferably, the antigenic peptide according to the present invention is a sequence variant of the EGFR fragment (human reference peptide) "LLLLLVVAL" (SEQ ID NO: 638), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 146. More preferably, the antigenic peptide according to the present invention is a sequence variant of the EGFR fragment (human reference peptide) "MVGALLLLL" (SEQ ID NO: 639), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 147.More preferably, the antigenic peptide according to the present invention is a sequence variant of the EGFR fragment (human reference peptide) "NLQEILHGA" (SEQ ID NO: 640), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 148. Still more preferably, the antigenic peptide according to the present invention is a sequence variant of the EGFR fragment (human reference peptide) "SLAVVSLNI" (SEQ ID NO: 641), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 149 or 150.

[0188] In another embodiment, the antigenic peptide according to the present invention is a fragment of the tumor antigen ERBB2 (human reference peptide), such as a microbial sequence variant of "AVVGILLVV" (SEQ ID NO: 642), "ILDEAYVMA" (SEQ ID NO: 643), "LLALLPPGA" (SEQ ID NO: 644), "SIISAVVGI" (SEQ ID NO: 645), or "VVLGVVFGI" (SEQ ID NO: 646). In another preferred embodiment, the antigenic peptide according to the present invention is a sequence variant of a fragment of the tumor antigen ERBB2, such as an antigenic peptide comprising or consisting of the amino acid sequence shown in any one of SEQ ID NOs: 151-162. More preferably, the antigenic peptide according to the present invention is a sequence variant of the ERBB2 fragment (human reference peptide) "AVVGILLVV" (SEQ ID NO: 642), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NOs: 151, 152, 153, or 154. More preferably, the antigenic peptide according to the present invention is a sequence variant of the ERBB2 fragment (human reference peptide) "ILDEAYVMA" (SEQ ID NO: 643), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 155. More preferably, the antigenic peptide according to the present invention is a sequence variant of the ERBB2 fragment (human reference peptide) "LLALLPPGA" (SEQ ID NO: 644), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 156, 157, 158 or 159. More preferably, the antigenic peptide according to the present invention is a sequence variant of the ERBB2 fragment (human reference peptide) "SIISAVVGI" (SEQ ID NO: 645), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 160. And more preferably, the antigenic peptide according to the present invention is a sequence variant of the ERBB2 fragment (human reference peptide) "VVLGVVFGI" (SEQ ID NO: 646), such as an antigenic peptide comprising or consisting of the following: the amino acid sequence shown in SEQ ID NO: 161 or 162, specifically the antigenic peptide comprising or consisting of the following: the amino acid sequence shown in SEQ ID NO: 162.

[0189] In another embodiment, the antigenic peptide according to the present invention is a fragment of the tumor antigen ERG (human reference peptide), such as a microbial sequence variant of "FLLELLSDS" (SEQ ID NO: 647) or "QLWQFLLEL" (SEQ ID NO: 857). In another preferred embodiment, the antigenic peptide according to the present invention is a sequence variant of a fragment of the tumor antigen ERG, such as an antigenic peptide comprising or consisting of the amino acid sequence shown in any one of SEQ ID NOs: 163-164. More preferably, the antigenic peptide according to the present invention is a sequence variant of the ERG fragment (human reference peptide) "FLLELLSDS" (SEQ ID NO: 647), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 163. Even more preferably, the antigenic peptide according to the present invention is a sequence variant of the ERG fragment (human reference peptide) "QLWQFLLEL" (SEQ ID NO: 857), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 164.

[0190] In another embodiment, the antigenic peptide according to the present invention is a microbial sequence variant of a fragment of the tumor antigen CDH17 (human reference peptide), such as a peptide comprising or consisting of the amino acid sequence of any one of SEQ ID NOs: 165-192. More preferably, the antigenic peptide according to the present invention is a sequence variant of the ESR1 fragment (human reference peptide) "ALLDAEPPI" (SEQ ID NO: 648), such as a peptide comprising or consisting of the amino acid sequence of SEQ ID NO: 165. Even more preferably, the antigenic peptide according to the present invention is a sequence variant of the ESR1 fragment (human reference peptide) "KITDTLIHL" (SEQ ID NO: 649), such as a peptide comprising or consisting of the amino acid sequence of SEQ ID NOs: 166 or 167. More preferably, the antigenic peptide according to the present invention is a sequence variant of the ESR1 fragment (human reference peptide) "KLLFAPNLL" (SEQ ID NO: 650), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 168 or 169. More preferably, the antigenic peptide according to the present invention is a sequence variant of the ESR1 fragment (human reference peptide) "LLDAEPPIL" (SEQ ID NO: 651), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 170. More preferably, the antigenic peptide according to the present invention is a sequence variant of the ESR1 fragment (human reference peptide) "LLNSGVYTF" (SEQ ID NO: 652), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 171 or 172. More preferably, the antigenic peptide according to the present invention is a sequence variant of the ESR1 fragment (human reference peptide) "LMIGLVWRS" (SEQ ID NO: 653), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 173. More preferably, the antigenic peptide according to the present invention is a sequence variant of the ESR1 fragment (human reference peptide) "PLYDLLLEM" (SEQ ID NO: 654), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 174, 175, 176, 177, 178, 179, 180 or 181. More preferably, the antigenic peptide according to the present invention is a sequence variant of the ESR1 fragment (human reference peptide) "QLLLILSHI" (SEQ ID NO: 655), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 182, 183, 184, 185, 186, 187 or 188.More preferably, the antigenic peptide according to the present invention is a sequence variant of the ESR1 fragment (human reference peptide) "RLAQLLLIL" (SEQ ID NO: 656), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 189 or 190. More preferably, the antigenic peptide according to the present invention is a sequence variant of the ESR1 fragment (human reference peptide) "TLIHLMAKA" (SEQ ID NO: 657), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 191. More preferably, the antigenic peptide according to the present invention is a sequence variant of the ESR1 fragment (human reference peptide) "VLD kit DTL" (SEQ ID NO: 658), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 192.

[0191] In another embodiment, the antigenic peptide according to the present invention is a microbial sequence variant of a fragment of the tumor antigen CDH17 (human reference peptide), such as a peptide comprising or consisting of the amino acid sequence set forth in any one of SEQ ID NOs: 193-194. More preferably, the antigenic peptide according to the present invention is a sequence variant of the EZH2 fragment (human reference peptide) "FMVEDETVL" (SEQ ID NO: 659), such as a peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 193. Even more preferably, the antigenic peptide according to the present invention is a sequence variant of the EZH2 fragment (human reference peptide) "SMFRVLIGT" (SEQ ID NO: 660), such as a peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 194.

[0192] In another embodiment, the antigenic peptide according to the present invention is a microbial sequence variant of a fragment of the tumor antigen CDH17 (human reference peptide), such as In another preferred embodiment, the antigenic peptide according to the present invention is a sequence variant of a fragment of the tumor antigen FAP, such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in any one of SEQ ID NOs: 195-201. More preferably, the antigenic peptide according to the present invention is a sequence variant of the FAP fragment (human reference peptide) "ATSAVLALL" (SEQ ID NO: 661), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NOs: 195, 196, or 197. Even more preferably, the antigenic peptide according to the present invention is a sequence variant of the FAP fragment (human reference peptide) "TGWAGGFFV" (SEQ ID NO: 662), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 198. And more preferably, the antigenic peptide according to the present invention is a sequence variant of the FAP fragment (human reference peptide) "VLALLVMCI" (SEQ ID NO: 663), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 199, 200 or 201.

[0193] In another embodiment, the antigenic peptide according to the present invention is a microbial sequence variant of a fragment of the tumor antigen CDH17 (human reference peptide), such as, in another preferred embodiment, the antigenic peptide according to the present invention is a sequence variant of a fragment of the tumor antigen FLT1, such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in any one of SEQ ID NOs: 202-216. More preferably, the antigenic peptide according to the present invention is a sequence variant of the FLT1 fragment (human reference peptide) "ALLSCLLLT" (SEQ ID NO: 664), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NOs: 202, 203, 204, 205, 206, 207, or 208. Even more preferably, the antigenic peptide according to the present invention is a sequence variant of the FLT1 fragment (human reference peptide) "CVAATLFWL" (SEQ ID NO: 665), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 209. More preferably, the antigenic peptide according to the present invention is a sequence variant of the FLT1 fragment (human reference peptide) "EMYSEIPEI" (SEQ ID NO: 666), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 210. More preferably, the antigenic peptide according to the present invention is a sequence variant of the FLT1 fragment (human reference peptide) "KMASTLVVA" (SEQ ID NO: 667), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 211 or 212. More preferably, the antigenic peptide according to the present invention is a sequence variant of the FLT1 fragment (human reference peptide) "SIFDKIYST" (SEQ ID NO: 668), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 213. More preferably, the antigenic peptide according to the present invention is a sequence variant of the FLT1 fragment (human reference peptide) "TLFWLLLTL" (SEQ ID NO: 669), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 214. More preferably, the antigenic peptide according to the present invention is a sequence variant of the FLT1 fragment (human reference peptide) "VLLWEIFSL" (SEQ ID NO: 670), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 215. Still more preferably, the antigenic peptide according to the present invention is a sequence variant of the FLT1 fragment (human reference peptide) "WLKDGLPAT" (SEQ ID NO: 671), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 216.

[0194] In another embodiment, the antigenic peptide according to the present invention is a microbial sequence variant of a fragment of the tumor antigen CDH17 (human reference peptide), such as, in another preferred embodiment, the antigenic peptide according to the present invention is a sequence variant of a fragment of the tumor antigen FOXM1, such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in any one of SEQ ID NOs: 217–227 and 861–877, for example, as set forth in any one of SEQ ID NOs: 217–227. More preferably, the antigenic peptide according to the present invention is a sequence variant of the FOXM1 fragment (human reference peptide) "ILLDISFPG" (SEQ ID NO: 672), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NOs: 217 or 218. Further examples of antigenic peptides according to the present invention that are sequence variants of the FOXM1 fragment (human reference peptide) "ILLDISFPG" (SEQ ID NO: 672) include antigenic peptides comprising or consisting of the amino acid sequence set forth in SEQ ID NOs: 861, 862, 863, 864, 865, or 866. And more preferably, the antigenic peptide according to the present invention is a sequence variant of the FOXM1 fragment (human reference peptide) "LLDISFPGL" (SEQ ID NO: 673), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 219. Another example of the antigenic peptide according to the present invention, which is a sequence variant of the FOXM1 fragment (human reference peptide) "LLDISFPGL" (SEQ ID NO: 673), includes an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 867. More preferably, the antigenic peptide according to the present invention is a sequence variant of the FOXM1 fragment (human reference peptide) "LMDLSTTPL" (SEQ ID NO: 674), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 220. Another example of the antigenic peptide according to the present invention, which is a sequence variant of the FOXM1 fragment (human reference peptide) "LMDLSTTPL" (SEQ ID NO: 674), includes an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 868. More preferably, the antigenic peptide according to the present invention is a sequence variant of the FOXM1 fragment (human reference peptide) "RVSSYLVPI" (SEQ ID NO: 675), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: NO: 221, 222 or 223. Further examples of the antigenic peptide according to the present invention that is a sequence variant of the FOXM1 fragment (human reference peptide) "RVSSYLVPI" (SEQ ID NO: 675) include the following antigenic peptides: comprising or consisting of the amino acid sequence shown in SEQ ID NO: 869, 870 or 871.More preferably, the antigenic peptide according to the present invention is a sequence variant of the FOXM1 fragment (human reference peptide) "SLSKILLDI" (SEQ ID NO: 676), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 224. More preferably, the antigenic peptide according to the present invention is a sequence variant of the FOXM1 fragment (human reference peptide) "SQLSYSQEV" (SEQ ID NO: 677), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 225 or 226. More preferably, the antigenic peptide according to the present invention is a sequence variant of the FOXM1 fragment (human reference peptide) "WAAELPFPA" (SEQ ID NO: 678), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 227. More preferably, the antigenic peptide according to the present invention is a sequence variant of the FOXM1 fragment (human reference peptide) "NLSLHDMFV" (SEQ ID NO: 888), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 872. More preferably, the antigenic peptide according to the present invention is a sequence variant of the FOXM1 fragment (human reference peptide) "KMKPLLPRV" (SEQ ID NO: 889), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 873 or 874. More preferably, the antigenic peptide according to the present invention is a sequence variant of the FOXM1 fragment (human reference peptide) "YLVPIQFPV" (SEQ ID NO: 890), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 875 or 876. More preferably, the antigenic peptide according to the present invention is a sequence variant of the FOXM1 fragment (human reference peptide) "YMAMIQFAI" (SEQ ID NO: 891), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 877. Even more preferably, the antigenic peptide comprises or consists of SEQ ID NO: 32.

[0195] In another embodiment, the antigenic peptide according to the present invention is a microbial sequence variant of a fragment of the tumor antigen CDH17 (human reference peptide), such as a peptide comprising or consisting of the amino acid sequence set forth in any one of SEQ ID NOs: 228-231. More preferably, the antigenic peptide according to the present invention is a sequence variant of the FSIP1 fragment (human reference peptide) "LLNESETKV" (SEQ ID NO: 679), such as a peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 228. Even more preferably, the antigenic peptide according to the present invention is a sequence variant of the FSIP1 fragment (human reference peptide) "RLVELLKDL" (SEQ ID NO: 680), such as a peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NOs: 229, 230, or 231.

[0196] In another embodiment, the antigenic peptide according to the present invention is a microbial sequence variant of a fragment of the tumor antigen GAL3ST1 (human reference peptide), such as "GLASTTPEA" (SEQ ID NO: 681) or "RMAREVAAL" (SEQ ID NO: 682). In another preferred embodiment, the antigenic peptide according to the present invention is a sequence variant of a fragment of the tumor antigen GAL3ST1, such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in any one of SEQ ID NOs: 232-234. More preferably, the antigenic peptide according to the present invention is a sequence variant of the GAL3ST1 fragment (human reference peptide) "GLASTTPEA" (SEQ ID NO: 681), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 232. Even more preferably, the antigenic peptide according to the present invention is a sequence variant of the GAL3ST1 fragment (human reference peptide) "RMAREVAAL" (SEQ ID NO: 682), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NOs: 233 or 234.

[0197] In another embodiment, the antigenic peptide according to the present invention is a microbial sequence variant of a fragment of the tumor antigen GPR143 (human reference peptide), such as "FLLSLAFYG" (SEQ ID NO: 683), "ILNPAQGFL" (SEQ ID NO: 684), "MAWGLATLL" (SEQ ID NO: 685), or "RLALGLLQL" (SEQ ID NO: 686). In another preferred embodiment, the antigenic peptide according to the present invention is a sequence variant of a fragment of the tumor antigen GPR143, such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in any one of SEQ ID NOs: 235-247. More preferably, the antigenic peptide according to the present invention is a sequence variant of the GPR143 fragment (human reference peptide) "FLLSLAFYG" (SEQ ID NO: 683), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NOs: 235, 236, or 237. More preferably, the antigenic peptide according to the present invention is a sequence variant of the GPR143 fragment (human reference peptide) "ILNPAQGFL" (SEQ ID NO: 684), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 238. More preferably, the antigenic peptide according to the present invention is a sequence variant of the GPR143 fragment (human reference peptide) "MAWGLATLL" (SEQ ID NO: 685), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 239. More preferably, the antigenic peptide according to the present invention is a sequence variant of the GPR143 fragment (human reference peptide) "RLALGLLQL" (SEQ ID NO: 686), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 240, 241, 242, 243, 245, 246, or 247.

[0198] In another embodiment, the antigenic peptide according to the present invention is a fragment of the tumor antigen HES6 (human reference peptide), such as a microbial sequence variant of "RLLLAGAEV" (SEQ ID NO: 687). In another preferred embodiment, the antigenic peptide according to the present invention is a sequence variant of a fragment of the tumor antigen HES6, such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 248. That is, the antigenic peptide according to the present invention comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 248 is a sequence variant of the HES6 fragment (human reference peptide) "RLLLAGAEV" (SEQ ID NO: 687).

[0199] In another embodiment, the antigenic peptide according to the present invention is a microbial sequence variant of a fragment of the tumor antigen CDH17 (human reference peptide), such as In another preferred embodiment, the antigenic peptide according to the present invention is a sequence variant of a fragment of the tumor antigen IL13RA2, such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in any one of SEQ ID NOs: 249-255. More preferably, the antigenic peptide according to the present invention is a sequence variant of the IL13RA2 fragment (human reference peptide) "CLYTFLIST" (SEQ ID NO: 688), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NOs: 249, 250, or 251. Even more preferably, the antigenic peptide according to the present invention is a sequence variant of the IL13RA2 fragment (human reference peptide) "FLISTTFGC" (SEQ ID NO: 689), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 252. More preferably, the antigenic peptide according to the present invention is a sequence variant of the IL13RA2 fragment (human reference peptide) "VLLDTNYNL" (SEQ ID NO: 690), such as an antigenic peptide comprising or consisting of the amino acid sequence of SEQ ID NO: 253. More preferably, the antigenic peptide according to the present invention is a sequence variant of the IL13RA2 fragment (human reference peptide) "WLPFGFILI" (SEQ ID NO: 691) or "WLPFGFILIL" (SEQ ID NO: 692), such as an antigenic peptide comprising or consisting of the amino acid sequence of SEQ ID NO: 254 or 255, specifically an antigenic peptide comprising or consisting of the amino acid sequence of SEQ ID NO: 255. Further examples of antigenic peptides according to the present invention that are sequence variants of the IL13RA2 fragment (human reference peptide) "WLPFGFILIL" (SEQ ID NO: 692) include antigenic peptides comprising or consisting of the amino acid sequence of SEQ ID NO: 878 or 879. More preferably, the antigenic peptide according to the present invention is a sequence variant of the IL13RA2 fragment (human reference peptide) "FLISTTFGCT" (SEQ ID NO: 892), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 880, 881, or 882. Still more preferably, the antigenic peptide according to the present invention is a sequence variant of the IL13RA2 fragment (human reference peptide) "YLYLQWQPPL" (SEQ ID NO: 893), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 883.More preferably, the antigenic peptide according to the present invention is a sequence variant of the IL13RA2 fragment (human reference peptide) "GVLLDTNYNL" (SEQ ID NO: 894), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 884 or 885. More preferably, the antigenic peptide according to the present invention is a sequence variant of the IL13RA2 fragment (human reference peptide) "FQLQNIVKPL" (SEQ ID NO: 895), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 886 or 887. Even more preferably, the antigenic peptide comprises or consists of SEQ ID NO: 255.

[0200] In another embodiment, the antigenic peptide according to the present invention is a fragment of the tumor antigen KISS1R (human reference peptide), such as a microbial sequence variant of "ALYLLPLLA" (SEQ ID NO: 693), "FALYNLLAL" (SEQ ID NO: 694), "QLFLVLQAL" (SEQ ID NO: 695), "RLVAAVVLL" (SEQ ID NO: 696), "VLAERAGAV" (SEQ ID NO: 697), "WLVPLFFAA" (SEQ ID NO: 698) or "YLLPLLATC" (SEQ ID NO: 699). In another preferred embodiment, the antigenic peptide according to the present invention is a sequence variant of a fragment of the tumor antigen KISS1R, such as an antigenic peptide comprising or consisting of the amino acid sequence shown in any one of SEQ ID NOs: 256-287. More preferably, the antigenic peptide according to the present invention is a sequence variant of the KISS1R fragment (human reference peptide) "ALYLLPLLA" (SEQ ID NO: 693), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 256, 257 or 258. Still more preferably, the antigenic peptide according to the present invention is a sequence variant of the KISS1R fragment (human reference peptide) "FALYNLLAL" (SEQ ID NO: 694), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 259, 260 or 261. Still more preferably, the antigenic peptide according to the present invention is a sequence variant of the KISS1R fragment (human reference peptide) "QLFLVLQAL" (SEQ ID NO: 695), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 262. Still more preferably, the antigenic peptide according to the present invention is a sequence variant of the KISS1R fragment (human reference peptide) "RLVAAVVLL" (SEQ ID NO: 696), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 263. More preferably, the antigenic peptide according to the present invention is a sequence variant of the KISS1R fragment (human reference peptide) "VLAERAGAV" (SEQ ID NO: 697), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 264. More preferably, the antigenic peptide according to the present invention is a sequence variant of the KISS1R fragment (human reference peptide) "WLVPLFFAA" (SEQ ID NO: 698), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 266, 267, 268 or 269.And more preferably, the antigenic peptide according to the present invention is a sequence variant of the KISS1R fragment (human reference peptide) "YLLPLLATC" (SEQ ID NO: 699), such as an antigenic peptide comprising or consisting of the following: the amino acid sequence shown in SEQ ID NO: 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286 or 287.

[0201] In another embodiment, the antigenic peptide according to the present invention is a microbial sequence variant of a fragment of the tumor antigen KLHDC8A (human reference peptide), such as "GLSDAVEAL" (SEQ ID NO: 700) or "MLREAAMGI" (SEQ ID NO: 701). In another preferred embodiment, the antigenic peptide according to the present invention is a sequence variant of a fragment of the tumor antigen KLHDC8A, such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in any one of SEQ ID NOs: 288-289. More preferably, the antigenic peptide according to the present invention is a sequence variant of the KLHDC8A fragment (human reference peptide) "GLSDAVEAL" (SEQ ID NO: 700), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 288. Even more preferably, the antigenic peptide according to the present invention is a sequence variant of the KLHDC8A fragment (human reference peptide) "MLREAAMGI" (SEQ ID NO: 701), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 289.

[0202] In another embodiment, the antigenic peptide according to the present invention is a microbial sequence variant of a fragment of the tumor antigen KLHL14 (human reference peptide), such as "ALIPAPELV" (SEQ ID NO: 702), "NLLHGLNLL" (SEQ ID NO: 703), or "YVSSLPQPL" (SEQ ID NO: 704). In another preferred embodiment, the antigenic peptide according to the present invention is a sequence variant of a fragment of the tumor antigen KLHL14, such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in any one of SEQ ID NOs: 290-292. More preferably, the antigenic peptide according to the present invention is a sequence variant of the KLHL14 fragment (human reference peptide) "ALIPAPELV" (SEQ ID NO: 702), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 290. Even more preferably, the antigenic peptide according to the present invention is a sequence variant of the KLHL14 fragment (human reference peptide) "NLLHGLNLL" (SEQ ID NO: 703), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 291. And more preferably, the antigenic peptide according to the present invention is a sequence variant of the KLHL14 fragment (human reference peptide) "YVSSLPQPL" (SEQ ID NO: 704), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 292.

[0203] In another embodiment, the antigenic peptide according to the present invention is a fragment of the tumor antigen KLK4 (human reference peptide), such as a microbial sequence variant of "YLILGVAGS" (SEQ ID NO: 705). In another preferred embodiment, the antigenic peptide according to the present invention is a sequence variant of a fragment of the tumor antigen KLK4, such as an antigenic peptide comprising or consisting of the amino acid sequence shown in any one of SEQ ID NOs: 293-296. More preferably, the antigenic peptide according to the present invention is a sequence variant of the KLK4 fragment (human reference peptide) "YLILGVAGS" (SEQ ID NO: 705), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NOs: 293, 294, 295 or 296.

[0204] In another embodiment, the antigenic peptide according to the present invention is a fragment of the tumor antigen KRT81 (human reference peptide), such as a microbial sequence variant of "NMDCIIAEI" (SEQ ID NO: 706). In another preferred embodiment, the antigenic peptide according to the present invention is a sequence variant of a fragment of the tumor antigen KRT81, such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 297. That is, the antigenic peptide according to the present invention comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 297 is a sequence variant of the KRT81 fragment (human reference peptide) "NMDCIIAEI" (SEQ ID NO: 706).

[0205] In another embodiment, the antigenic peptide according to the present invention is a microbial sequence variant of a fragment of the tumor antigen LEMD1 (human reference peptide), such as "AVLGIFIIV" (SEQ ID NO: 707) or "KLAVLGIFI" (SEQ ID NO: 708). In another preferred embodiment, the antigenic peptide according to the present invention is a sequence variant of a fragment of the tumor antigen LEMD1, such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in any one of SEQ ID NOs: 298-299. More preferably, the antigenic peptide according to the present invention is a sequence variant of the LEMD1 fragment (human reference peptide) "AVLGIFIIV" (SEQ ID NO: 707), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 298. Even more preferably, the antigenic peptide according to the present invention is a sequence variant of the LEMD1 fragment (human reference peptide) "KLAVLGIFI" (SEQ ID NO: 708), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 299.

[0206] In another embodiment, the antigenic peptide according to the present invention is a fragment of the tumor antigen LRRC15 (human reference peptide), such as a microbial sequence variant of "AIAAIVIGI" (SEQ ID NO: 709), ALACSLAAC" (SEQ ID NO: 710), "IVIGIVALA" (SEQ ID NO: 711), "RIVAVPTPL" (SEQ ID NO: 712) or "SLKELSPGI" (SEQ ID NO: 713). In another preferred embodiment, the antigenic peptide according to the present invention is a sequence variant of a fragment of the tumor antigen LRRC15, such as an antigenic peptide comprising or consisting of the amino acid sequence shown in any one of SEQ ID NOs: 300-307. More preferably, the antigenic peptide according to the present invention is a sequence variant of the LRRC15 fragment (human reference peptide) "AIAAIVIGI" (SEQ ID NO: 709), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 300. And more preferably, the antigenic peptide according to the present invention is the LRRC15 fragment (human reference peptide) "ALACSLAAC" (SEQ ID NO: 711). The antigenic peptide according to the present invention is a sequence variant of the LRRC15 fragment (human reference peptide) "IVIGIVALA" (SEQ ID NO: 711), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 302. Furthermore, the antigenic peptide according to the present invention is a sequence variant of the LRRC15 fragment (human reference peptide) "RIVAVPTPL" (SEQ ID NO: 712), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 303, 304 or 305. Furthermore, the antigenic peptide according to the present invention is a sequence variant of the LRRC15 fragment (human reference peptide) "SLKELSPGI" (SEQ ID NO: 713), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 306 or 307.

[0207] In another embodiment, the antigenic peptide according to the present invention is a microbial sequence variant of a fragment of the tumor antigen MAGEA1 (human reference peptide), such as "KVADLVGFL" (SEQ ID NO: 714) or "LVLGTLEEV" (SEQ ID NO: 858). In another preferred embodiment, the antigenic peptide according to the present invention is a sequence variant of a fragment of the tumor antigen MAGEA1, such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in any one of SEQ ID NOs: 308-309. More preferably, the antigenic peptide according to the present invention is a sequence variant of the MAGEA1 fragment (human reference peptide) "KVADLVGFL" (SEQ ID NO: 714), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 308. Even more preferably, the antigenic peptide according to the present invention is a sequence variant of the MAGEA1 fragment (human reference peptide) "LVLGTLEEV" (SEQ ID NO: 858), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 309.

[0208] In another embodiment, the antigenic peptide according to the present invention is a microbial sequence variant of a fragment of the tumor antigen MAGEA4 (human reference peptide), such as "AVSSSSPLV" (SEQ ID NO: 722), "KVDELAHFL" (SEQ ID NO: 723), or "KVLEHVVRV" (SEQ ID NO: 724). In another preferred embodiment, the antigenic peptide according to the present invention is a sequence variant of a fragment of the tumor antigen MAGEA4, such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in any one of SEQ ID NOs: 320-322. More preferably, the antigenic peptide according to the present invention is a sequence variant of the MAGEA4 fragment (human reference peptide) "AVSSSSPLV" (SEQ ID NO: 722), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 320. Even more preferably, the antigenic peptide according to the present invention is a sequence variant of the MAGEA4 fragment (human reference peptide) "KVDELAHFL" (SEQ ID NO: 723), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 321. And more preferably, the antigenic peptide according to the present invention is a sequence variant of the MAGEA4 fragment (human reference peptide) "KVLEHVVRV" (SEQ ID NO: 724), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 322.

[0209] In another embodiment, the antigenic peptide according to the present invention is a microbial sequence variant of a fragment of the tumor antigen MAGEA10 (human reference peptide), such as "GMLSDVQSM" (SEQ ID NO: 715) or "ILILILSIV" (SEQ ID NO: 716). In another preferred embodiment, the antigenic peptide according to the present invention is a sequence variant of a fragment of the tumor antigen MAGEA10, such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in any one of SEQ ID NOs: 310-313. More preferably, the antigenic peptide according to the present invention is a sequence variant of the MAGEA10 fragment (human reference peptide) "GMLSDVQSM" (SEQ ID NO: 715), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NOs: 310 or 311. Even more preferably, the antigenic peptide according to the present invention is a sequence variant of the MAGEA10 fragment (human reference peptide) "ILILILSIV" (SEQ ID NO: 716), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NOs: 312 or 313.

[0210] In another embodiment, the antigenic peptide according to the present invention is a fragment of the tumor antigen MAGEA11 (human reference peptide), such as a microbial sequence variant of "AMDAIFGSL" (SEQ ID NO: 717), "GLITKAEML" (SEQ ID NO: 718), "GTLEELPAA" (SEQ ID NO: 719) or "KVLEYIANA" (SEQ ID NO: 720). In another preferred embodiment, the antigenic peptide according to the present invention is a sequence variant of a fragment of the tumor antigen MAGEA11, such as an antigenic peptide comprising or consisting of the amino acid sequence shown in any one of SEQ ID NOs: 314-318. More preferably, the antigenic peptide according to the present invention is a sequence variant of the MAGEA11 fragment (human reference peptide) "AMDAIFGSL" (SEQ ID NO: 717), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 314. More preferably, the antigenic peptide according to the present invention is a sequence variant of the MAGEA11 fragment (human reference peptide) "GLITKAEML" (SEQ ID NO: 718), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 315. More preferably, the antigenic peptide according to the present invention is a sequence variant of the MAGEA11 fragment (human reference peptide) "GTLEELPAA" (SEQ ID NO: 719), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 316 or 317. More preferably, the antigenic peptide according to the present invention is a sequence variant of the MAGEA11 fragment (human reference peptide) "KVLEYIANA" (SEQ ID NO: 720), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 318.

[0211] In another embodiment, the antigenic peptide according to the present invention is a fragment of the tumor antigen MAGEA12 (human reference peptide), such as a microbial sequence variant of "QLVFGIEVV" (SEQ ID NO: 721). In another preferred embodiment, the antigenic peptide according to the present invention is a sequence variant of a fragment of the tumor antigen MAGEA12, such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 319. That is, the antigenic peptide according to the present invention comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 319 is a sequence variant of the MAGEA12 fragment (human reference peptide) "QLVFGIEVV" (SEQ ID NO: 721).

[0212] In another embodiment, the antigenic peptide according to the present invention is a fragment of the tumor antigen MLANA (human reference peptide), such as a microbial sequence variant of "VILGVLLLI" (SEQ ID NO: 725). In another preferred embodiment, the antigenic peptide according to the present invention is a sequence variant of a fragment of the tumor antigen MLANA, such as an antigenic peptide comprising or consisting of the amino acid sequence shown in any one of SEQ ID NOs: 323-334. More preferably, the antigenic peptide according to the present invention is a sequence variant of the MLANA fragment (human reference peptide) "VILGVLLLI" (SEQ ID NO: 725), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NOs: 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333 or 334.

[0213] In another embodiment, the antigenic peptide according to the present invention is a microbial sequence variant of a fragment of the tumor antigen NKX2-1 (human reference peptide), such as "MTAAGVPQL" (SEQ ID NO: 726) or "SVSDILSPL" (SEQ ID NO: 727). In another preferred embodiment, the antigenic peptide according to the present invention is a sequence variant of a fragment of the tumor antigen NKX2-1, such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in any one of SEQ ID NOs: 335–340. More preferably, the antigenic peptide according to the present invention is a sequence variant of the NKX2-1 fragment (human reference peptide) "MTAAGVPQL" (SEQ ID NO: 726), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 335. Even more preferably, the antigenic peptide according to the present invention is a sequence variant of the NKX2-1 fragment (human reference peptide) "SVSDILSPL" (SEQ ID NO: 727), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NOs: 336, 337, 338, 339, or 340.

[0214] In another embodiment, the antigenic peptide according to the present invention is a fragment of the tumor antigen NPTX2 (human reference peptide), such as a microbial sequence variant of "ALLAASVAL" (SEQ ID NO: 728), "LLAASVALA" (SEQ ID NO: 729), "QLLRKVAEL" (SEQ ID NO: 730), "TLPELYAFT" (SEQ ID NO: 731) or "YLYGKIKKT" (SEQ ID NO: 732). In another preferred embodiment, the antigenic peptide according to the present invention is a sequence variant of a fragment of the tumor antigen NPTX2, such as an antigenic peptide comprising or consisting of the amino acid sequence shown in any one of SEQ ID NOs: 341-351. More preferably, the antigenic peptide according to the present invention is a sequence variant of the NPTX2 fragment (human reference peptide) "ALLAASVAL" (SEQ ID NO: 728), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NOs: 341, 342, 343 or 344. And more preferably, the antigenic peptide according to the present invention is the NPTX2 fragment (human reference peptide) "LLAASVALA" (SEQ ID NO: 731). The antigenic peptide according to the present invention is a sequence variant of the NPTX2 fragment (human reference peptide) "QLLRKVAEL" (SEQ ID NO: 730), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 349. Furthermore, the antigenic peptide according to the present invention is a sequence variant of the NPTX2 fragment (human reference peptide) "TLPELYAFT" (SEQ ID NO: 731), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 350. Furthermore, the antigenic peptide according to the present invention is a sequence variant of the NPTX2 fragment (human reference peptide) "YLYGKIKKT" (SEQ ID NO: 732), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 351.

[0215] In another embodiment, the antigenic peptide according to the present invention is a microbial sequence variant of a fragment of the tumor antigen CDH17 (human reference peptide), such as In another preferred embodiment, the antigenic peptide according to the present invention is a sequence variant of a fragment of the tumor antigen PAGE3, such as an antigenic peptide comprising or consisting of the amino acid sequence shown in any one of SEQ ID NOs: 352-354. More preferably, the antigenic peptide according to the present invention is a sequence variant of the PAGE3 fragment (human reference peptide) "QVLGLAAYL" (SEQ ID NO: 733), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NOs: 352, 353 or 354.

[0216] In another embodiment, the antigenic peptide according to the present invention is a microbial sequence variant of a fragment of the tumor antigen CDH17 (human reference peptide), such as In another preferred embodiment, the antigenic peptide according to the present invention is a sequence variant of a fragment of the tumor antigen PAX2, such as an antigenic peptide comprising or consisting of the amino acid sequence shown in any one of SEQ ID NOs: 355-358. More preferably, the antigenic peptide according to the present invention is a sequence variant of the PAX2 fragment (human reference peptide) "GLDEVKSSL" (SEQ ID NO: 734), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NOs: 355, 356, 357 or 358.

[0217] In another embodiment, the antigenic peptide according to the present invention is a microbial sequence variant of a fragment of the tumor antigen CDH17 (human reference peptide), such as In another preferred embodiment, the antigenic peptide according to the present invention is a sequence variant of a fragment of the tumor antigen PCDHB16, such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in any one of SEQ ID NOs: 359-365. More preferably, the antigenic peptide according to the present invention is a sequence variant of the PCDHB16 fragment (human reference peptide) "FVLLSLSGA" (SEQ ID NO: 735), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 359. Even more preferably, the antigenic peptide according to the present invention is a sequence variant of the PCDHB16 fragment (human reference peptide) "SLFLFSVLL" (SEQ ID NO: 736), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 360. More preferably, the antigenic peptide according to the present invention is a sequence variant of the PCDHB16 fragment (human reference peptide) "SLTVYLVVA" (SEQ ID NO: 737), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 361. More preferably, the antigenic peptide according to the present invention is a sequence variant of the PCDHB16 fragment (human reference peptide) "VLLFVAVRL" (SEQ ID NO: 738), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 362, 363 or 364. More preferably, the antigenic peptide according to the present invention is a sequence variant of the PCDHB16 fragment (human reference peptide) "VSSLFLFSV" (SEQ ID NO: 739), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 365.

[0218] In another embodiment, the antigenic peptide according to the present invention is a fragment of the tumor antigen PIWIL1 (human reference peptide), such as a microbial sequence variant of "SIAGFVASI" (SEQ ID NO: 740). In another preferred embodiment, the antigenic peptide according to the present invention is a sequence variant of a fragment of the tumor antigen PIWIL1, such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 366. That is, the antigenic peptide according to the present invention comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 366 is a sequence variant of the PIWIL1 fragment (human reference peptide) "SIAGFVASI" (SEQ ID NO: 740).

[0219] In another embodiment, the antigenic peptide according to the present invention is a fragment of the tumor antigen PMEL (human reference peptide), such as a microbial sequence variant of "ILLVLMAVV" (SEQ ID NO: 741), "LIVGILLVL" (SEQ ID NO: 742), "LMAVVLASL" (SEQ ID NO: 743), "PLLDGTATL" (SEQ ID NO: 744), "SLADTNSLA" (SEQ ID NO: 745) or "VLQAAIPLT" (SEQ ID NO: 746). In another preferred embodiment, the antigenic peptide according to the present invention is a sequence variant of a fragment of the tumor antigen PMEL, such as an antigenic peptide comprising or consisting of the amino acid sequence shown in any one of SEQ ID NOs: 367-379. More preferably, the antigenic peptide according to the present invention is a sequence variant of the PMEL fragment (human reference peptide) "ILLVLMAVV" (SEQ ID NO: 741), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 367. More preferably, the antigenic peptide according to the present invention is a sequence variant of the PMEL fragment (human reference peptide) "LIVGILLVL" (SEQ ID NO: 742), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 368, 369, 370, 371, 372 or 373. More preferably, the antigenic peptide according to the present invention is a sequence variant of the PMEL fragment (human reference peptide) "LMAVVLASL" (SEQ ID NO: 743), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 374 or 375. More preferably, the antigenic peptide according to the present invention is a sequence variant of the PMEL fragment (human reference peptide) "PLLDGTATL" (SEQ ID NO: 744), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 376. More preferably, the antigenic peptide according to the present invention is a sequence variant of the PMEL fragment (human reference peptide) "SLADTNSLA" (SEQ ID NO: 745), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 377 or 378. Still more preferably, the antigenic peptide according to the present invention is a sequence variant of the PMEL fragment (human reference peptide) "VLQAAIPLT" (SEQ ID NO: 746), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 379.

[0220] In another embodiment, the antigenic peptide according to the present invention is a fragment of the tumor antigen PRAME (human reference peptide), such as a microbial sequence variant of "AVLDGLDVL" (SEQ ID NO: 747), "QLLALLPSL" (SEQ ID NO: 748), "RLRELLCEL" (SEQ ID NO: 749), or "VLYPVPLES" (SEQ ID NO: 750). In another preferred embodiment, the antigenic peptide according to the present invention is a sequence variant of a fragment of the tumor antigen PRAME, such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in any one of SEQ ID NOs: 380-387. More preferably, the antigenic peptide according to the present invention is a sequence variant of the PRAME fragment (human reference peptide) "AVLDGLDVL" (SEQ ID NO: 747), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NOs: 380 or 381. More preferably, the antigenic peptide according to the present invention is a sequence variant of the PRAME fragment (human reference peptide) "QLLALLPSL" (SEQ ID NO: 748), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 382, ​​383, 384 or 385. More preferably, the antigenic peptide according to the present invention is a sequence variant of the PRAME fragment (human reference peptide) "RLRELLCEL" (SEQ ID NO: 749), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 386. More preferably, the antigenic peptide according to the present invention is a sequence variant of the PRAME fragment (human reference peptide) "VLYPVPLES" (SEQ ID NO: 750), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 387.

[0221] In another embodiment, the antigenic peptide according to the present invention is a fragment of the tumor antigen PTHLH (human reference peptide), such as a microbial sequence variant of "AVFLLSYAV" (SEQ ID NO: 751). In another preferred embodiment, the antigenic peptide according to the present invention is a sequence variant of a fragment of the tumor antigen PTHLH, such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 388. That is, the antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 388 according to the present invention is a sequence variant of the PTHLH fragment (human reference peptide) "AVFLLSYAV" (SEQ ID NO: 751).

[0222] In another embodiment, the antigenic peptide according to the present invention is a fragment of the tumor antigen SEMG1 (human reference peptide), such as a microbial sequence variant of "FVLSLLLIL" (SEQ ID NO: 752), "IIFVLSLLL" (SEQ ID NO: 753), or "LILEKQAAV" (SEQ ID NO: 754). In another preferred embodiment, the antigenic peptide according to the present invention is a sequence variant of a fragment of the tumor antigen SEMG1, such as an antigenic peptide comprising or consisting of the amino acid sequence shown in any one of SEQ ID NOs: 389-400. More preferably, the antigenic peptide according to the present invention is a sequence variant of the SEMG1 fragment (human reference peptide) "FVLSLLLIL" (SEQ ID NO: 752), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NOs: 389, 390, 391, 392, 393, 394, 395, 396, or 397. More preferably, the antigenic peptide according to the present invention is a sequence variant of the SEMG1 fragment (human reference peptide) "IIFVLSLLL" (SEQ ID NO: 753), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 398 or 399. Still more preferably, the antigenic peptide according to the present invention is a sequence variant of the SEMG1 fragment (human reference peptide) "LILEKQAAV" (SEQ ID NO: 754), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 400.

[0223] In another embodiment, the antigenic peptide according to the present invention is a fragment of the tumor antigen SERHL2 (human reference peptide), such as a microbial sequence variant of "LISELKLAV" (SEQ ID NO: 755), "RAIEHVLQV" (SEQ ID NO: 756), "SSFDRLIPL" (SEQ ID NO: 757) or "TLKEQFQFV" (SEQ ID NO: 758). In another preferred embodiment, the antigenic peptide according to the present invention is a sequence variant of a fragment of the tumor antigen SERHL2, such as an antigenic peptide comprising or consisting of the amino acid sequence shown in any one of SEQ ID NOs: 401–405. More preferably, the antigenic peptide according to the present invention is a sequence variant of the SERHL2 fragment (human reference peptide) "LISELKLAV" (SEQ ID NO: 755), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 401. And more preferably, the antigenic peptide according to the present invention is a sequence variant of the SERHL2 fragment (human reference peptide) "RAIEHVLQV" (SEQ ID NO: 756), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 402. And more preferably, the antigenic peptide according to the present invention is a sequence variant of the SERHL2 fragment (human reference peptide) "SSFDRLIPL" (SEQ ID NO: 757), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 403 or 404. And more preferably, the antigenic peptide according to the present invention is a sequence variant of the SERHL2 fragment (human reference peptide) "TLKEQFQFV" (SEQ ID NO: 758), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 405.

[0224] In another embodiment, the antigenic peptide according to the present invention is a fragment of the tumor antigen SLC45A3 (human reference peptide), such as a microbial biota sequence variant of "AILDSAFLL" (SEQ ID NO: 759), "AISLVFSLV" (SEQ ID NO: 760), "ALQILPYTL" (SEQ ID NO: 761), "ALTGFTFSA" (SEQ ID NO: 762), "AQLLLVNLL" (SEQ ID NO: 763), "CLFGLLTLI" (SEQ ID NO: 764), "GILLSLFLI" (SEQ ID NO: 765), "GLLPPPPAL" (SEQ ID NO: 766), "GLLTLIFLT" (SEQ ID NO: 767), "GLVAIYFAT" (SEQ ID NO: 768), "NLGALLPRL" (SEQ ID NO: 769) or "SVAAFPVAA" (SEQ ID NO: 770). In another preferred embodiment, the antigenic peptide according to the present invention is a sequence variant of a fragment of the tumor antigen SLC45A3, such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in any one of SEQ ID NOs: 406-427. More preferably, the antigenic peptide according to the present invention is a sequence variant of the SLC45A3 fragment (human reference peptide) "AILDSAFLL" (SEQ ID NO: 759), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 406. Even more preferably, the antigenic peptide according to the present invention is a sequence variant of the SLC45A3 fragment (human reference peptide) "AISLVFSLV" (SEQ ID NO: 760), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NOs: 407 or 408. Even more preferably, the antigenic peptide according to the present invention is a sequence variant of the SLC45A3 fragment (human reference peptide) "ALQILPYTL" (SEQ ID NO: 761), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 409. More preferably, the antigenic peptide according to the present invention is a sequence variant of the SLC45A3 fragment (human reference peptide) "ALTGFTFSA" (SEQ ID NO: 762), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 410. Still more preferably, the antigenic peptide according to the present invention is a sequence variant of the SLC45A3 fragment (human reference peptide) "AQLLLVNLL" (SEQ ID NO: 763), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 411.More preferably, the antigenic peptide according to the present invention is a sequence variant of the SLC45A3 fragment (human reference peptide) "CLFGLLTLI" (SEQ ID NO: 764), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 412, 413, 414 or 415. More preferably, the antigenic peptide according to the present invention is a sequence variant of the SLC45A3 fragment (human reference peptide) "GILLSLFLI" (SEQ ID NO: 765), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 416 or 417. More preferably, the antigenic peptide according to the present invention is a sequence variant of the SLC45A3 fragment (human reference peptide) "GLLPPPPAL" (SEQ ID NO: 766), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 418. More preferably, the antigenic peptide according to the present invention is a sequence variant of the SLC45A3 fragment (human reference peptide) "GLLTLIFLT" (SEQ ID NO: 767), such as an antigenic peptide comprising or consisting of the amino acid sequence of SEQ ID NO: 419, 420, 421, 422, or 423. More preferably, the antigenic peptide according to the present invention is a sequence variant of the SLC45A3 fragment (human reference peptide) "GLVAIYFAT" (SEQ ID NO: 768), such as an antigenic peptide comprising or consisting of the amino acid sequence of SEQ ID NO: 424. More preferably, the antigenic peptide according to the present invention is a sequence variant of the SLC45A3 fragment (human reference peptide) "NLGALLPRL" (SEQ ID NO: 769), such as an antigenic peptide comprising or consisting of the amino acid sequence of SEQ ID NO: 425 or 426. More preferably, the antigenic peptide according to the present invention is a sequence variant of the SLC45A3 fragment (human reference peptide) "SVAAFPVAA" (SEQ ID NO: 770), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 427.

[0225] In another embodiment, the antigenic peptide according to the present invention is a fragment of the tumor antigen SLC6A3 (human reference peptide), such as a microbial sequence variant of "FLLSLFCVT" (SEQ ID NO: 771), "FSLGVGFGV" (SEQ ID NO: 772), "GLIDEFQLL" (SEQ ID NO: 773), "GMESVITGL" (SEQ ID NO: 774), "ILFGVLIEA" (SEQ ID NO: 775), "KIDFLLSVI" (SEQ ID NO: 776), "LLFMVIAGM" (SEQ ID NO: 777), "LVPYLLFMV" (SEQ ID NO: 778), or "QLTACLVLV" (SEQ ID NO: 779). In another preferred embodiment, the antigenic peptide according to the present invention is a sequence variant of a fragment of the tumor antigen SLC6A3, such as an antigenic peptide comprising or consisting of the amino acid sequence shown in any one of SEQ ID NOs: 428-441. More preferably, the antigenic peptide according to the present invention is a sequence variant of the SLC6A3 fragment (human reference peptide) "FLLSLFCVT" (SEQ ID NO: 771), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 428, 429 or 430. Even more preferably, the antigenic peptide according to the present invention is a sequence variant of the SLC6A3 fragment (human reference peptide) "FSLGVGFGV" (SEQ ID NO: 772), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 431 or 432. Even more preferably, the antigenic peptide according to the present invention is a sequence variant of the SLC6A3 fragment (human reference peptide) "GLIDEFQLL" (SEQ ID NO: 773), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 433. Even more preferably, the antigenic peptide according to the present invention is a sequence variant of the SLC6A3 fragment (human reference peptide) "GMESVITGL" (SEQ ID NO: 774), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 434. More preferably, the antigenic peptide according to the present invention is a sequence variant of the SLC6A3 fragment (human reference peptide) "ILFGVLIEA" (SEQ ID NO: 775), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 435 or 436. Still more preferably, the antigenic peptide according to the present invention is a sequence variant of the SLC6A3 fragment (human reference peptide) "KIDFLLSVI" (SEQ ID NO: 776), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 437.More preferably, the antigenic peptide according to the present invention is a sequence variant of the SLC6A3 fragment (human reference peptide) "LLFMVIAGM" (SEQ ID NO: 777), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 438 or 439. More preferably, the antigenic peptide according to the present invention is a sequence variant of the SLC6A3 fragment (human reference peptide) "LVPYLLFMV" (SEQ ID NO: 778), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 440. More preferably, the antigenic peptide according to the present invention is a sequence variant of the SLC6A3 fragment (human reference peptide) "QLTACLVLV" (SEQ ID NO: 779), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 441.

[0226] In another embodiment, the antigenic peptide according to the present invention is a fragment of the tumor antigen SNX31 (human reference peptide), such as a microbial sequence variant of "MISEKMVKL" (SEQ ID NO: 780). In another preferred embodiment, the antigenic peptide according to the present invention is a sequence variant of a fragment of the tumor antigen SNX31, such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 442. That is, the antigenic peptide according to the present invention comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 442 is a sequence variant of the SNX31 fragment (human reference peptide) "MISEKMVKL" (SEQ ID NO: 780).

[0227] In another embodiment, the antigenic peptide according to the present invention is a fragment of the tumor antigen SOX11 (human reference peptide), such as a microbial sequence variant of "LMFDLSLNF" (SEQ ID NO: 781). In another preferred embodiment, the antigenic peptide according to the present invention is a sequence variant of a fragment of the tumor antigen SOX11, such as an antigenic peptide comprising or consisting of the amino acid sequence shown in any one of SEQ ID NOs: 443–445. More preferably, the antigenic peptide according to the present invention is a sequence variant of the SOX11 fragment (human reference peptide) "LMFDLSLNF" (SEQ ID NO: 781), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NOs: 443, 444 or 445.

[0228] In another embodiment, the antigenic peptide according to the present invention is a microbial sequence variant of a fragment of the tumor antigen SOX17 (human reference peptide), such as "ALPAVMAGL" (SEQ ID NO: 782) or "GLAEPQAAA" (SEQ ID NO: 783). In another preferred embodiment, the antigenic peptide according to the present invention is a sequence variant of a fragment of the tumor antigen SOX17, such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in any one of SEQ ID NOs: 446-449. More preferably, the antigenic peptide according to the present invention is a sequence variant of the SOX17 fragment (human reference peptide) "ALPAVMAGL" (SEQ ID NO: 782), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 446. Even more preferably, the antigenic peptide according to the present invention is a sequence variant of the SOX17 fragment (human reference peptide) "GLAEPQAAA" (SEQ ID NO: 783), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NOs: 447, 448, or 449.

[0229] In another embodiment, the antigenic peptide according to the present invention is a fragment of the tumor antigen SPINK1 (human reference peptide), such as a microbial sequence variant of "GIFLLSALA" (SEQ ID NO: 784). In another preferred embodiment, the antigenic peptide according to the present invention is a sequence variant of a fragment of the tumor antigen SPINK1, such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 450. That is, the antigenic peptide according to the present invention comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 450 is a sequence variant of the SPINK1 fragment (human reference peptide) "GIFLLSALA" (SEQ ID NO: 784).

[0230] In another embodiment, the antigenic peptide according to the present invention is a fragment of the tumor antigen STEAP1 (human reference peptide), such as a microbial sequence variant of "ASLTFLYTL" (SEQ ID NO: 785), "AVLHAIYSL" (SEQ ID NO: 786), "FFFAVLHAI" (SEQ ID NO: 787), "GVIAAIVQL" (SEQ ID NO: 788), "KIAAIIASL" (SEQ ID NO: 789), "LIFKSILFL" (SEQ ID NO: 790), "LLLGTIHAL" (SEQ ID NO: 791), "LLSFFFAVL" (SEQ ID NO: 792), "MIAVFLPIV" (SEQ ID NO: 793), or "SLLLGTIHA" (SEQ ID NO: 794). In another preferred embodiment, the antigenic peptide according to the present invention is a sequence variant of a fragment of the tumor antigen STEAP1, such as an antigenic peptide comprising or consisting of the amino acid sequence shown in any one of SEQ ID NOs: 451-468. More preferably, the antigenic peptide according to the present invention is a sequence variant of the STEAP1 fragment (human reference peptide) "ASLTFLYTL" (SEQ ID NO: 785), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 451. Still more preferably, the antigenic peptide according to the present invention is a sequence variant of the STEAP1 fragment (human reference peptide) "AVLHAIYSL" (SEQ ID NO: 786), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 452. Still more preferably, the antigenic peptide according to the present invention is a sequence variant of the STEAP1 fragment (human reference peptide) "FFFAVLHAI" (SEQ ID NO: 787), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 453. Still more preferably, the antigenic peptide according to the present invention is a sequence variant of the STEAP1 fragment (human reference peptide) "GVIAAIVQL" (SEQ ID NO: 788), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 454, 455, 456, or 457. And more preferably, the antigenic peptide according to the present invention is a sequence variant of the STEAP1 fragment (human reference peptide) "KIAAIIASL" (SEQ ID NO: 789), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 458, 459 or 460.More preferably, the antigenic peptide according to the present invention is a sequence variant of the STEAP1 fragment (human reference peptide) "LIFKSILFL" (SEQ ID NO: 790), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 461. More preferably, the antigenic peptide according to the present invention is a sequence variant of the STEAP1 fragment (human reference peptide) "LLLGTIHAL" (SEQ ID NO: 791), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 462. More preferably, the antigenic peptide according to the present invention is a sequence variant of the STEAP1 fragment (human reference peptide) "LLSFFFAVL" (SEQ ID NO: 792), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 463, 464, or 465. More preferably, the antigenic peptide according to the present invention is a sequence variant of the STEAP1 fragment (human reference peptide) "MIAVFLPIV" (SEQ ID NO: 793), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 466. More preferably, the antigenic peptide according to the present invention is a sequence variant of the STEAP1 fragment (human reference peptide) "SLLLGTIHA" (SEQ ID NO: 794), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 467 or 468.

[0231] In another embodiment, the antigenic peptide according to the present invention is a fragment of the tumor antigen TBL1Y (human reference peptide), such as a microbial sequence variant of "SLSLIVAVI" (SEQ ID NO: 795). In another preferred embodiment, the antigenic peptide according to the present invention is a sequence variant of a fragment of the tumor antigen TBL1Y, such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in any one of SEQ ID NOs: 469-470. More preferably, the antigenic peptide according to the present invention is a sequence variant of the TBL1Y fragment (human reference peptide) "SLSLIVAVI" (SEQ ID NO: 795), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NOs: 469 or 470.

[0232] In another embodiment, the antigenic peptide according to the present invention is a fragment of the tumor antigen TDRD1 (human reference peptide), such as a microbial sequence variant of "IISPNLFYA" (SEQ ID NO: 796), "LLDHVLIEM" (SEQ ID NO: 797), "VLIDEHLVL" (SEQ ID NO: 798), or "YSSEVLEYM" (SEQ ID NO: 799). In another preferred embodiment, the antigenic peptide according to the present invention is a sequence variant of a fragment of the tumor antigen TDRD1, such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in any one of SEQ ID NOs: 471-474. More preferably, the antigenic peptide according to the present invention is a sequence variant of the TDRD1 fragment (human reference peptide) "IISPNLFYA" (SEQ ID NO: 796), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 471. More preferably, the antigenic peptide according to the present invention is a sequence variant of the TDRD1 fragment (human reference peptide) "LLDHVLIEM" (SEQ ID NO: 797), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 472. More preferably, the antigenic peptide according to the present invention is a sequence variant of the TDRD1 fragment (human reference peptide) "VLIDEHLVL" (SEQ ID NO: 798), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 473. More preferably, the antigenic peptide according to the present invention is a sequence variant of the TDRD1 fragment (human reference peptide) "YSSEVLEYM" (SEQ ID NO: 799), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 474.

[0233] In another embodiment, the antigenic peptide according to the present invention is a fragment of the tumor antigen TOP2A (human reference peptide), such as a microbial sequence variant of "ILLRPDTYI" (SEQ ID NO: 800), "LMMTIINLA" (SEQ ID NO: 801), "QLAGSVAEM" (SEQ ID NO: 802), "SLMMTIINL" (SEQ ID NO: 803), "TMLSSLARL" (SEQ ID NO: 804), or "YIFTMLSSL" (SEQ ID NO: 805). In another preferred embodiment, the antigenic peptide according to the present invention is a sequence variant of a fragment of the tumor antigen TOP2A, such as an antigenic peptide comprising or consisting of the amino acid sequence shown in any one of SEQ ID NOs: 475-483. More preferably, the antigenic peptide according to the present invention is a sequence variant of the TOP2A fragment (human reference peptide) "ILLRPDTYI" (SEQ ID NO: 800), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 475. More preferably, the antigenic peptide according to the present invention is a sequence variant of the TOP2A fragment (human reference peptide) "LMMTIINLA" (SEQ ID NO: 801), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NOs: 476, 477, or 478. More preferably, the antigenic peptide according to the present invention is a sequence variant of the TOP2A fragment (human reference peptide) "QLAGSVAEM" (SEQ ID NO: 802), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NOs: 479 or 480. More preferably, the antigenic peptide according to the present invention is a sequence variant of the TOP2A fragment (human reference peptide) "SLMMTIINL" (SEQ ID NO: 803), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 481. More preferably, the antigenic peptide according to the present invention is a sequence variant of the TOP2A fragment (human reference peptide) "TMLSSLARL" (SEQ ID NO: 804), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 482. And more preferably, the antigenic peptide according to the present invention is a sequence variant of the TOP2A fragment (human reference peptide) "YIFTMLSSL" (SEQ ID NO: 805), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 483.

[0234] In another embodiment, the antigenic peptide according to the present invention is a fragment of the tumor antigen TPTE (human reference peptide), such as a microbial sequence variant of "DLAGVIIEL" (SEQ ID NO: 806), "FGLFGVFLV" (SEQ ID NO: 807), "GLFGVFLVL" (SEQ ID NO: 808), "ILDTAIIVI" (SEQ ID NO: 809), "IVSSFAFGL" (SEQ ID NO: 810), "RLLRLIILL" (SEQ ID NO: 811), "SLAIALFFL" (SEQ ID NO: 812) or "YFWLHTSFI" (SEQ ID NO: 813). In another preferred embodiment, the antigenic peptide according to the present invention is a sequence variant of a fragment of the tumor antigen TPTE, such as an antigenic peptide comprising or consisting of the amino acid sequence shown in any one of SEQ ID NOs: 484-504. More preferably, the antigenic peptide according to the present invention is a sequence variant of the TPTE fragment (human reference peptide) "DLAGVIIEL" (SEQ ID NO: 806), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in any one of SEQ ID NOs: 484-504. NO: 484, 485, 486, 487, 488, 489 or 490. More preferably, the antigenic peptide according to the present invention is a sequence variant of the TPTE fragment (human reference peptide) "FGLFGVFLV" (SEQ ID NO: 807), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 491, 492, 493 or 494. More preferably, the antigenic peptide according to the present invention is a sequence variant of the TPTE fragment (human reference peptide) "GLFGVFLVL" (SEQ ID NO: 808), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 495, 496 or 497. More preferably, the antigenic peptide according to the present invention is a sequence variant of the TPTE fragment (human reference peptide) "ILDTAIIVI" (SEQ ID NO: 809), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 810. The amino acid sequence shown in SEQ ID NO: 498 or 499. Furthermore, more preferably, the antigenic peptide according to the present invention is a sequence variant of the TPTE fragment (human reference peptide) "IVSSFAFGL" (SEQ ID NO: 810), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 500 or 501. Furthermore, more preferably, the antigenic peptide according to the present invention is a sequence variant of the TPTE fragment (human reference peptide) "RLLRLIILL" (SEQ ID NO: 811), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 502.More preferably, the antigenic peptide according to the present invention is a sequence variant of the TPTE fragment (human reference peptide) "SLAIALFFL" (SEQ ID NO: 812), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 503. Still more preferably, the antigenic peptide according to the present invention is a sequence variant of the TPTE fragment (human reference peptide) "YFWLHTSFI" (SEQ ID NO: 813), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 504.

[0235] In another embodiment, the antigenic peptide according to the present invention is a fragment of the tumor antigen TRPM8 (human reference peptide), such as a microbial sequence variant of "AMFGYTVGT" (SEQ ID NO: 814), "FIAGIVFRL" (SEQ ID NO: 815), "FLLLFAYVL" (SEQ ID NO: 816), "LLFAYVLLM" (SEQ ID NO: 817), "LLLFAYVLL" (SEQ ID NO: 818), "LVLYSLVFV" (SEQ ID NO: 819), "NILLVNLLV" (SEQ ID NO: 820), "QIADVIASL" (SEQ ID NO: 821), "VLYSLVFVL" (SEQ ID NO: 822), or "YLVKINTKA" (SEQ ID NO: 823). In another preferred embodiment, the antigenic peptide according to the present invention is a sequence variant of a fragment of the tumor antigen TRPM8, such as an antigenic peptide comprising or consisting of the amino acid sequence shown in any one of SEQ ID NOs: 505-518. More preferably, the antigenic peptide according to the present invention is a sequence variant of the TRPM8 fragment (human reference peptide) "AMFGYTVGT" (SEQ ID NO: 814), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 505. Still more preferably, the antigenic peptide according to the present invention is a sequence variant of the TRPM8 fragment (human reference peptide) "FIAGIVFRL" (SEQ ID NO: 815), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 506. Still more preferably, the antigenic peptide according to the present invention is a sequence variant of the TRPM8 fragment (human reference peptide) "FLLLFAYVL" (SEQ ID NO: 816), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 507. Still more preferably, the antigenic peptide according to the present invention is a sequence variant of the TRPM8 fragment (human reference peptide) "LLFAYVLLM" (SEQ ID NO: 817), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 508 or 509. More preferably, the antigenic peptide according to the present invention is a sequence variant of the TRPM8 fragment (human reference peptide) "LLLFAYVLL" (SEQ ID NO: 818), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 510. More preferably, the antigenic peptide according to the present invention is a sequence variant of the TRPM8 fragment (human reference peptide) "LVLYSLVFV" (SEQ ID NO: 819), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 511.More preferably, the antigenic peptide according to the present invention is a sequence variant of the TRPM8 fragment (human reference peptide) "NILLVNLLV" (SEQ ID NO: 820), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 512. More preferably, the antigenic peptide according to the present invention is a sequence variant of the TRPM8 fragment (human reference peptide) "QIADVIASL" (SEQ ID NO: 821), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 513, 514, 515 or 516. More preferably, the antigenic peptide according to the present invention is a sequence variant of the TRPM8 fragment (human reference peptide) "VLYSLVFVL" (SEQ ID NO: 822), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 517. More preferably, the antigenic peptide according to the present invention is a sequence variant of the TRPM8 fragment (human reference peptide) "YLVKINTKA" (SEQ ID NO: 823), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 518.

[0236] In another embodiment, the antigenic peptide according to the present invention is a microbial sequence variant of a fragment of the tumor antigen TYMS (human reference peptide), such as "FLDSLGFST" (SEQ ID NO: 824), "SLRDEFPLL" (SEQ ID NO: 825), or "VLEELLWFI" (SEQ ID NO: 826). In another preferred embodiment, the antigenic peptide according to the present invention is a sequence variant of a fragment of the tumor antigen TYMS, such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in any one of SEQ ID NOs: 519-524. More preferably, the antigenic peptide according to the present invention is a sequence variant of the TYMS fragment (human reference peptide) "FLDSLGFST" (SEQ ID NO: 824), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NOs: 519, 520, or 521. Even more preferably, the antigenic peptide according to the present invention is a sequence variant of the TYMS fragment (human reference peptide) "SLRDEFPLL" (SEQ ID NO: 825), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NOs: 522 or 523. And more preferably, the antigenic peptide according to the present invention is a sequence variant of the TYMS fragment (human reference peptide) "VLEELLWFI" (SEQ ID NO: 826), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 524.

[0237] In another embodiment, the antigenic peptide according to the present invention is a fragment of the tumor antigen TYR (human reference peptide), such as a microbial sequence variant of "ALLAGLVSL" (SEQ ID NO: 827), "AMVGAVLTA" (SEQ ID NO: 828), "ISSDYVIPI" (SEQ ID NO: 829), "LLAGLVSLL" (SEQ ID NO: 830), "LLSPASFFS" (SEQ ID NO: 831), "MVGAVLTAL" (SEQ ID NO: 832), or "VLTALLAGL" (SEQ ID NO: 833). In another preferred embodiment, the antigenic peptide according to the present invention is a sequence variant of a fragment of the tumor antigen TYR, such as an antigenic peptide comprising or consisting of the amino acid sequence shown in any one of SEQ ID NOs: 525-539. More preferably, the antigenic peptide according to the present invention is a sequence variant of the TYR fragment (human reference peptide) "ALLAGLVSL" (SEQ ID NO: 827), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 525 or 526. More preferably, the antigenic peptide according to the present invention is a sequence variant of the TYR fragment (human reference peptide) "AMVGAVLTA" (SEQ ID NO: 828), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NOs: 527, 528, 529, or 530. More preferably, the antigenic peptide according to the present invention is a sequence variant of the TYR fragment (human reference peptide) "ISSDYVIPI" (SEQ ID NO: 829), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 531. More preferably, the antigenic peptide according to the present invention is a sequence variant of the TYR fragment (human reference peptide) "LLAGLVSLL" (SEQ ID NO: 830), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 532. More preferably, the antigenic peptide according to the present invention is a sequence variant of the TYR fragment (human reference peptide) "LLSPASFFS" (SEQ ID NO: 831), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 533. And more preferably, the antigenic peptide according to the present invention is a sequence variant of the TYR fragment (human reference peptide) "MVGAVLTAL" (SEQ ID NO: 832), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 534.And more preferably, the antigenic peptide according to the present invention is a sequence variant of the TYR fragment (human reference peptide) "VLTALLAGL" (SEQ ID NO: 833), such as an antigenic peptide comprising or consisting of the following amino acid sequence: SEQ ID NO: 535, 536, 537, 538 or 539.

[0238] In another embodiment, the antigenic peptide according to the present invention is a fragment of the tumor antigen UPK2 (human reference peptide), such as a microbial sequence variant of "ALTESLLVA" (SEQ ID NO: 834), "LLALLSPGA" (SEQ ID NO: 835), "LVLGFIIAL" (SEQ ID NO: 836), "SLSGLLSPA" (SEQ ID NO: 837), "TLPLILILL" (SEQ ID NO: 838), "VLGFIIALA" (SEQ ID NO: 839), or "VVITVLLSV" (SEQ ID NO: 840). In another preferred embodiment, the antigenic peptide according to the present invention is a sequence variant of a fragment of the tumor antigen UPK2, such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in any one of SEQ ID NOs: 540-556. More preferably, the antigenic peptide according to the present invention is a sequence variant of the UPK2 fragment (human reference peptide) "ALTESLLVA" (SEQ ID NO: 834), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NOs: 540, 541, or 542. More preferably, the antigenic peptide according to the present invention is a sequence variant of the UPK2 fragment (human reference peptide) "LLALLSPGA" (SEQ ID NO: 835), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 543. More preferably, the antigenic peptide according to the present invention is a sequence variant of the UPK2 fragment (human reference peptide) "LVLGFIIAL" (SEQ ID NO: 836), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 544, 545, 546, or 547. More preferably, the antigenic peptide according to the present invention is a sequence variant of the UPK2 fragment (human reference peptide) "SLSGLLSPA" (SEQ ID NO: 837), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 548 or 549. More preferably, the antigenic peptide according to the present invention is a sequence variant of the UPK2 fragment (human reference peptide) "TLPLILILL" (SEQ ID NO: 838), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 550. And more preferably, the antigenic peptide according to the present invention is a sequence variant of the UPK2 fragment (human reference peptide) "VLGFIIALA" (SEQ ID NO: 839), such as an antigenic peptide comprising or consisting of the following amino acid sequence: SEQ ID NO: 551, 552, 553 or 554.And more preferably, the antigenic peptide according to the present invention is a sequence variant of the UPK2 fragment (human reference peptide) "VVITVLLSV" (SEQ ID NO: 840), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 555 or 556.

[0239] In another embodiment, the antigenic peptide according to the present invention is a fragment of the tumor antigen VCAM1 (human reference peptide), such as a microbial sequence variant of "AQIGDSVML" (SEQ ID NO: 841), "FASSLIIPA" (SEQ ID NO: 842), "KSIDGAYTI" (SEQ ID NO: 843), or "SILEEGSSV" (SEQ ID NO: 844). In another preferred embodiment, the antigenic peptide according to the present invention is a sequence variant of a fragment of the tumor antigen VCAM1, such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in any one of SEQ ID NOs: 557-560. More preferably, the antigenic peptide according to the present invention is a sequence variant of the VCAM1 fragment (human reference peptide) "AQIGDSVML" (SEQ ID NO: 841), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 557. More preferably, the antigenic peptide according to the present invention is a sequence variant of the VCAM1 fragment (human reference peptide) "FASSLIIPA" (SEQ ID NO: 842), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 558. More preferably, the antigenic peptide according to the present invention is a sequence variant of the VCAM1 fragment (human reference peptide) "KSIDGAYTI" (SEQ ID NO: 843), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 559. More preferably, the antigenic peptide according to the present invention is a sequence variant of the VCAM1 fragment (human reference peptide) "SILEEGSSV" (SEQ ID NO: 844), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 560.

[0240] In another embodiment, the antigenic peptide according to the present invention is a fragment of the tumor antigen WFDC2 (human reference peptide), such as a microbial sequence variant of "LLFGFTLVS" (SEQ ID NO: 845), "LLLFGFTLV" (SEQ ID NO: 846), or "RLGPLAAAL" (SEQ ID NO: 847). In another preferred embodiment, the antigenic peptide according to the present invention is a sequence variant of a fragment of the tumor antigen WFDC2, such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in any one of SEQ ID NOs: 561-568. More preferably, the antigenic peptide according to the present invention is a sequence variant of the WFDC2 fragment (human reference peptide) "LLFGFTLVS" (SEQ ID NO: 845), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NOs: 561, 562, 563, 564, or 565. More preferably, the antigenic peptide according to the present invention is a sequence variant of the WFDC2 fragment (human reference peptide) "LLLFGFTLV" (SEQ ID NO: 846), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 566. Still more preferably, the antigenic peptide according to the present invention is a sequence variant of the WFDC2 fragment (human reference peptide) "RLGPLAAAL" (SEQ ID NO: 847), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 567 or 568.

[0241] In another embodiment, the antigenic peptide according to the present invention is a fragment of the tumor antigen WT1 (human reference peptide), such as a microbial sequence variant of "DLNALLPAV" (SEQ ID NO: 848). In another preferred embodiment, the antigenic peptide according to the present invention is a sequence variant of a fragment of the tumor antigen WT1, such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 569. That is, the antigenic peptide according to the present invention comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 569 is a sequence variant of the WT1 fragment (human reference peptide) "DLNALLPAV" (SEQ ID NO: 848).

[0242] In another embodiment, the antigenic peptide according to the present invention is a fragment of the tumor antigen ZEB1 (human reference peptide), such as a microbial sequence variant of "ILIPQVAYT" (SEQ ID NO: 849), "NLSDIQNVL" (SEQ ID NO: 850), or "VQAVVLPTV" (SEQ ID NO: 851). In another preferred embodiment, the antigenic peptide according to the present invention is a sequence variant of a fragment of the tumor antigen ZEB1, such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in any one of SEQ ID NOs: 570-574. More preferably, the antigenic peptide according to the present invention is a sequence variant of the ZEB1 fragment (human reference peptide) "ILIPQVAYT" (SEQ ID NO: 849), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 570 or 571. More preferably, the antigenic peptide according to the present invention is a sequence variant of the ZEB1 fragment (human reference peptide) "NLSDIQNVL" (SEQ ID NO: 850), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 572 or 573. Still more preferably, the antigenic peptide according to the present invention is a sequence variant of the ZEB1 fragment (human reference peptide) "VQAVVLPTV" (SEQ ID NO: 851), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 574.

[0243] In another embodiment, the antigenic peptide according to the present invention is a microbial sequence variant of a fragment of the tumor antigen ZNF165 (human reference peptide), such as "LVLEQFLTI" (SEQ ID NO: 852) or "RISGYISEA" (SEQ ID NO: 853). In another preferred embodiment, the antigenic peptide according to the present invention is a sequence variant of a fragment of the tumor antigen ZNF165, such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in any one of SEQ ID NOs: 575-578. More preferably, the antigenic peptide according to the present invention is a sequence variant of the ZNF165 fragment (human reference peptide) "LVLEQFLTI" (SEQ ID NO: 852), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NOs: 575, 576, or 577. Even more preferably, the antigenic peptide according to the present invention is a sequence variant of the ZNF165 fragment (human reference peptide) "RISGYISEA" (SEQ ID NO: 853), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 578.

[0244] In another embodiment, the antigenic peptide according to the present invention is a microbial sequence variant of a fragment of the tumor antigen ZNF280A (human reference peptide), such as "AMTDISSLA" (SEQ ID NO: 854) or "VLLSNFYYG" (SEQ ID NO: 855). In another preferred embodiment, the antigenic peptide according to the present invention is a sequence variant of a fragment of the tumor antigen ZNF280A, such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in any one of SEQ ID NOs: 579-580. More preferably, the antigenic peptide according to the present invention is a sequence variant of the ZNF280A fragment (human reference peptide) "AMTDISSLA" (SEQ ID NO: 854), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 579. Even more preferably, the antigenic peptide according to the present invention is a sequence variant of the ZNF280A fragment (human reference peptide) "VLLSNFYYG" (SEQ ID NO: 855), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 580.

[0245] Preferably, the antigenic peptide according to the present invention comprises or consists of the amino acid sequence represented by any one of SEQ ID NOs: 1-160, 162-253, and 255-580. More preferably, the antigenic peptide according to the present invention comprises or consists of the amino acid sequence represented by any one of SEQ ID NOs: 30, 31, 32, 87, 97, 145, 193, 194, 220, 221, 255, 521, and 524. Even more preferably, the antigenic peptide according to the present invention comprises or consists of the amino acid sequence represented by any one of SEQ ID NOs: 30, 31, 32, 87, 97, 193, 194, 220, 255, 521, and 524. Even more preferably, the antigenic peptide according to the present invention comprises or consists of the amino acid sequence represented by any one of SEQ ID NOs: 30, 31, 32, 87, 97, 194, 220, 255, 521, and 524. Most preferably, the antigenic peptide according to the present invention comprises or consists of the amino acid sequence shown in any one of SEQ ID NOs: 30, 32, 87, 97 and 194.

[0246] Furthermore, it is particularly preferred that the antigenic peptide according to the present invention comprises or consists of the amino acid sequence shown in any one of SEQ ID NOs: 30, 32, 194, 220, 254, or 255. Most preferably, the antigenic peptide according to the present invention comprises or consists of the amino acid sequence shown in SEQ ID NOs: 30 or 32. Most preferably, the antigenic peptide according to the present invention comprises or consists of the amino acid sequence shown in SEQ ID NOs: 194 or 220. Most preferably, the antigenic peptide according to the present invention comprises or consists of the amino acid sequence shown in SEQ ID NOs: 254 or 255.

[0247] As shown in the examples herein, specific antigenic peptides according to the present invention allow the generation of an enhanced strong immune response against themselves and, most importantly, against peptides contained in tumor antigens that have amino acid similarity thereto, even though the human reference peptide contained in the tumor antigen may be tolerogenic.

[0248] Advantageously, the antigenic peptides according to the invention may be in the form of immunogenic compounds, in particular for use in the prevention or treatment of cancer.

[0249] Immunogenic compounds comprising the antigenic peptide according to the present invention

[0250] In a further aspect, the present invention also provides an immunogenic compound comprising an antigenic peptide according to the present invention as described above. Specifically, the preferred embodiments of the above-mentioned antigenic peptides are also applicable to the immunogenic compounds according to the present invention. For example, the antigenic peptide included in the immunogenic compound preferably comprises or consists of the following: an amino acid sequence represented by any one of SEQ ID NOs: 1 to 580 and 861 to 887, such as an antigenic peptide comprising or consisting of the following: an amino acid sequence represented by any one of SEQ ID NOs: 1 to 580. For example, more preferably, the antigenic peptide according to the present invention comprises or consists of the following: an amino acid sequence represented by any one of SEQ ID NOs: 1–160, 162–253, and 255–580. For example, even more preferably, the antigenic peptide according to the present invention comprises or consists of the following: an amino acid sequence represented by any one of SEQ ID NOs: 30, 31, 32, 87, 97, 145, 193, 194, 220, 221, 255, 521, and 524. For example, an antigenic peptide according to the present invention comprising or consisting of the amino acid sequence represented by any one of SEQ ID NOs: 30, 31, 32, 87, 97, 193, 194, 220, 255, 521, and 524 is more preferred. For example, an antigenic peptide according to the present invention comprising or consisting of the amino acid sequence represented by any one of SEQ ID NOs: 30, 31, 32, 87, 97, 194, 220, 255, 521, and 524 is still more preferred. For example, an antigenic peptide according to the present invention comprising or consisting of the amino acid sequence represented by any one of SEQ ID NOs: 30, 32, 87, 97, 194, 220, 255, 521, and 524 is most preferred. For example, an antigenic peptide according to the present invention comprising or consisting of the amino acid sequence represented by any one of SEQ ID NOs: 30, 32, 87, 97, and 194 is particularly preferred. Furthermore, a combination thereof is preferred, that is, the immunogenic compound comprises different antigenic peptides according to the present invention.

[0251] As used herein, the term "immunogenic compound" refers to a compound capable of inducing, increasing, prolonging or maintaining an immune response, particularly when administered to a mammal and especially a human subject.

[0252] In general, the term "immunogenic compound" includes all kinds of compounds comprising the antigenic peptide according to the present invention. For example, the antigenic peptide according to the present invention may be linked to a carrier molecule, or the antigenic peptide according to the present invention may be contained in a polypeptide or protein (the polypeptide or protein may exist "alone", i.e. not linked to any other compound, or the polypeptide or protein comprising the antigenic peptide may be linked to a carrier molecule).

[0253] Preferably, the immunogenic compound according to the present invention comprises an antigenic peptide and a carrier molecule, specifically wherein the antigenic peptide (or a polypeptide or protein comprising the antigenic peptide) is connected to a carrier molecule. Preferred carrier molecules are carrier proteins or carrier peptides. According to a preferred embodiment, the antigenic peptide as defined above or the polypeptide / protein comprising the antigenic peptide is, for example, connected to a carrier protein or carrier peptide by a covalent or non-covalent bond. Alternatively, such carrier proteins or carrier peptides as described herein can be co-administered (i.e., not as an "immunogenic compound," but as co-administration / combination therapy, as described below) in the form of an immunoadjuvant.

[0254] The carrier molecule can also be a lipid or lipid-like portion. In this case, the immunogenic compound can be a lipopeptide. As used herein, the term "lipopeptide" refers to a molecule comprising a lipid or lipid-like portion covalently linked to a peptide portion. In general, "lipid" is soluble in non-polar solvents, but generally "lipid" is not (or not easily) soluble in water. Examples of lipid or lipid-like portions include, but are not limited to, fatty acids, waxes, sterols, monoglycerides, diglycerides, triglycerides, and phospholipids. The lipid can be a fatty acid, a glycerolipid, a glycerophospholipid, a sphingolipid, a sterol lipid, a prenol lipid, a glycolipid, or a polyacetyl. Preferably, the lipid is a fatty acid or a derivative thereof (including monoglycerides, diglycerides, triglycerides, and phospholipids). Fatty acids typically comprise a hydrocarbon chain terminated by a carboxyl group. Fatty acids can be saturated or unsaturated. Fatty acids can be attached to functional groups, such as those containing oxygen, halogen, nitrogen, or sulfur. Preferred fatty acids are saturated or unsaturated long chain fatty acids, such as myristic acid (CH3(CH2) 12 COOH) or palmitic acid (CH3(CH2) 14 COOH), and phospholipids such as phosphatidylglycerol (PG).

[0255] Preferably, the antigenic peptides described herein or polypeptides / proteins comprising the antigenic peptides can be co-administered or, for example, covalently or non-covalently linked to proteins / peptides having immunoadjuvant properties, such as providing stimulation of CD4+ Th1 cells. Although the antigenic peptides described herein preferably bind to MHC class I, CD4+ helper epitopes can additionally be used to provide an effective immune response. Th1 helper cells can maintain effective dendritic cell (DC) activation and specific CTL activation by secreting interferon-γ (IFN-g), tumor necrosis factor-α (TNF-a) and interleukin-2 (IL-2) and enhancing the expression of costimulatory signals on DCs and T cells (Galaine et al., Interest of Tumor-Specific CD4 T Helper 1 Cells for Therapeutic Anticancer Vaccine. Vaccines (Basel). 2015 Jun 30; 3(3): 490-502).

[0256] For example, the adjuvant peptide / protein may preferably be a non-tumor antigen that restores immune memory or provides nonspecific assistance, or may be a specific tumor-derived helper peptide. Several helper peptides have been described in the literature for providing nonspecific T cell assistance, such as tetanus helper peptide, spike-shaped shellfish hemocyanin peptide or PADRE peptide (Adotévi et al., Targeting antitumor CD4 helper T cells with universal tumor-reactive helper peptides derived from telomerase for cancer vaccine. Hum Vaccin Immunother. 2013 May; 9(5): 1073-7, Slingluff CL, The present and future of peptide vaccines for cancer: single or multiple, long or short, alone or in combination? Cancer J. 2011 September-October; 17(5): 343-50). Therefore, tetanus helper peptide, spike-shaped shellfish hemocyanin peptide and PADRE peptide are preferred examples of such adjuvant peptides / proteins. In addition, specific tumor-derived helper peptides are preferred. Specific tumor-derived helper peptides are typically presented by MHC class II, specifically HLA-DR, HLA-DP, or HLA-DQ. Specific tumor-derived helper peptides can be fragments of sequences of shared, overexpressed tumor antigens, such as HER2, NY-ESO-1, hTERT, or IL13RA2. Such fragments are preferably at least 10 amino acids in length, more preferably at least 11 amino acids, even more preferably at least 12 amino acids, and most preferably at least 13 amino acids in length. Specifically, fragments of shared, overexpressed tumor antigens, such as HER2, NY-ESO-1, hTERT, or IL13RA2, having a length of 13 to 24 amino acids are preferred. Preferred fragments bind to MHC class II and can therefore be determined using the MHC class II binding prediction tool of the IEDB (Immune Epitope Database and Analysis Resource; supported by the National Institute of Allergy and Infectious Diseases, a division of the National Institutes of Health in the Department of Health and Human Services; URL: http: / / www.iedb.org / ; http: / / tools.iedb.org / mhcii / ).Preferably, the adjuvant peptide / protein may be an HHD-DR3 peptide of the sequence MAKTIAYDEEARRGLERGLN (SEQ ID NO: 856). Another preferred example is h-pAg T13L (sequence: TPPAYRPPNAPIL; SEQ ID NO: 860; Bhasin M, Singh H, Raghava GP (2003) MHCBN: a comprehensive database of MHC binding and non-binding peptides. Bioinformatics 19: 665–666). Other examples of preferred adjuvant peptides / proteins (particularly helper peptides) include UCP2 peptide (e.g., as described in WO 2013 / 135553 A1 or Dosset et al. Clin Cancer Res. 2012 Nov 15; 18(22): 6284-9) and BIRC5 peptide (e.g., as described in EP 2119726 A1 or Widenmeyer et al. Int J Cancer. 2012 Jul 1; 131(1): 140-9). The most preferred helper peptide is UCP2 peptide (amino acid sequence: KSVWSKLQSIGIRQH; SEQ ID NO: 859, e.g., as described in WO 2013 / 135553 A1 or Dosset et al., Clin Cancer Res. 2012 Nov 15; 18(22): 6284-95).

[0257] It is also preferred that the immunogenic compound according to the invention is a polypeptide or protein comprising an antigenic peptide according to the invention. Preferably, such a protein or polypeptide is a recombinant protein or polypeptide, such as a fusion protein. The term "recombinant" means that it does not exist in nature.

[0258] In a preferred embodiment, the immunogenic compound according to the present invention comprises or consists of a polypeptide of formula (I)

[0259] PepNt-CORE-PepCt (I)

[0260] in:

[0261] - "PepNt" consists of a polypeptide whose length varies between 0 and 500 amino acid residues and is located at the N-terminus of the polypeptide of formula (I);

[0262] - CORE consists of the antigenic peptide according to the invention as defined above; and

[0263] - "PepCt" consists of a polypeptide whose length varies between 0 and 500 amino acid residues and is located at the C-terminus of the polypeptide of formula (I).

[0264] For example, the immunogenic compound may comprise or consist of a polypeptide of formula (Ia) or (Ib)

[0265] PepNt-CORE (Ia); or

[0266] CORE-PepCt (Ib)

[0267] wherein "PepNt", "PepCt" and "CORE" are as defined above.

[0268] Preferably, the polypeptide of formula (I), (Ia) or (Ib) is a fusion peptide or fusion protein, in particular a recombinant fusion peptide or protein.

[0269] It is also preferred that the polypeptide or immunogenic compound as defined above comprises 9 to 1000 amino acids; it comprises 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65 400, 450, 500, 600, 700, 800, 900, and 1000 amino acids. Therefore, the lengths of "PepNt" and "PepCt," if applicable, may be defined accordingly.

[0270] 47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110 170, 180, 190, 200, 250, 300, 350, 400, 450, and 500 amino acid residues.

[0271] The types of carrier molecules used to generate the immunogenic compounds of the present invention (e.g., immunogenic compounds comprising or consisting of a polypeptide of Formula (I) linked to a carrier molecule) are well within the purview of those skilled in the art. Specifically, the function of the carrier molecule is to provide cytokine help (or T cell help) to enhance the immune response against tumor antigens.

[0272] Preferably, the antigenic peptide is linked to a carrier molecule, specifically to a carrier protein, preferably by a covalent or non-covalent bond. The carrier molecule to which the peptide is optionally bound can be selected from a variety of known carriers. Examples of carrier molecules for vaccine use include proteins such as human or bovine serum albumin and KLH peptides and fatty acids. Other embodiments of carrier molecules to which the antigenic peptide of formula (I) can be covalently linked include bacterial toxins or toxoids, such as diphtheria, cholera, Escherichia coli (E. coli) heat-labile or tetanus toxoids, Neisseria meningitidis (N. meningitidis) outer membrane proteins (European Patent Application No. EP0372501), synthetic peptides (European Patent Application No. EP0378881 and EP0427347), heat shock proteins (PCT Application No. WO93 / 17712), pertussis proteins (PCT Application No. WO98 / 58668), protein D of Haemophilus influenzae (H. influenzae) (PCT Application No. WO00 / 56360) and toxin A or B of Clostridium difficile (C. difficile) (International Patent Application WO00 / 61761).

[0273] More preferably, the carrier protein or carrier peptide is a protein / peptide with immunoadjuvant properties, such as providing stimulation of CD4+ Th1 cells, as described herein. Preferred examples thereof are non-tumor antigens that restore immune memory or provide nonspecific helper, or may be specific tumor-derived helper peptides, such as tetanus helper peptide, scutellaria hemocyanin peptide, or PADRE peptide. Another preferred example is a specific tumor-derived helper peptide that can be presented by MHC class II, specifically HLA-DR, HLA-DP, or HLA-DQ, such as a fragment of a shared overexpressed tumor antigen, such as HER2, NY-ESO-1, hTERT, or IL13RA2, as described above. In a preferred embodiment, the carrier protein or carrier peptide is a protein / peptide with immunoadjuvant properties, and may be the HHD-DR3 carrier peptide MAKXIAYDEEARRGLERGLN (SEQ ID NO: 856). Specifically, "PepNt" and / or "PepCt" may correspond to a carrier protein or carrier peptide, such as the HHD-DR3 carrier peptide MAKTIAYDEEARRGLERGLN (SEQ ID NO: 856). Another preferred example is h-pAg T13L (sequence: TPPAYRPPNAPIL; SEQ ID NO: 860; Bhasin M, Singh H, Raghava GP (2003) MHCBN: a comprehensive database of MHC binding and non-binding peptides. Bioinformatics 19: 665–666). Other examples of preferred carrier proteins / peptides (particularly helper peptides) include UCP2 peptide (e.g., as described in WO 2013 / 135553 A1 or Dosset et al., Clin Cancer Res. 2012 Nov 15; 18(22): 6284-95) and BIRC5 peptide (e.g., as described in EP 2119726 A1 or Widenmeyer et al., Int J Cancer. 2012 Jul 1; 131(1): 140-9). The most preferred helper peptide is UCP2 peptide (amino acid sequence: KSVWSKLQSIGIRQH; SEQ ID NO: 859).

[0274] Furthermore, in the polypeptides according to formula (I), (Ia) or (Ib), "PepNt" and / or "PepCt" may preferably correspond to such proteins / peptides having immunoadjuvant properties, such as providing stimulation of CD4+ Th1 cells, as described herein.

[0275] Furthermore, the immunogenic compound may comprise or consist of a protein / peptide having immunoadjuvant properties covalently linked to the N-terminus of the antigenic peptide of the invention or to the N-terminus of a polypeptide / protein comprising said antigenic peptide, e.g. providing stimulation of CD4+ Th1 cells as described herein.

[0276] Preferably, the antigenic peptide according to the present invention (or a polypeptide / protein comprising said antigenic peptide) is covalently bound to the carrier molecule via a linker moiety.

[0277] Preferred linker agents include those designated GMBS, Sulfo-GMBS, SMPB, and Sulfo-SMPB.

[0278] In some embodiments of the immunogenic compound as defined above, the linker agent is selected from GMBS (N-[γ-maleimidobutyryl-oxy]succinimide ester), Sulfo-GMBS (N-[γ-maleimidobutyryl-oxy]succinimide ester), SMPB (4-[p-maleimidophenyl]butyric acid succinimide ester) and Sulfo-SMPB (4-[p-maleimidophenyl]butyric acid succinimide ester).

[0279] Methods for conjugating two proteins using linker reagents in general and more specifically linker reagents selected from GMBS, sulfo-GMBS, SMPB and sulfo-SMPB are well known to those skilled in the art. For example, such protocols are disclosed in publicly available leaflets from Pierce Corporation (Illinois, USA). GMBS, sulfo-GMBS, SMPB and sulfo-SMPB consist of bifunctional linker reagents comprising an N-hydroxysuccinimide (NHS) ester group and a maleimido group. Conjugation coating using GMBS, sulfo-GMBS, SMPB or sulfo-SMPB is performed in a two-step procedure. In the first step, the amine-containing protein is reacted with a molar excess of the linker reagent at pH 7-9 to form an amide bond, and then the excess unreacted linker reagent is removed, typically by desalting or dialysis. In the second step, a sulfhydryl-containing molecule (eg, a peptide of formula (I)) is added to react with the maleimide group already attached to the first protein at pH 6.5-7.5 to form a stable thioether bond.

[0280] SMPB or sulfo-SMPB is used as a linker reagent to covalently link the antigenic peptide according to the present invention (or a polypeptide / protein comprising the antigenic peptide, such as a polypeptide of formula (I)) to an amine-containing carrier protein to produce the conjugate of the following formula (II):

[0281]

[0282] in:

[0283] - R1 consists of a reactive group of an amine-containing transporter protein, and wherein the NH group to which it is attached is derived from (i) the alpha amino group located at the N-terminus of the amine-containing transporter protein or (ii) the side chain amino group of a lysine (K) amino acid residue of the amine-containing transporter protein; and

[0284] -R2 consists of an antigenic peptide according to the present invention (or a polypeptide / protein comprising the antigenic peptide, such as a polypeptide of formula (I)), and wherein the sulfur (S) atom to which it is attached is derived from a sulfhydryl (SH) group of a cysteine ​​residue located at the N-terminus or C-terminus of the peptide of formula (I). In some embodiments, the sulfhydryl moiety may be part of a non-natural amino acid, or any other molecule present at the terminus of the peptide of formula (I).

[0285] GMBS or sulfo-GMBS is used as a linker reagent to covalently link the antigenic peptide according to the present invention (or a polypeptide / protein comprising the antigenic peptide, such as a polypeptide of formula (I)) to an amine-containing carrier protein (specifically CRM197 carrier protein) to produce a conjugate of the following formula (III):

[0286]

[0287] in:

[0288] - R1 consists of a reactive group of an amine-containing transporter protein, and wherein the NH group to which it is attached is derived from (i) the alpha amino group located at the N-terminus of the amine-containing transporter protein or (ii) the side chain amino group of a lysine (K) amino acid residue of the amine-containing transporter protein; and

[0289] -R2 consists of an antigenic peptide according to the present invention (or a polypeptide / protein comprising the antigenic peptide, such as a polypeptide of formula (I)), and wherein the sulfur (S) atom to which it is attached is derived from a sulfhydryl (SH) group of a cysteine ​​residue located at the N-terminus or C-terminus of the peptide of formula (I). In some embodiments, the sulfhydryl moiety may be part of a non-natural amino acid, or any other molecule present at the terminus of the peptide of formula (I).

[0290] Peptide–MHC (pMHC) multimers including antigenic peptides

[0291] In a further aspect, the present invention also provides a peptide-MHC (pMHC) multimer comprising the antigenic peptide according to the present invention.

[0292] As used herein, the term "peptide-MHC multimer" (pMHC) refers to a stable multimeric complex composed of major histocompatibility complex (MHC) protein subunits loaded with antigenic peptides of the present invention. In general, an "MHC multimer" is an oligomeric form of an MHC molecule. The main function of an MHC molecule is to bind to an antigen. According to the present invention, the antigen is an antigenic peptide according to the present invention. Therefore, an MHC protein complex "loaded" with an antigenic peptide of the present invention generally means that the antigenic peptide of the present invention is bound to one or more MHC proteins. The "peptide-MHC multimer" (pMHC) of the present invention includes, but is not limited to, peptide-MHC dimers, trimers, tetramers, pentamers, hexamers, heptamers or octamers. MHC tetramers and pentamers are preferred. The term "major histocompatibility complex" (MHC) is a general term intended to encompass the histocompatibility antigen systems described in different species, including human leukocyte antigens (HLA). In humans, there are three genetic loci that encode MHC class I molecules: HLA-A, HLA-B, and HLA-C. HLA-A*01, HLA-A*02, and HLA-A*11 are examples of different MHC class I alleles that can be expressed by these loci.

[0293] In one embodiment of the present invention, the pMHC multimer is a peptide / MHC class I multimer. In another specific embodiment, the pMHC multimer is an HLA corresponding to an MHC class I / peptide multimer. Thus, the pMHC multimer can be an HLA-peptide multimer selected from the group consisting of an HLA-A-peptide multimer, an HLA-B-peptide multimer, an HLA-C-peptide multimer, an HLA-E-peptide multimer, a MICA-peptide multimer, and a MICB-peptide multimer.

[0294] Methods of obtaining pHMC multimers are known in the art and are described, for example, in WO 96 / 26962 and WO 01 / 18053, which are incorporated herein by reference.

[0295] In addition to MHC molecules and antigenic peptides of the present invention, pMHC may also include other components, such as polymerizing agents and / or labels (e.g., for visualization). Examples of labels include, but are not limited to, fluorescent labels, such as fluorescent markers. Fluorescently labeled proteins, such as streptavidin. Fluorescent labels include allophycocyanin (APC), phycoerythrin (PE), R-phycoerythrin (R-PE), and fluorescein isothiocyanate (FITC). Preferred labels are biotin.

[0296] In one embodiment of the present invention, the pMHC multimer can be used to visualize a specific T cell population for an MHC class I peptide complex as described above or an HLA corresponding to an MHC class I / peptide complex. For example, the pMHC multimer can be a multimer in which the heavy chain of the MHC is biotinylated, allowing it to be combined with streptavidin to form a tetramer. Such pMHC tetramers have increased affinity for appropriate TCR-carrier T lymphocytes and can therefore be used to visualize reactive populations by immunofluorescence. In another embodiment of the present invention, the pMHC multimer can be used to detect and / or separate specific T cell populations for the pMHC complex as described above by screening (in flow cytometry or by immunomagnetic screening).

[0297] Cells loaded with antigenic peptides or immunogenic compounds

[0298] In a further aspect, the present invention also provides a cell loaded with an antigenic peptide according to the present invention as described above, or an immunogenic compound comprising an antigenic peptide according to the present invention. Specifically, the preferred embodiments of the antigenic peptide described above also apply to such a cell according to the present invention. For example, the antigenic peptide loaded into the cell or the antigenic peptide included in the immunogenic compound loaded into the cell preferably comprises or consists of the amino acid sequence shown in any one of SEQ ID NOs: 1 to 580 and 861 to 887, such as an antigenic peptide comprising or consisting of the amino acid sequence shown in any one of SEQ ID NOs: 1 to 580. For example, more preferably, the antigenic peptide according to the present invention comprises or consists of the amino acid sequence shown in any one of SEQ ID NOs: 1-160, 162-253, and 255-580. For example, even more preferably, the antigenic peptide according to the present invention comprises or consists of the amino acid sequence shown in any one of SEQ ID NOs: 30, 31, 32, 87, 97, 145, 193, 194, 220, 221, 255, 521, and 524. For example, an antigenic peptide according to the present invention comprising or consisting of the amino acid sequence represented by any one of SEQ ID NOs: 30, 31, 32, 87, 97, 193, 194, 220, 255, 521, and 524 is more preferred. For example, an antigenic peptide according to the present invention comprising or consisting of the amino acid sequence represented by any one of SEQ ID NOs: 30, 31, 32, 87, 97, 194, 220, 255, 521, and 524 is still more preferred. For example, an antigenic peptide according to the present invention comprising or consisting of the amino acid sequence represented by any one of SEQ ID NOs: 30, 32, 87, 97, 194, 220, 255, 521, and 524 is most preferred. For example, an antigenic peptide according to the present invention comprising or consisting of the amino acid sequence represented by any one of SEQ ID NOs: 30, 32, 87, 97, and 194 is particularly preferred. Furthermore, a combination thereof, i.e., cells loaded with different antigenic peptides according to the present invention (or corresponding immunogenic compound(s)).

[0299] Preferred cells loaded with the antigenic peptide according to the present invention or the immunogenic compound according to the present invention are antigen presenting cells (APCs), more preferably dendritic cells (DCs).

[0300] APCs are of particular interest because their primary function is to process antigens and present them on the cell surface of immune system T cells, thereby initiating and regulating T cell responses in vivo. In the context of the present invention, it is preferred that APCs are loaded with antigenic peptides (one or more) and / or immunogenic compounds (one or more) according to the present invention. This can be accomplished by exposing APCs to the antigenic peptides (one or more) and / or immunogenic compounds (one or more) in vitro (e.g., Rizzo MM, Alaniz L, Mazzolini G. Ex vivo loading of autologous dendritic cells with tumor antigens. Methods Mol Biol. 2014; 1139: 41-4; Rolinski J, Hus I. Breaking immunotolerance of tumors: a new perspective for dendritic cell therapy. J Immunotoxicol. 2014 October; 11(4): 311-8).

[0301] Preferred APCs according to the present invention are dendritic cells (DCs). Combining at least one antigenic peptide or immunogenic compound according to the present invention with DCs is indeed advantageous because they are the most effective APCs and are reported to be often functionally defective in cancer patients. Those skilled in the art can easily obtain DCs from healthy compatible donors (i.e., DCs are HLA-associated) or the patient themselves, as long as they are functional (i.e., DCs are autologous), for example by direct isolation from peripheral blood or by deriving from peripheral blood cells (e.g., CD14+ monocytes or CD34+ hematopoietic precursors) (Figdor CG, de Vries IJ, Lesterhuis WJ, Melief CJ. Dendritic cell immunotherapy: mapping the way. Nat Med. 2004 May; 10(5): 475-80). In fact, DCs can be distinguished from other cells of peripheral blood by their surface markers (e.g., S100, p55, CD83, and / or OX62), and therefore can be isolated and purified based on these markers using cell culture techniques well known in the art.

[0302] Nucleic acid encoding the antigenic peptide and host cell comprising the nucleic acid

[0303] In a further aspect, the present invention also provides a nucleic acid encoding an antigenic peptide according to the present invention, a polypeptide of formula (I) as defined above, or an immunogenic compound according to the present invention, wherein the immunogenic compound is a peptide or protein. In particular, the preferred embodiments of the antigenic peptide described above also apply to such a nucleic acid according to the present invention. For example, the antigenic peptide encoded by the nucleic acid preferably comprises or consists of the following: an amino acid sequence as shown in any one of SEQ ID NOs: 1 to 580 and 861 to 887, such as an antigenic peptide comprising or consisting of the following: an amino acid sequence as shown in any one of SEQ ID NOs: 1 to 580. For example, more preferably, an antigenic peptide according to the present invention comprises or consists of the following: an amino acid sequence as shown in any one of SEQ ID NOs: 1–160, 162–253, and 255–580. For example, even more preferably, an antigenic peptide according to the present invention comprises or consists of the following: an amino acid sequence as shown in any one of SEQ ID NOs: 30, 31, 32, 87, 97, 145, 193, 194, 220, 221, 255, 521, and 524. For example, an antigenic peptide according to the present invention comprising or consisting of the amino acid sequence represented by any one of SEQ ID NOs: 30, 31, 32, 87, 97, 193, 194, 220, 255, 521, and 524 is more preferred. For example, an antigenic peptide according to the present invention comprising or consisting of the amino acid sequence represented by any one of SEQ ID NOs: 30, 31, 32, 87, 97, 194, 220, 255, 521, and 524 is still more preferred. For example, an antigenic peptide according to the present invention comprising or consisting of the amino acid sequence represented by any one of SEQ ID NOs: 30, 32, 87, 97, 194, 220, 255, 521, and 524 is most preferred. For example, an antigenic peptide according to the present invention comprising or consisting of the amino acid sequence represented by any one of SEQ ID NOs: 30, 32, 87, 97, and 194 is particularly preferred. Furthermore, combinations thereof, i.e., nucleic acids encoding different antigenic peptides according to the present invention are preferred.

[0304] The nucleic acid preferably comprises a single-stranded, double-stranded or partially double-stranded nucleic acid, preferably selected from gDNA, cDNA, RNA, antisense DNA, antisense RNA, complementary RNA / DNA sequences with or without expression elements, minigenes, gene fragments, regulatory elements, promoters and combinations thereof. Further preferred examples of nucleic acids (molecules) and / or polynucleotides include, for example, recombinant polynucleotides, vectors, oligonucleotides, RNA molecules such as rRNA, mRNA or tRNA, or DNA molecules, as described above. Thus, it is preferred that the nucleic acid (molecule) is a DNA molecule or an RNA molecule; preferably selected from gDNA; cDNA; rRNA; mRNA; antisense DNA; antisense RNA; complementary RNA and / or DNA sequences; RNA and / or DNA sequences with or without expression elements, regulatory elements, and / or promoters; vectors; and combinations thereof.

[0305] In the field of treatment, diagnosis, reagents and biological assays, whether in vitro, in vivo, in situ or in vitro, nucleic acids, such as ribonucleic acids (RNA), can be delivered intracellularly, such as to produce intracellular translation of nucleic acids and target encoded peptides, which are of great concern. Of particular importance is the delivery and function of non-integrative polynucleotides. Therefore, nucleic acids, such as mRNA, are preferably not integrated into the host chromosome. In general, nucleic acids, such as mRNA, can be optimized to express the antigenic peptides of the present invention, for example, by methods known in the art, such as codon optimization. In addition, nucleic acids can be modified, for example, to enhance their stability, extend their lifespan and / or increase the expression of the antigenic peptides of the present invention. Therefore, optimized or modified mRNA (mmRNA) encoding the antigenic peptides according to the present invention is preferred. mmRNA is distinguished from wild-type mRNA in terms of its functional and / or structural design features, for optimal delivery of mRNA and / or for optimal expression of the antigenic peptides of the present invention (e.g., as WO2013 / 151672A2, WO2013 / 101690A1, WO2013 / 052523A, which are incorporated herein by reference). In general, nucleic acid can be delivered or combined with carrier (for example, cationic carrier). Cationic carrier (positively charged) is usually easily combined with negatively charged nucleic acid. Carrier can be any carrier of any kind, including for example polymer, protein, lipid and nanoparticle. Cationic lipid and nanoparticle (particularly, lipid nanoparticle, LNP) are preferably used for nucleic acid delivery. Therefore, the present invention also provides nucleic acid as herein described combined with carrier (for example lipid, particularly cationic lipid or LNP).

[0306] In some embodiments, the nucleic acid molecule can be a vector. The term "vector", as described in the context of the present invention, refers to a nucleic acid molecule, preferably an artificial nucleic acid molecule, i.e., a nucleic acid molecule that does not exist in nature. The vector in the context of the present invention is suitable for containing and or containing a desired nucleic acid sequence. Such a vector can be a storage vector, an expression vector, a cloning vector, a transfer vector, etc. A storage vector is a vector that allows for convenient storage of nucleic acid molecules. Therefore, the vector can contain, for example, a sequence corresponding to a desired antigenic peptide according to the present invention. An expression vector can be used to produce an expression product, such as RNA (e.g., mRNA), or a peptide, polypeptide, or protein. For example, an expression vector can contain a sequence required for transcription of a sequence of the vector, such as a promoter sequence. A cloning vector is typically a vector comprising a cloning site, which can be used to incorporate a nucleic acid sequence into a vector. A cloning vector can be, for example, a plasmid vector or a phage vector. A transfer vector can be a vector suitable for transferring a nucleic acid molecule into a cell or organism, such as a viral vector. In the context of the present invention, a vector can be, for example, an RNA vector or a DNA vector. Preferably, the vector is a DNA molecule. For example, a vector in the sense of the present application includes a cloning site, a selection marker such as an antibiotic resistance factor, and a sequence suitable for vector multiplication, such as a replication origin. Preferably, the vector in the context of the present application is a plasmid vector. Preferably, the vector in the context of the present application is an expression vector. Preferred vectors are vectors for expression in bacterial cells. More preferably, the vector can be used for expression in so-called "live bacterial vaccine vectors", in which live bacterial cells (such as bacteria or bacterial spores, such as endospores, exospores or microbial cysts) can serve as vaccines. Preferred examples thereof are described in da Silva et al., Live bacterial vaccine vectors: an overview; Braz J Microbiol. 2015 Mar 4; 45(4): 1117-29.

[0307] The nucleic acid encoding the antigenic peptide according to the present invention can be in the form of naked nucleic acid, or cloned into the form of nucleic acid in a plasmid or viral vector (Tregoning and Kinnear, Using Plasmids as DNA Vaccines for Infectious Diseases.Microbiol Spectr. December 2014; 2(6).doi:10.1128 / microbiolspec.PLAS-0028-2014), the latter being particularly preferred. Suitable examples of viral vectors according to the present invention include, but are not limited to, retroviruses, adenoviruses, adeno-associated viruses (AAV), herpes viruses, and poxvirus vectors. Utilizing standard recombinant techniques in the art, nucleic acid cloning into a plasmid or viral vector is within the capabilities of those skilled in the art.

[0308] In a further aspect, the present invention also provides a host cell comprising a nucleic acid according to the present invention. And preferably a combination thereof, that is, a host cell comprising different nucleic acids according to the present invention (e.g. encoding different antigenic peptides according to the present invention).

[0309] Preferably, the nucleic acid contained in the host cell is preferably a vector. Preferably, the host cell is a bacterial cell. Such host cells can be preferably used to produce antigenic peptides according to the present invention or immunogenic compounds according to the present invention. In addition, such host cells can also be the active ingredient in a vaccine.

[0310] Preferably, the host cell is a bacterial cell, more preferably an enteric bacterial cell.The term "enteric bacterial cell" refers to bacteria that reside in the (human) intestine.

[0311] Such bacterial host cells can serve as "live bacterial vaccine vectors," where live bacterial cells (e.g., bacteria or bacterial spores, e.g., endospores, exospores, or microbial cysts) can serve as vaccines. Preferred examples are described in da Silva et al., Live bacterial vaccine vectors: an overview; Braz J Microbiol. 2015 Mar 4; 45(4): 1117-29.

[0312] Bacterial cells (such as bacteria or bacterial spores, for example endospores, exospores or microbial cysts), in particular (whole) enteric bacterial species, may be advantageous because they have the potential to elicit a greater immune response than the (poly)peptide or nucleic acid they contain.

[0313] Alternatively, the bacterial cells, in particular enteric bacteria, according to the present invention may be in the form of probiotics, i.e. live enteric bacteria, which may therefore be used as a food additive due to the health benefits they may provide. They may be freeze-dried, for example in the form of granules, pills or capsules, or consumed directly mixed with dairy products.

[0314] Nanoparticles comprising antigenic peptides or immunogenic compounds

[0315] In a further aspect, the present invention also provides nanoparticles comprising, specifically loaded with, the following nanoparticles:

[0316] - at least one antigenic peptide according to the invention, or

[0317] - at least one immunogenic compound according to the invention;

[0318] And the nanoparticles are optionally loaded with an adjuvant.

[0319] Specifically, the preferred embodiments of the above-mentioned antigenic peptides are also applicable to the nanoparticles according to the present invention. For example, the antigenic peptide loaded onto the nanoparticles or the antigenic peptide loaded onto the nanoparticles included in the immunogenic compound preferably includes or consists of the following: the amino acid sequence shown in any one of SEQ ID NOs: 1 to 580 and 861 to 887, such as the antigenic peptide including or consisting of the following: the amino acid sequence shown in any one of SEQ ID NOs: 1 to 580. For example, more preferably, the antigenic peptide according to the present invention includes or consists of the following: the amino acid sequence shown in any one of SEQ ID NOs: 1-160, 162-253, and 255-580. For example, even more preferably, the antigenic peptide according to the present invention includes or consists of the following: the amino acid sequence shown in any one of SEQ ID NOs: 30, 31, 32, 87, 97, 145, 193, 194, 220, 221, 255, 521, and 524. For example, an antigenic peptide according to the present invention comprising or consisting of the amino acid sequence shown in any one of SEQ ID NOs: 30, 31, 32, 87, 97, 193, 194, 220, 255, 521, and 524 is more preferred. For example, an antigenic peptide according to the present invention comprising or consisting of the amino acid sequence shown in any one of SEQ ID NOs: 30, 31, 32, 87, 97, 194, 220, 255, 521, and 524 is still more preferred. For example, an antigenic peptide according to the present invention comprising or consisting of the amino acid sequence shown in any one of SEQ ID NOs: 30, 32, 87, 97, 194, 220, 255, 521, and 524 is most preferred. For example, an antigenic peptide according to the present invention comprising or consisting of the amino acid sequence shown in any one of SEQ ID NOs: 30, 32, 87, 97, and 194 is particularly preferred. Moreover, combinations thereof, i.e., nanoparticles loaded with different antigenic peptides according to the present invention (or corresponding immunogenic compound(s)), are preferred.

[0320] Nanoparticles, in particular for use as vaccines, are known in the art and are described, for example, in Shao et al., Nanoparticle-based immunotherapy for cancer, ACS Nano 2015, 9(1):16-30; Zhao et al., Nanoparticle vaccines, Vaccine 2014, 32(3):327-37; and Gregory et al., Vaccine delivery using nanoparticles, Front Cell Infect Microbiol. 2013, 3:13, doi:10.3389 / fcimb.2013.00013.eCollection 2013, Review. In particular, nanoparticles are used to deliver antigenic peptides (or immunogenic compounds / polypeptides / proteins / nucleic acids comprising antigenic peptides) and may optionally also act as adjuvants. Antigenic peptides (immunogenic compounds / polypeptides / proteins / nucleic acids comprising antigenic peptides) are typically encapsulated within nanoparticles, or connected / bound to the surface of the nanoparticles (decorated thereon) ("coat"). Compared to conventional methods, nanoparticles can protect the payload (antigen / adjuvant) from the surrounding biological environment, increase half-life, minimize systemic toxicity, promote delivery to APCs, or even directly trigger the activation of TAA-specific T cells. Preferably, the size (diameter) of the nanoparticles is no more than 300 nm, more preferably no more than 200 nm, and most preferably no more than 100 nm. Such nanoparticles are fully evaded by phagocyte uptake, have a high degree of structural integrity and a long circulation time in the circulation, can accumulate at sites of tumor growth, and can penetrate deeply into the tumor mass.

[0321] Examples of nanoparticles include polymeric nanoparticles, such as polyethylene glycol (PEG) and poly(D,L-lactic-co-glycolic acid) (PLGA); inorganic nanoparticles, such as gold nanoparticles, iron oxide beads, iron oxide zinc oxide nanoparticles, carbon nanotubes, and mesoporous silica nanoparticles; liposomes, such as cationic liposomes; immunostimulatory complexes (ISCOMs); virus-like particles (VLPs); and self-assembling proteins.

[0322] Polymer nanoparticles are nanoparticles based on / comprising polymers such as poly(D,L-lactide-co-glycolide) (PLG), poly(D,L-lactic acid-co-glycolic acid) (PLGA), poly(γ-glutamic acid) (g-PGA), poly(ethylene glycol) (PEG) and polystyrene. Polymer nanoparticles can entrap antigens (e.g., antigenic peptides or (poly)peptides comprising the same), or bind / conjugate to antigens (e.g., antigenic peptides or (poly)peptides comprising the same). Polymer nanoparticles can be used for delivery to certain cells, or to maintain antigen release through their slow biodegradation rate. For example, g-PGA nanoparticles can be used to encapsulate hydrophobic antigens. Polystyrene nanoparticles can be conjugated to various antigens because they can be surface-modified with various functional groups. Polymers such as poly(L-lactic acid) (PLA), PLGA, PEG, and natural polymers such as polysaccharides can also be used to synthesize hydrogel nanoparticles, which are a class of nanometer-sized hydrophilic three-dimensional polymer networks. Nanogels have advantageous properties, including flexible pore size, large area for multivalent conjugation, high water content, and high antigen loading capacity. Therefore, preferred nanoparticles are nanogels, such as chitosan nanogels. Preferred polymeric nanoparticles are nanoparticles based on / comprising PEG and PLGA.

[0323] Inorganic nanoparticles are nanoparticles based on / comprising inorganic substances, and examples of such nanoparticles include gold nanoparticles, iron oxide beads, iron oxide zinc oxide nanoparticles, carbon nanoparticles (e.g., carbon nanotubes) and mesoporous silica nanoparticles. Inorganic nanoparticles provide a rigid structure and controllable synthesis. For example, gold nanoparticles can be easily produced in different shapes, such as spherical, rod-shaped, cubical. Inorganic nanoparticles can be surface-modified, for example with carbohydrates. Carbon nanoparticles provide good biocompatibility and can be produced, for example, as nanotubes or (mesoporous) balls. For example, multiple copies of the antigenic peptide according to the present invention (or (poly)peptides comprising it) can be conjugated to carbon nanoparticles (e.g., carbon nanotubes). Mesoporous carbon nanoparticles are preferably used for oral administration. Silica-based nanoparticles (SiNPs) are also preferred. SiNPs have biocompatibility and demonstrate excellent properties in selective tumor targeting and vaccine delivery. The abundant silanol groups on the SiNP surface can be used for further modification to introduce additional functionalities such as cell recognition, absorption of specific biomolecules, improved interaction with cells, and enhanced cellular uptake. Mesoporous silica nanoparticles are particularly preferred.

[0324] Liposomes are typically formed from phospholipids such as 1,2-dioleoyl-3-trimethylammonium propane (DOTAP). In general, cationic liposomes are preferred. Liposomes self-assemble with a phospholipid bilayer shell and an aqueous core. Liposomes can be generated as unilamellar vesicles (having one phospholipid bilayer) or multilamellar vesicles (having several concentric phospholipid shells separated by aqueous layers). Thus, antigens can be encapsulated in the core or between different layers / shells. Preferred liposome systems are those approved for use in humans, such as V and

[0325] Immunostimulatory complexes (ISCOMs) are caged particles of approximately 40 nm (diameter) that are micelles containing colloidal saponins, for example made from the saponin adjuvant Quil-A, cholesterol, phospholipids, and (poly)peptide antigens (e.g., antigenic peptides or polypeptides containing them). These spherical particles can capture antigens through non-polar interactions. Two types of ISCOMs have been described, both consisting of cholesterol, phospholipids (usually phosphatidylethanolamine or phosphatidylcholine), and saponins (e.g., Quil-A).

[0326] Virus-like particles (VLPs) are self-assembled nanoparticles formed by the self-assembly of biocompatible capsid proteins. Due to the naturally optimized nanoparticle size and repeated structural order, VLPs can induce an effective immune response. VLPs can be derived from various viruses and range in size from 20 nm to 800 nm, typically within the range of 20-150 nm. VLPs can be engineered to express other peptides or proteins by fusing these peptides / proteins to particles or by expressing multiple antigens. In addition, antigens can be chemically linked to the viral surface to produce bioconjugate VLPs.

[0327] Examples of self-assembling proteins include ferritin and major vault protein (MVP). Ferritin is a protein that can self-assemble into a nearly spherical 10 nm structure. 96 MVP units can self-assemble into barrel-shaped vault nanoparticles, approximately 40 nm wide and 70 nm long. Antigens genetically fused with minimal interaction domains can be encapsulated into vault nanoparticles when mixed with MVP through a self-assembly process. Thus, an antigen (such as an antigenic peptide according to the present invention or a polypeptide comprising the same) can be fused with a self-assembling protein or a fragment / domain thereof (such as the minimal interaction domain of MVP). Therefore, the present invention also provides a fusion protein comprising a self-assembling protein (or a fragment / domain thereof) and an antigenic peptide according to the present invention.

[0328] In general, preferred examples of nanoparticles (NPs) include iron oxide beads, polystyrene microspheres, poly(γ-glutamic acid) (g-PGA) NPs, iron oxide-zinc oxide NPs, cationized gelatin NPs, pluronic-stabilized poly(propylene sulfide) (PPS) NPs, PLGA NPs, (cationic) liposomes, (pH-responsive) polymer micelles, PLGA, cancer cell membrane-coated PLGA, lipid-calcium phosphate (LCP) NPs, liposome-protamine-hyaluronic acid (LPH) NPs, polystyrene latex beads, magnetic beads, dextran iron particles, and quantum dot nanocrystals.

[0329] Preferably, the nanoparticles also include an adjuvant, such as a toll-like receptor (TLR) agonist. Thus, the antigenic peptide (immunogenic compound / polypeptide / protein / nucleic acid comprising the antigenic peptide) can be delivered to, for example, antigen presenting cells (APCs), such as dendritic cells (DCs), together with the adjuvant. The adjuvant can be encapsulated by the nanoparticles or bound / conjugated to the surface of the nanoparticles, preferably similar to the antigenic peptide.

[0330] Particularly preferred adjuvants are polyinosinic:polycytidylic acid (also known as "poly I:C") and / or its derivative poly-ICLC. Poly I:C is a mismatched double-stranded RNA in which one strand is an inosinic acid polymer and the other is a cytidylic acid polymer. Poly I:C is an immunostimulatory agent known to interact with Toll-like receptor 3 (TLR3). Poly I:C is structurally similar to double-stranded RNA, which is a "natural" stimulator of TLR3. Therefore, poly I:C can be considered a synthetic double-stranded RNA analog. Poly-ICLC is a synthetic complex of carboxymethylcellulose, polyinosinic-polycytidylic acid and poly-L-lysine double-stranded RNA. Similar to poly I:C, poly-ICLC is also a ligand for TLR3. Poly I:C and poly-ICLC generally stimulate the release of cytotoxic cytokines. Preferred examples of poly-ICLC are

[0331] Pharmaceutical composition

[0332] In a further aspect, the present invention also provides a pharmaceutical composition comprising at least one of the following:

[0333] - an antigenic peptide according to the invention as described herein,

[0334] - an immunogenic compound according to the invention as described herein,

[0335] - the nanoparticles according to the invention as described herein,

[0336] - a cell according to the invention as described herein,

[0337] - a nucleic acid according to the invention as described herein, and / or

[0338] - a host cell according to the invention as described herein,

[0339] and optionally one or more pharmaceutically acceptable excipients or carriers.

[0340] Specifically, the preferred embodiments of the antigenic peptides described above also apply to the pharmaceutical composition according to the present invention. For example, the antigenic peptide included in the pharmaceutical composition or the antigenic peptide included in any of the immunogenic compounds, nanoparticles, cells, nucleic acids, or host cells included in the pharmaceutical composition preferably includes or consists of the amino acid sequence shown in any one of SEQ ID NOs: 1 to 580 and 861 to 887, such as the antigenic peptide including or consisting of the amino acid sequence shown in any one of SEQ ID NOs: 1 to 580. For example, more preferably, the antigenic peptide according to the present invention includes or consists of the amino acid sequence shown in any one of SEQ ID NOs: 1-160, 162-253, and 255-580. For example, even more preferably, the antigenic peptide according to the present invention includes or consists of the amino acid sequence shown in any one of SEQ ID NOs: 30, 31, 32, 87, 97, 145, 193, 194, 220, 221, 255, 521, and 524. For example, an antigenic peptide according to the present invention comprising or consisting of the amino acid sequence represented by any one of SEQ ID NOs: 30, 31, 32, 87, 97, 193, 194, 220, 255, 521, and 524 is more preferred. For example, an antigenic peptide according to the present invention comprising or consisting of the amino acid sequence represented by any one of SEQ ID NOs: 30, 31, 32, 87, 97, 194, 220, 255, 521, and 524 is still more preferred. For example, an antigenic peptide according to the present invention comprising or consisting of the amino acid sequence represented by any one of SEQ ID NOs: 30, 31, 32, 87, 97, 194, 220, 255, 521, and 524 is most preferred. For example, an antigenic peptide according to the present invention comprising or consisting of the amino acid sequence represented by any one of SEQ ID NOs: 30, 32, 87, 97, and 194 is particularly preferred.

[0341] And preferably, a combination thereof, that is, a pharmaceutical composition comprising different antigenic peptides according to the present invention. For example, a pharmaceutical composition may comprise

[0342] (i) at least two different antigenic peptides according to the present invention;

[0343] (ii) at least two different immunogenic compounds according to the invention;

[0344] (iii) at least two different nanoparticles according to the invention; and / or

[0345] (iv) at least two different nucleic acids according to the invention.

[0346] Thus, the present invention provides pharmaceutical compositions comprising (at least) one antigenic peptide according to the present invention as described herein. Additionally, the present invention provides pharmaceutical compositions comprising (at least) one immunogenic compound according to the present invention as described herein. Additionally, the present invention provides pharmaceutical compositions comprising (at least) one nanoparticle according to the present invention as described herein. Additionally, the present invention provides pharmaceutical compositions comprising (at least) one cell according to the present invention as described herein. Additionally, the present invention provides pharmaceutical compositions comprising (at least) one nucleic acid according to the present invention as described herein. Additionally, the present invention provides pharmaceutical compositions comprising (at least) one host cell according to the present invention as described herein.

[0347] Preferably, the pharmaceutical composition comprises at least two different antigenic peptides according to the present invention.

[0348] Specifically, the present invention provides a pharmaceutical composition comprising a first antigenic peptide according to the present invention, comprising or consisting of a microbial sequence variant of a fragment of the human tumor antigen BIRC5; and a second antigenic peptide according to the present invention, comprising or consisting of a microbial sequence variant of a fragment of the human tumor antigen FOXM1. Preferably, the first antigenic peptide comprises or consists of a microbial sequence variant of the BIRC5 fragment (human reference peptide) "LTLGEFLKL" (SEQ ID NO: 593), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NOs: 30, 31, or 32; and the second antigenic peptide comprises or consists of a microbial sequence variant of the FOXM1 fragment (human reference peptide) "LMDLSTTPL" (SEQ ID NO: 674), such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NOs: 220 or 868. Even more preferably, the pharmaceutical composition comprises: an antigenic peptide comprising or consisting of SEQ ID NO: 32; and an antigenic peptide comprising or consisting of SEQ ID NO: 220.

[0349] Specifically, the present invention also provides a pharmaceutical composition comprising a first antigenic peptide according to the present invention comprising or consisting of a microbial biota sequence variant of a fragment of the human tumor antigen BIRC5; and a second antigenic peptide according to the present invention comprising or consisting of a microbial biota sequence variant of a fragment of the tumor antigen IL13RA2. Preferably, the first antigenic peptide comprises or consists of a microbial biota sequence variant of the BIRC5 fragment (human reference peptide) "LTLGEFLKL" (SEQ ID NO: 593), such as an antigenic peptide comprising or consisting of the amino acid sequence of SEQ ID NO: 30, 31, or 32, and the second antigenic peptide comprises or consists of a microbial biota sequence variant of the IL13RA2 fragment (human reference peptide) "WLPFGFILI" (SEQ ID NO: 691) or "WLPFGFILIL" (SEQ ID NO: 692), such as an antigenic peptide comprising or consisting of the amino acid sequence of SEQ ID NO: 254, 255, 878, or 879. Still more preferably, the pharmaceutical composition comprises: an antigenic peptide comprising or consisting of SEQ ID NO: 32 and an antigenic peptide comprising or consisting of SEQ ID NO: 255.

[0350] Specifically, the present invention also provides a pharmaceutical composition comprising a first antigenic peptide according to the present invention comprising or consisting of a microbial biota sequence variant of a fragment of the human tumor antigen FOXM1; and a second antigenic peptide according to the present invention comprising or consisting of a microbial biota sequence variant of a fragment of the human tumor antigen IL13RA2. Preferably, the first antigenic peptide comprises or consists of a microbial biota sequence variant of the FOXM1 fragment (human reference peptide) "LMDLSTTPL" (SEQ ID NO: 674), such as an antigenic peptide comprising or consisting of the amino acid sequence of SEQ ID NO: 220 or 868, and the second antigenic peptide comprises or consists of a microbial biota sequence variant of the IL13RA2 fragment (human reference peptide) "WLPFGFILI" (SEQ ID NO: 691) or "WLPFGFILIL" (SEQ ID NO: 692), such as an antigenic peptide comprising or consisting of the amino acid sequence of SEQ ID NO: 254, 255, 878, or 879. Still more preferably, the pharmaceutical composition comprises: an antigenic peptide comprising or consisting of SEQ ID NO: 220; and an antigenic peptide comprising or consisting of SEQ ID NO: 255.

[0351] More preferably, the pharmaceutical composition comprises at least three different antigenic peptides according to the present invention.

[0352] Specifically, the present invention also provides a pharmaceutical composition comprising a first antigenic peptide according to the present invention, which comprises or consists of a microbial biota sequence variant of a fragment of the human tumor antigen BIRC5; a second antigenic peptide according to the present invention, which comprises or consists of a microbial biota sequence variant of a fragment of the human tumor antigen FOXM1; and a third antigenic peptide according to the present invention, which comprises or consists of a microbial biota sequence variant of a fragment of the human tumor antigen IL13RA2. Preferably, the first antigenic peptide comprises or consists of a microbial biota sequence variant of the BIRC5 fragment (human reference peptide) "LTLGEFLKL" (SEQ ID NO: 593), such as an antigenic peptide comprising or consisting of the amino acid sequence of SEQ ID NO: 30, 31 or 32; the second antigenic peptide comprises or consists of a microbial biota sequence variant of the FOXM1 fragment (human reference peptide) "LMDLSTTPL" (SEQ ID NO: 674), such as an antigenic peptide comprising or consisting of the amino acid sequence of SEQ ID NO: 220 or 868; and the third antigenic peptide comprises or consists of a microbial biota sequence variant of the IL13RA2 fragment (human reference peptide) "WLPFGFILI" (SEQ ID NO: 691) or "WLPFGFILIL" (SEQ ID NO: 692), such as an antigenic peptide comprising or consisting of the amino acid sequence of SEQ ID NO: 254, 255, 878 or 879. Still more preferably, the pharmaceutical composition comprises: an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 30, an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 220, and an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 255.

[0353] It will be appreciated that the pharmaceutical composition may also comprise - instead of the preferred combinations of antigenic peptides described above - corresponding combinations of immunogenic compounds of the invention, corresponding combinations of nanoparticles of the invention or corresponding combinations of nucleic acids of the invention.

[0354] Preferably, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients or carriers.

[0355] The pharmaceutical compositions of the present invention may be in any form suitable for the purposes of the present invention. For example, the compositions may be in a form suitable for parenteral, enteral, or topical administration, such as a liquid suspension, a solid dosage form (granules, pills, capsules, or tablets), or a paste or gel. It is within the skill of those skilled in the art to select a composition in an appropriate form for the intended purpose.

[0356] The composition according to the present invention may further comprise other active agents, such as those that enhance the effect of the antigenic peptide or immunogenic compound. Alternatively, the composition may not comprise any other active agent (i.e., an antigenic peptide according to the present invention, an immunogenic compound according to the present invention, a nanoparticle according to the present invention, a cell according to the present invention, a nucleic acid according to the present invention, and / or a host cell according to the present invention).

[0357] The pharmaceutical compositions defined herein are preferably immunogenic compositions, i.e., compositions capable of inducing, increasing, prolonging, or maintaining an immune response. This can be achieved by including an antigenic peptide according to the invention or an immunogenic compound according to the invention in the composition. Preferably, the pharmaceutical composition also includes one or more immunoadjuvant substances. Pharmaceutical compositions, particularly immunogenic compositions, may also be referred to as "vaccine compositions" in this specification.

[0358] Preferably, the pharmaceutical composition also includes at least one immunostimulant, specifically to increase, enhance, prolong or maintain the immune response mediated by the antigenic peptide. Preferred immunostimulants according to the present invention include, but are not limited to, immune adjuvants, antigen presenting cells, and combinations thereof. Preferably, the immunostimulant is an immune adjuvant or antigen presenting cells (APC).

[0359] Preferably, immunostimulant is an immunoadjuvant. Some immunoadjuvants can be beneficial to and prolong the duration of the interaction between antigen and immune system, while others can recruit and activate innate immune cells to induce adaptive response. Adjuvants belonging to the former class include, but are not limited to, mineral compounds, such as alum, aluminum hydroxide, aluminum phosphate, calcium phosphate hydroxide; and oil-based emulsions, such as paraffin oil, starch oil, Freund's complete / incomplete adjuvant (FCA / FIA), saponin (e.g., from plant soap tree (Quillaja), soybean, Polygala senega (Polygala senega)). Adjuvants belonging to the latter category include, but are not limited to, immunostimulatory complexes (ISCOMs), such as cytokines (e.g., GM-CSF; interleukins such as IL-1, IL-2, IL6, IL8, or IL12; tumor necrosis factor (TNF), such as TNFα or TNFβ; interferons IFNS, such as IFNα, IFNβ, IFNγ, or IFNδ, etc.); ligands of toll-like receptors (TLRs), such as imiquimod, resiquimod, or MPL; exosomes, such as exosomes derived from dendritic cells (DCs) or tumor cells; bacterial products, such as heat shock proteins (HSPs, such as gp96, hsp90, hsp70, calreticulin, hsp110, hsp170), pathogen-associated molecular patterns (PAMPs), trehalose dichotomate (TDM), muramyl dipeptide (MDP), polysaccharides (PLS) (e.g., polysaccharide K).

[0360] More preferably, the immunoadjuvant is a protein / peptide with immunoadjuvant properties, such as providing stimulation of CD4+ Th1 cells, as described herein. Preferred examples thereof are non-tumor antigens that restore immune memory or provide nonspecific help, or may be specific tumor-derived helper peptides, such as tetanus helper peptides, scutellaria hemocyanin peptides, or PADRE peptides, as described herein. Another preferred example is a specific tumor-derived helper peptide that can be presented by MHC II, specifically by HLA-DR, HLA-DP, or HLA-DQ, such as fragments of shared overexpressed tumor antigens, such as HER2, NY-ESO-1, hTERT, or IL13RA2. Specifically, the immunoadjuvant may be the HHD-DR3 peptide of the sequence MAKTIAYDEEARRGLERGLN (SEQ ID NO: 856). This peptide represents another example of a helper peptide (with immunoadjuvant properties) that is preferred in the context of the present invention. Another preferred example is h-pAg T13L (sequence: TPPAYRPPNAPIL; SEQ ID NO: 860; Bhasin M, Singh H, Raghava GP (2003) MHCBN: a comprehensive database of MHC binding and non-binding peptides. Bioinformatics 19: 665–666). Other examples of preferred immune adjuvants (particularly, helper peptides) include UCP2 peptides (e.g., as described in WO 2013 / 135553 A1 or Dosset et al., Clin Cancer Res. 2012 Nov 15; 18(22): 6284-95) and BIRC5 peptides (e.g., as described in EP 2119726 A1 or Widenmeyer et al., Int J Cancer. 2012 Jul 1; 131(1): 140-9). The most preferred helper peptide is the UCP2 peptide (amino acid sequence: KSVWSKLQSIGIRQH; SEQ ID NO: 859).

[0361] Preferably, the pharmaceutical composition comprises at least two different antigenic peptides according to the present invention and a helper peptide, preferably a UCP2 peptide (SEQ ID NO: 859).

[0362] Preferably, the pharmaceutical composition comprises a first antigenic peptide according to the present invention comprising or consisting of a microbial biota sequence variant of a fragment of the human tumor antigen BIRC5; a second antigenic peptide according to the present invention comprising or consisting of a microbial biota sequence variant of a fragment of the human tumor antigen FOXM1; and an auxiliary peptide, preferably a UCP2 peptide (SEQ ID NO: 859). More preferably, the pharmaceutical composition comprises a first antigenic peptide according to the present invention comprising or consisting of a microbial biota sequence variant of the BIRC5 fragment (human reference peptide) "LTLGEFLKL" (SEQ ID NO: 593), such as an antigenic peptide comprising or consisting of the amino acid sequence of SEQ ID NO: 30, 31, or 32; a second antigenic peptide according to the present invention comprising or consisting of a microbial biota sequence variant of the FOXM1 fragment (human reference peptide) "LMDLSTTPL" (SEQ ID NO: 674), such as an antigenic peptide comprising or consisting of the amino acid sequence of SEQ ID NO: 220 or 868; and an auxiliary peptide, preferably a UCP2 peptide (SEQ ID NO: 859). Still more preferably, the pharmaceutical composition comprises: an antigenic peptide comprising or consisting of SEQ ID NO: 32; an antigenic peptide comprising or consisting of SEQ ID NO: 220; and a UCP2 helper peptide (SEQ ID NO: 859).

[0363] It is also preferred that the pharmaceutical composition comprises a first antigenic peptide according to the present invention, which comprises or consists of a microbial biota sequence variant of a fragment of the human tumor antigen BIRC5; a second antigenic peptide according to the present invention, which comprises or consists of a microbial biota sequence variant of a fragment of the human tumor antigen IL13RA2; and an auxiliary peptide, preferably a UCP2 peptide (SEQ ID NO: 859). More preferably, the pharmaceutical composition comprises a first antigenic peptide according to the present invention comprising or consisting of a microbial biota sequence variant of the BIRC5 fragment (human reference peptide) "LTLGEFLKL" (SEQ ID NO: 593), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 30, 31 or 32; a second antigenic peptide according to the present invention comprising or consisting of a microbial biota sequence variant of the tumor antigen IL13RA2 fragment (human reference peptide) "WLPFGFILI" (SEQ ID NO: 691) or "WLPFGFILIL" (SEQ ID NO: 692), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 254, 255, 878 or 879; and an auxiliary peptide, preferably a UCP2 peptide (SEQ ID NO: 859). Still more preferably, the pharmaceutical composition comprises: an antigenic peptide comprising or consisting of SEQ ID NO: 32; an antigenic peptide comprising or consisting of SEQ ID NO: 255; and a UCP2 helper peptide (SEQ ID NO: 859).

[0364] It is also preferred that the pharmaceutical composition comprises a first antigenic peptide according to the present invention, which comprises or consists of a microbial biota sequence variant of a fragment of the human tumor antigen FOXM1; a second antigenic peptide according to the present invention, which comprises or consists of a microbial biota sequence variant of a fragment of the tumor antigen IL13RA2; and an auxiliary peptide, preferably a UCP2 peptide (SEQ ID NO: 859). More preferably, the pharmaceutical composition comprises a first antigenic peptide according to the present invention comprising or consisting of a microbial sequence variant of the FOXM1 fragment (human reference peptide) "LMDLSTTPL" (SEQ ID NO: 674), such as an antigenic peptide comprising or consisting of the amino acid sequence of SEQ ID NO: 220 or 868; a second antigenic peptide according to the present invention comprising or consisting of a microbial sequence variant of the IL13RA2 fragment (human reference peptide) "WLPFGFILI" (SEQ ID NO: 691) or "WLPFGFILIL" (SEQ ID NO: 692), such as an antigenic peptide comprising or consisting of the amino acid sequence of SEQ ID NO: 254, 255, 878, or 879; and an auxiliary peptide, preferably a UCP2 peptide (SEQ ID NO: 859). Even more preferably, the pharmaceutical composition comprises: an antigenic peptide comprising or consisting of SEQ ID NO: 220; an antigenic peptide comprising or consisting of SEQ ID NO: 255; and a UCP2 auxiliary peptide (SEQ ID NO: 859).

[0365] More preferably, the pharmaceutical composition comprises at least three different antigenic peptides according to the present invention and a helper peptide, preferably a UCP2 peptide (SEQ ID NO: 859).

[0366] Specifically, the pharmaceutical composition may include a first antigenic peptide according to the present invention, which comprises or consists of a microbial biota sequence variant of a fragment of the human tumor antigen BIRC5; a second antigenic peptide according to the present invention, which comprises or consists of a microbial biota sequence variant of a fragment of the human tumor antigen FOXM1; a third antigenic peptide according to the present invention, which comprises or consists of a microbial biota sequence variant of a fragment of the human tumor antigen IL13RA2; and an auxiliary peptide, preferably a UCP2 peptide (SEQ ID NO: 859). Still more preferably, the pharmaceutical composition comprises a first antigenic peptide according to the present invention comprising or consisting of a microbial biota sequence variant of the BIRC5 fragment (human reference peptide) "LTLGEFLKL" (SEQ ID NO: 593), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 30, 31 or 32; a second antigenic peptide according to the present invention comprising or consisting of a microbial biota sequence variant of the FOXM1 fragment (human reference peptide) "LMDLSTTPL" (SEQ ID NO: 674), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 220 or 868; a third antigenic peptide according to the present invention comprising or consisting of a microbial biota sequence variant of the IL13RA2 fragment (human reference peptide) "WLPFGFILI" (SEQ ID NO: 691) or "WLPFGFILIL" (SEQ ID NO: 692), such as an antigenic peptide comprising or consisting of the amino acid sequence shown in SEQ ID NO: 30, 31 or 32. More preferably, the pharmaceutical composition comprises: an antigenic peptide comprising or consisting of the amino acid sequence of SEQ ID NO: 30; an antigenic peptide comprising or consisting of the amino acid sequence of SEQ ID NO: 220; an antigenic peptide comprising or consisting of the amino acid sequence of SEQ ID NO: 255; and an auxiliary peptide, preferably a UCP2 peptide (SEQ ID NO: 859).

[0367] Particularly preferred immunoadjuvants are polyinosinic:polycytidylic acid (also known as "poly I:C") and / or its derivative poly-ICLC. Poly I:C is a mismatched double-stranded RNA in which one strand is a polymer of inosinic acid and the other is a polymer of cytidylic acid. Poly I:C is an immunostimulatory agent known to interact with Toll-like receptor 3 (TLR3). Poly I:C is structurally similar to double-stranded RNA, which is a "natural" stimulator of TLR3. Therefore, poly I:C can be considered a synthetic double-stranded RNA analog. Poly-ICLC is a synthetic complex of carboxymethylcellulose, polyinosinic-polycytidylic acid and poly-L-lysine double-stranded RNA. Similar to poly I:C, poly-ICLC is a ligand for TLR3. Poly I:C and poly-ICLC generally stimulate the release of cytotoxic cytokines. Preferred examples of poly-ICLC are

[0368] Most preferably, the adjuvant is Montanide, such as Montanide ISA 51 VG and / or Montanide ISA 720 VG. These adjuvants can provide stable water-in-oil emulsions when mixed with an aqueous antigenic medium. Montanide ISA 51 VG is based on a mixture of mannose monooleate surfactant and mineral oil, while Montanide ISA 720 VG uses a non-mineral oil (Aucouturier J, Dupuis L, Deville S, Ascarateil S, Ganne V. Montanide ISA 720 and 51: a new generation of water in oil emulsions as adjuvants for human vaccines. Expert Rev Vaccines. 2002 Jun; 1(1): 111-8; Ascarateil S, Puget A, Koziol M-E. Safety data of Montanide ISA 51 VG and Montanide ISA 720 VG, two adjuvants dedicated to human therapeutic vaccines. Journal for Immunotherapy of Cancer. 2015; 3(Suppl 2): ​​P428. doi: 10.1186 / 2051-1426-3-S2-P428).

[0369] It is also preferred that the immunostimulant is an antigen presenting cell (APC). APC is also particularly concerned because its main function is to process antigens and present them on the cell surface of the T cells of the immune system, thereby starting and regulating T cell responses in vivo. In the composition of the present invention, it is preferred that APC is loaded with antigenic peptides (one or more) and / or immunogenic compounds (one or more) according to the present invention, which can be completed by exposing APC to the antigenic peptides (one or more) and / or immunogenic compounds (one or more) in vitro (Rizzo et al., Methods Mol Biol. 2014; 1139: 41-4; Rolinski and Hus, J Immunotoxicol. 2014 October; 11 (4): 311-8).

[0370] Preferably, APC is dendritic cell (DC).DC is the most effective APC, and is often functionally defective according to reports in cancer patients.DC can be easily obtained by those skilled in the art from healthy compatible donors (i.e., dendritic cells are HLA-related) or the patient itself--as long as it is functional (i.e., DC is autologous), for example, by directly separating from peripheral blood, or by deriving from peripheral blood cells such as CD14+ monocytes or CD34+ hematopoietic precursors (Emens et al., 2008).In fact, DC can be distinguished from other cells of peripheral blood by its surface markers (such as S100, p55, CD83 and / or OX62), and therefore can be separated and purified based on the markers utilizing cell culture techniques well known in the art.

[0371] According to a preferred embodiment, the pharmaceutical composition may further comprise at least one anticancer therapeutic agent. Therefore, the therapeutic agent is preferably capable of preventing and / or treating the same type of cancer as the antigenic peptide according to the present invention. Preferably, the anticancer therapeutic agent is selected from antibodies, tumor cell lysates, chemotherapeutic agents, radiotherapeutic agents, immune checkpoint modulators, and combinations thereof.

[0372] Antibodies are particularly advantageous in cancer treatment because they can bind to specific antigens on the surface of cancer cells, thereby directing treatment to tumors (ie, these are referred to as tumor-targeting antibodies), or blocking immune checkpoints that are dysregulated in cancer (ie, these are referred to herein as immunomodulatory antibodies). The purpose of the latter type of antibody is to suppress cancer immune resistance, which can be significantly observed for tumor antigen-specific T cells. In fact, as is well known in the art, under normal physiological conditions, immune checkpoints are crucial for maintaining self-tolerance (ie, preventing autoimmunity) and protect tissues from damage when the immune system responds to pathogenic infections. However, in cancer, immune checkpoint expression can be dysregulated as an important mechanism of immune resistance. With respect to the PD-L1 checkpoint, such resistance has been observed in melanoma, ovarian cancer, lung cancer, glioblastoma, breast cancer, and pancreatic cancer (Konishi et al., B7-H1 expression on non-small cell lung cancer cells and its relationship with tumor-infiltrating lymphocytes and their PD-1 expression. Clin Cancer Res. 2004 Aug 1;10(15):5094-100; Ghebeh et al., The B7-H1(PD-L1)T lymphocyte-inhibitory molecule is expressed in breast cancer patients with infiltrating ductal carcinoma: correlation with important high-risk prognostic factors. Neoplasia. 2006 Mar;8(3):190-8; Hino et al., Tumor cell expression of programmed cell death-1 ligand 1 is a prognostic factor form alignant Melanoma. Cancer. 2010 Apr 1; ​​116(7): 1757-66). Other examples of immune checkpoints include, but are not limited to, PD-L2, PD-1, CD80, CD86, CTLA-4, B7H3, B7H4, PVR, TIGIT, GAL9, LAG-3, GITR, CD137, TIM3, VISTA, VISTA-R (Pico de et al., Checkpoint blockade for cancer therapy: revitalizing a suppressed immune system. Trends Mol Med. 2015 Aug;21(8):482-91; Pardoll DM. The blockade of immune checkpoints in cancerimmunotherapy. Nat Rev Cancer. 2012 Mar 22;12(4):252-64).

[0373] Antibodies are typically used for these purposes in the form of naked monoclonal antibodies (ie, unconjugated) or conjugated to other molecules that are cytotoxic or radioactive.

[0374] Examples of well-known monoclonal tumor-targeting antibodies used in cancer immunotherapy include, but are not limited to, alemtuzumab (chronic lymphocytic leukemia), bevacizumab (colorectal cancer, glioblastoma multiforme, cervical cancer, lung cancer, kidney cancer), brentuximab / vedotin (lymphoma), blinatumumab (acute lymphoblastic leukemia), catumaxomab (malignant ascites in EPCAM+ cancers), cetuximab (head and neck cancer, colorectal cancer), denosumab (breast cancer, prostate cancer, and bone cancer), gemtuzumab / ozogamicin (tumor cells), and scleroderma. n) (acute myeloid leukemia), ibritumomab / tiuxetan (non-Hodgkin's lymphoma), panitumumab (colorectal cancer), pertuzumab (breast cancer), obinutuzumab (chronic lymphocytic leukemia), ofatumumab (chronic lymphocytic leukemia), opilimumab (melanoma), ramucirumab (gastric and gastroesophageal cancer), rituximab (chronic lymphocytic leukemia and non-Hodgkin's lymphoma), siltuximab (multicentric's Catsleman's disease)), tositumomab (non-Hodgkin's lymphoma) and trastuzumab (breast cancer, gastric cancer and gastro-esophageal cancer); while examples of immunomodulatory antibodies include, but are not limited to, ipilimumab (melanoma) - which blocks the CTLA4-dependent immune checkpoint, nivolumab (melanoma, lung cancer) and prembrolizubmab (melanoma) - both of which block the PDCD1-dependent immune checkpoint, and MPDL3280A, MEDI4736, MEDI0680 and MSB0010718C - all of which block the PD-L1-dependent immune checkpoint (Sharma and Allison, The future of immune checkpoint therapy. Science. 2015 Apr 3;348(6230):56-61).

[0375] Other antibodies for cancer immunotherapy have been described in Buqué et al., Trial Watch: Immunomodulatory monoclonal antibodies for oncological indications. Oncoimmunology. 2015 Mar 2;4(4):e1008814. eCollection 2015 Apr; Redman et al., Mechanisms of action of therapeutic antibodies for cancer. Mol Immunol. 2015 Oct;67(2Pt A):28-45; Simpson and Caballero, Monoclonal antibodies for the therapy of cancer MC Proc. 2014;8(Suppl 4):06 and on the Antibody Society website (a list of therapeutic monoclonal antibodies approved or under review in the European Union or United States is available at http: / / www.antibodysociety.org / news / approved_mabs.php).

[0376] Tumor cell lysates can also be combined with antigenic peptides according to the present invention (one or more). By presenting endogenous peptide-MHC complexes, and via host dendritic cells (DCs) that can process and present the antigen delivered by the lysate, tumor cells can indeed elicit an immune response. Thus the scope of the antigen that can induce an immune response can be increased. Tumor cell lysates can be easily obtained by processing tumor cells with heat shock and / or chemical treatment, and can be autologous (i.e., separating from the patient) or allogeneic (i.e., separating from another experimenter).

[0377] Standard chemotherapeutic drugs and radiotherapeutic agents do not need to be described further herein as they have been extensively described in the literature, in particular by Baskar et al. (Baskar et al., Cancer and radiation therapy: current advances and future directions. Int J Med Sci. 2012; 9(3): 193-9), Paci et al. (Paci et al., Review of therapeutic drug monitoring of anticancer drugs part 1--cytotoxics. Eur J Cancer. 2014 Aug; 50(12): 2010-9) and Widmer et al. (Widmer et al., Review of therapeutic drug monitoring of anticancer drugs part two--targeted therapies. Eur J Cancer. 2014 Aug; 50(12): 2020-36). A list of such drugs and agents is also available on the cancer.gov website (http: / / www.cancer.gov / about-cancer / treatment / drugs).

[0378] Preferably, the immune checkpoint regulator for use in combination with the antigenic peptides defined herein is an activator or inhibitor of one or more immune checkpoint molecules selected from the group consisting of CD27, CD28, CD40, CD122, CD137, OX40, GITR, ICOS, A2AR, B7-H3, B7-H4, BTLA, CD40, CTLA-4, IDO, KIR, LAG3, PD-1, TIM-3, VISTA, CEACAM1, GARP, PS, CSF1R, CD94 / NKG2A, TDO, GITR, TNFR and / or FasR / DcR3; or an activator or inhibitor of one or more of its ligands.

[0379] More preferably, the immune checkpoint regulator is an activator of a (co)stimulatory checkpoint molecule or an inhibitor of an inhibitory checkpoint molecule or a combination thereof. Therefore, the immune checkpoint regulator is more preferably an activator of (i) CD27, CD28, CD40, CD122, CD137, OX40, GITR and / or ICOS or an inhibitor of (ii) A2AR, B7-H3, B7-H4, BTLA, CD40, CTLA-4, IDO, KIR, LAG3, PD-1, PDL-1, PD-L2, TIM-3, VISTA, CEACAM1, GARP, PS, CSF1R, CD94 / NKG2A, TDO, TNFR and / or FasR / DcR3.

[0380] Still more preferably, the immune checkpoint regulator is an inhibitor of an inhibitory checkpoint molecule (but preferably not an inhibitor of a stimulatory checkpoint molecule). Therefore, the immune checkpoint regulator is still more preferably an inhibitor of A2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, PDL-1, PD-L2, TIM-3, VISTA, CEACAM1, GARP, PS, CSF1R, CD94 / NKG2A, TDO, TNFR and / or DcR3 or its ligand.

[0381] It is also preferred that the immune checkpoint regulator is an activator of a stimulatory or co-stimulatory checkpoint molecule (but preferably not an activator of an inhibitory checkpoint molecule). Therefore, the immune checkpoint regulator is more preferably an activator of CD27, CD28, CD40, CD122, CD137, OX40, GITR and / or ICOS or its ligand.

[0382] It is also more preferred that the immune checkpoint regulator is a regulator of the CD40 pathway, the IDO pathway, the LAG3 pathway, the CTLA-4 pathway and / or the PD-1 pathway. Specifically, the immune checkpoint regulator is preferably a regulator of CD40, LAG3, CTLA-4, PD-L1, PD-L2, PD-1 and / or IDO, more preferably the immune checkpoint regulator is an inhibitor of CTLA-4, PD-L1, PD-L2, PD-1, LAG3, and / or IDO or an activator of CD40, still more preferably the immune checkpoint regulator is an inhibitor of CTLA-4, PD-L1, PD-1, LAG3 and / or IDO, still more preferably the immune checkpoint regulator is an inhibitor of LAG3, CTLA-4 and / or PD-1, and most preferably the immune checkpoint regulator is an inhibitor of CTLA-4 and / or PD-1.

[0383] Therefore, the checkpoint regulator for combination with the antigenic peptide can be selected from known regulators of the CTLA-4 pathway or the PD-1 pathway. Preferably, the checkpoint regulator for combination with the antigenic peptide defined herein can be selected from known regulators of the CTLA-4 pathway or the PD-1 pathway. Particularly preferably, the immune checkpoint regulator is a PD-1 inhibitor. Preferred inhibitors of the CTLA-4 pathway or the PD-1 pathway include monoclonal antibodies (ipilimumab; Bristol Myers Squibb) and tremelimumab (Pfizer / MedImmune) and (nivolumab; Bristol Myers Squibb), (Pembrolizumab, also known as Lambrolizumab or MK-3475; Merck), (Durvalumab, also known as MEDI4736; MedImmune / AstraZeneca), (Atezolizumab, also known as MPDL3280A; Roche / Genentech), Pidilizumab (CT-011; CureTech), MEDI0680 (AMP-514; AstraZeneca), (Avelumab; Merck KGaA / Pfizer, also known as MSB-0010718C), MIH1 (Affymetrix), LY3300054 (Eli Lilly), and Spartalizumab (also known as PDR001; Novartis). More preferred checkpoint inhibitors include CTLA-4 inhibitors (ipilimumab; Bristol Myers Squibb) and tesimumab (Pfizer / MedImmune), as well as PD-1 inhibitors (nivolumab; Bristol Myers Squibb), (pembrolizumab; Merck), Pidilizumab (CT-011; CureTech), MEDI0680 (AMP-514; AstraZeneca), AMP-224 (PD-L2 Fc fusion protein; MedImmune).

[0384] It is also preferred that the immune checkpoint regulator for combination with the antigenic peptide defined herein is selected from the group consisting of pembrolizumab, ipilimumab, nivolumab, atezolizumab, durvalumab, tesitumomab, avelumab, spartalizumab, LAG525 (anti-LAG-3 monoclonal antibody), Epacadostat (also known as INCB24360; IDO inhibitor), Varlilumab (anti-CD27 monoclonal antibody), Urelumab (anti-CD137 monoclonal antibody), AMP-224 and CM-24 (anti-CEACAM1 monoclonal antibody).

[0385] It is within the capabilities of one of ordinary skill in the art to select an immunotherapy agent suitable for the purposes of the present invention. For example, if it is desired to prevent or treat melanoma, then a melanoma cell lysate and / or the antibody ipilimumab may be preferably used together with an appropriate antigenic peptide. Suitable antigenic peptides can be selected by: (i) selecting a tumor antigen suitable for a particular cancer type known in the art and / or described in Table 1B herein, and (ii) selecting an antigenic peptide according to the present invention that is suitable for the selected tumor antigen as described above (e.g., in Table 1A).

[0386] Anti-cancer therapeutic agents may also be administered in combination with the compositions of the invention, either simultaneously, separately or sequentially.If the composition and therapeutic agent are administered in a separate or sequential manner, they may be administered in different pharmaceutical forms.

[0387] Therefore, in another aspect, the present invention relates to a composition of the present invention and at least one anticancer therapeutic agent as described above, as a combined preparation for simultaneous, separate or sequential administration. In other words, the present invention provides for the combined use of a composition of the present invention and at least one anticancer therapeutic agent as described above, for simultaneous, separate or sequential administration.

[0388] Kits-of-parts

[0389] In a further aspect, the present invention also provides a kit of parts (also referred to herein as a "kit") comprising at least one of:

[0390] - an antigenic peptide according to the invention as described herein,

[0391] - an immunogenic compound according to the invention as described herein,

[0392] - the nanoparticles according to the invention as described herein,

[0393] - a cell according to the invention as described herein,

[0394] - a nucleic acid according to the invention as described herein,

[0395] - a host cell according to the invention as described herein, and / or

[0396] - A pharmaceutical composition according to the invention as described herein.

[0397] Specifically, the preferred embodiments of the antigenic peptides described above also apply to the kit according to the present invention. For example, the antigenic peptide included in the kit or the antigenic peptide included in any of the immunogenic compounds, nanoparticles, cells, nucleic acids, host cells, or pharmaceutical compositions included in the kit preferably comprises or consists of the amino acid sequence set forth in any one of SEQ ID NOs: 1 to 580 and 861 to 887, such as an antigenic peptide comprising or consisting of the amino acid sequence set forth in any one of SEQ ID NOs: 1 to 580. For example, more preferably, the antigenic peptide according to the present invention comprises or consists of the amino acid sequence set forth in any one of SEQ ID NOs: 1–160, 162–253, and 255–580. For example, even more preferably, the antigenic peptide according to the present invention comprises or consists of the amino acid sequence set forth in any one of SEQ ID NOs: 30, 31, 32, 87, 97, 145, 193, 194, 220, 221, 255, 521, and 524. For example, an antigenic peptide according to the present invention comprising or consisting of the amino acid sequence represented by any one of SEQ ID NOs: 30, 31, 32, 87, 97, 193, 194, 220, 255, 521, and 524 is more preferred. For example, an antigenic peptide according to the present invention comprising or consisting of the amino acid sequence represented by any one of SEQ ID NOs: 30, 31, 32, 87, 97, 194, 220, 255, 521, and 524 is still more preferred. For example, an antigenic peptide according to the present invention comprising or consisting of the amino acid sequence represented by any one of SEQ ID NOs: 30, 31, 32, 87, 97, 194, 220, 255, 521, and 524 is most preferred. For example, an antigenic peptide according to the present invention comprising or consisting of the amino acid sequence represented by any one of SEQ ID NOs: 30, 32, 87, 97, and 194 is particularly preferred.

[0398] Moreover combinations thereof, ie kits comprising different antigenic peptides according to the invention are preferred. In particular, the kit of parts of the invention may comprise more than one of said components, for example 2, 3, 4, 5, 6, 7, 8, 9 or 10 different components. For example, a kit of parts according to the invention may comprise at least two (e.g. 2, 3, 4, 5, 6, 7, 8, 9, or 10) different immunogenic compounds, at least two (e.g. 2, 3, 4, 5, 6, 7, 8, 9, or 10) different antigenic peptides, at least two (e.g. 2, 3, 4, 5, 6, 7, 8, 9, or 10) different nanoparticles, at least two (e.g. 2, 3, 4, 5, 6, 7, 8, 9, or 10) different cells, at least two (e.g. 2, 3, 4, 5, 6, 7, 8, 9, or 10) different nucleic acids, at least two (e.g. 2, 3, 4, 5, 6, 7, 8, 9, or 10) different host cells, and / or at least two (e.g. 2, 3, 4, 5, 6, 7, 8, 9, or 10) different pharmaceutical compositions. Preferably, the different components comprised in the multi-part kit differ in that they are antigenic peptides according to the invention, e.g., one component relates to a first antigenic peptide and one component relates to a second antigenic peptide (different from the first antigenic peptide). For example, the kit may comprise at least two different immunogenic compounds according to the invention. For example, the kit may comprise at least two different antigenic peptides according to the invention. For example, the kit may comprise at least two different nanoparticles according to the invention. For example, the kit may comprise at least two different nucleic acids according to the invention.

[0399] The preferred combinations of antigenic peptides according to the present invention included in the kit correspond to the preferred combinations of antigenic peptides according to the present invention included in the above-mentioned pharmaceutical composition.

[0400] Thus, the present invention provides a kit comprising (at least one) antigenic peptide according to the present invention as described herein. Additionally, the present invention provides a kit comprising (at least one) immunogenic compound according to the present invention as described herein. Additionally, the present invention provides a kit comprising (at least one) nanoparticle according to the present invention as described herein. Additionally, the present invention provides a kit comprising (at least one) cell according to the present invention as described herein. Additionally, the present invention provides a kit comprising (at least one) nucleic acid according to the present invention as described herein. Additionally, the present invention provides a kit comprising (at least one) host cell according to the present invention as described herein.

[0401] The various components of the multi-part kit can be packaged in one or more containers. The above components can be provided in lyophilized or dry form or dissolved in an appropriate buffer. The kit can also include additional reagents, including, for example, preservatives, growth media, and / or buffers for storage and / or reconstitution of the above components, washing solutions, etc.

[0402] Thus, the present invention provides a kit comprising at least two, preferably three, different antigenic peptides according to the present invention as described herein (or the above-mentioned immunogenic compounds, nanoparticles, nucleic acids, cells, etc., which differ in terms of antigenic peptides), and optionally a helper peptide, such as a UCP2 peptide, and / or an adjuvant, such as MONTANIDE ISA 51. The different antigenic peptides (or the above-mentioned immunogenic compounds, nanoparticles, nucleic acids, cells, etc., which differ in terms of antigenic peptides) can be contained in the same or different containers. For example, the kit can comprise a (single) container comprising a first antigenic peptide as described herein and a second antigenic peptide as described herein. The (single) container can further comprise a helper peptide, such as UCP2. Optionally, the first and second antigenic peptides (and optionally the helper peptide) contained in the (single) container can be formulated together, for example, in water for injection and / or dimethyl sulfoxide (DMSO). In addition, the kit can comprise a further container (different from the container comprising the antigenic peptides) comprising an adjuvant, such as MONTANIDE ISA 51.

[0403] Therefore, preferably the kit comprises

[0404] (i) a first vial comprising one or more antigenic peptides of the invention (e.g., at least 200 or 300 μg of each antigenic peptide), and optionally a helper peptide, such as UCP2 (e.g., at least 200 or 300 μg of the helper peptide), optionally in water for injection and dimethyl sulfoxide (DMSO); and

[0405] (ii) A second vial comprising MONTANIDE ISA 51 (eg, at least 0.4 or 0.5 ml).

[0406] In addition, the kit may include one or more (eg, 2 or 3) syringes, such as silicone-free and rubber-free syringes. The kit may also include a connector, such as a Type I connector.

[0407] Non-limiting examples of such connectors are:

[0408] I-type connector developed by Green Peptide (Japan),

[0409] Didanorm (France) connector, number DIDRACDLLFT,

[0410] Promepla (Monaco) Type I connector (Part No. ODG0015ST), and

[0411] Smiths medical (US) Type I connector (Part No. MX494).

[0412] The syringe is preferably suitable for MONTANIDE, i.e., silicone-free and rubber-free (i.e., without any rubber tip on the plunger), and preferably also latex-free. Non-limiting examples of such syringes are:

[0413] 2ml INKJET (No. 4606701V, from B-Braun, Germany),

[0414] 5ml INKJET (No. 4606710V, from B-Braun, Germany),

[0415] 2 ml Norm-Ject (No. 4020.000V0, from Henke Sass Wolf GMBH, Germany), and

[0416] 5 ml Norm-Ject (No. 4050.000V0, from Henke Sass Wolf GMBH, Germany).

[0417] For example, the kit may comprise (i) a first vial comprising at least 300 μg of an antigenic peptide of the invention (or two or three antigenic peptides, at least 300 μg each), and optionally at least 300 μg of UCP2, formulated in water for injection and dimethyl sulfoxide (DMSO); (ii) a second vial comprising at least 0.5 ml of MONTANIDE ISA 51; (iii) two silicone-free and rubber-free syringes; and (iv) a type I connector.

[0418] Optionally, the kit may also include a vial of water for injection and / or a vial adapter. A sterile needle may also be included, for example, for vaccinating a patient after obtaining the emulsion. The syringe in the kit may be, for example, a 2 ml syringe.

[0419] In one embodiment, a kit comprises three different antigenic peptides according to the present invention, a UCP2 peptide, and MONTANIDE ISA 51, wherein the kit comprises (i) a first vial comprising at least 300 μg of each of the three antigenic peptides according to the present invention and at least 300 μg of UCP2 (SEQ ID NO: 859), formulated in water for injection and DMSO; (ii) a second vial comprising at least 0.5 ml of MONTANIDE ISA 51, (iii) two silicone-free and rubber-free syringes; and (iv) a type I connector. The three antigenic peptides of the present invention included in the kit are preferably an antigenic peptide comprising or consisting of the amino acid sequence of SEQ ID NO: 32, an antigenic peptide comprising or consisting of the amino acid sequence of SEQ ID NO: 220, and an antigenic peptide comprising or consisting of the amino acid sequence of SEQ ID NO: 255.

[0420] In addition, the kit of parts according to the present invention may optionally comprise instructions for use. Thus, preferably, the kit comprises a package insert or instructions with instructions for preventing or treating cancer by using the immunogenic compound according to the present invention, the antigenic peptide according to the present invention, the nanoparticle according to the present invention, the cell according to the present invention, the nucleic acid according to the present invention, the host cell according to the present invention, or the pharmaceutical composition according to the present invention.

[0421] It is also preferred that the kit further comprises, in addition to any of the components described above, an anti-cancer therapeutic agent as described herein.

[0422] In addition, the present invention also provides a vaccination kit for treating, preventing and / or stabilizing cancer, which comprises the pharmaceutical composition or the vaccine described herein and instructions for use of the pharmaceutical composition or the vaccine in preventing and / or treating cancer.

[0423] Medical treatment and use

[0424] As noted above, the compositions of the present invention are particularly useful for therapeutic applications, particularly for eliciting a specific immune response against a particular tumor antigen / protein, such as for preventing or treating cancer in a patient in need thereof.

[0425] In view of this, the present invention provides

[0426] - an antigenic peptide according to the invention as described herein,

[0427] - an immunogenic compound according to the invention as described herein,

[0428] - the nanoparticles according to the invention as described herein,

[0429] - a cell according to the invention as described herein,

[0430] - a nucleic acid according to the invention as described herein,

[0431] - a host cell according to the invention as described herein,

[0432] - a pharmaceutical composition according to the invention as described herein, or

[0433] - a kit according to the invention as described herein,

[0434] For the prevention and / or treatment of cancer.

[0435] Specifically, the preferred embodiments of the above-mentioned antigenic peptides are also applicable to the use of the present invention in preventing and / or treating cancer. For example, the antigenic peptide for preventing and / or treating cancer or the antigenic peptide included in any one of the immunogenic compounds, nanoparticles, cells, nucleic acids, host cells, or pharmaceutical compositions for preventing and / or treating cancer preferably includes or consists of the amino acid sequence shown in any one of SEQ ID NOs: 1 to 580 and 861 to 887, such as the antigenic peptide including or consisting of the amino acid sequence shown in any one of SEQ ID NOs: 1 to 580. For example, more preferably, the antigenic peptide according to the present invention includes or consists of the amino acid sequence shown in any one of SEQ ID NOs: 1-160, 162-253, and 255-580. For example, even more preferably, the antigenic peptide according to the present invention includes or consists of the amino acid sequence shown in any one of SEQ ID NOs: 30, 31, 32, 87, 97, 145, 193, 194, 220, 221, 255, 521, and 524. For example, it is more preferred that the antigenic peptide according to the present invention comprises or consists of the amino acid sequence represented by any one of SEQ ID NOs: 30, 31, 32, 87, 97, 193, 194, 220, 255, 521, and 524. For example, it is still more preferred that the antigenic peptide according to the present invention comprises or consists of the amino acid sequence represented by any one of SEQ ID NOs: 30, 31, 32, 87, 97, 194, 220, 255, 521, and 524. For example, it is most preferred that the antigenic peptide according to the present invention comprises or consists of the amino acid sequence represented by any one of SEQ ID NOs: 30, 32, 87, 97, and 194. For example, it is particularly preferred that the antigenic peptide according to the present invention comprises or consists of the amino acid sequence represented by any one of SEQ ID NOs: 30, 32, 194, 220, 254, or 255.

[0436] And preferably, a combination thereof, i.e., different antigenic peptides according to the present invention, is used for preventing and / or treating cancer. Specifically, more than one of the above components can be used for preventing and / or treating cancer. For example, at least two different antigenic peptides, at least two different immunogenic compounds, at least two different nanoparticles, at least two different cells, at least two different nucleic acids, at least two different host cells, and / or at least two different pharmaceutical compositions can be used for preventing and / or treating cancer. Preferably, the above-mentioned different components for preventing and / or treating cancer differ in that they are antigenic peptides according to the present invention, e.g., one component involves a first antigenic peptide, and one component involves a second antigenic peptide (different from the first antigenic peptide). For example, at least two different immunogenic compounds according to the present invention can be used for preventing and / or treating cancer. For example, at least two different antigenic peptides according to the present invention can be used for preventing and / or treating cancer. For example, at least two different nanoparticles according to the present invention can be used for preventing and / or treating cancer. For example, at least two different nucleic acids according to the present invention can be used for preventing and / or treating cancer.

[0437] Therefore, the present invention provides (at least one) antigenic peptide according to the present invention as described herein for use in preventing and / or treating cancer. In addition, the present invention also provides (at least one) immunogenic compound according to the present invention as described herein for use in preventing and / or treating cancer. In addition, the present invention also provides (at least one) nanoparticle according to the present invention as described herein for use in preventing and / or treating cancer. In addition, the present invention also provides (at least one) cell according to the present invention as described herein for use in preventing and / or treating cancer. In addition, the present invention also provides (at least one) nucleic acid according to the present invention as described herein for use in preventing and / or treating cancer. In addition, the present invention also provides (at least one) host cell according to the present invention as described herein for use in preventing and / or treating cancer. In addition, the present invention also provides (at least one) pharmaceutical composition according to the present invention as described herein for use in preventing and / or treating cancer. In addition, the present invention also provides a kit according to the present invention as described herein for use in preventing and / or treating cancer.

[0438] Therefore, the present invention also provides a method for preventing and / or treating cancer or inducing, enhancing or prolonging an anti-tumor response in a subject in need thereof, comprising administering to the subject

[0439] - an antigenic peptide according to the present invention,

[0440] - an immunogenic compound according to the invention,

[0441] - nanoparticles according to the invention,

[0442] - a cell according to the invention,

[0443] - a nucleic acid according to the invention,

[0444] - a host cell according to the invention,

[0445] - a pharmaceutical composition according to the invention,

[0446] - a kit according to the invention, or

[0447] - A combination according to the invention as described herein.

[0448] Preferably, the cancer to be prevented and / or treated is selected from glioma, renal cancer, skin cancer, in particular melanoma, lung cancer, ovarian cancer, breast cancer, colorectal cancer, liver cancer, pancreatic cancer, head and neck cancer, urothelial carcinoma and prostate cancer.

[0449] In addition, the present invention provides a method for inducing or increasing CD8-dependent + A method for enhancing an immune response of cytotoxic T cells against one or more epitopes, wherein the method comprises administering to the subject any of the following:

[0450] - an antigenic peptide according to the present invention,

[0451] - an immunogenic compound according to the invention,

[0452] - nanoparticles according to the invention,

[0453] - a cell according to the invention,

[0454] - a nucleic acid according to the invention,

[0455] - a host cell according to the invention,

[0456] - a pharmaceutical composition according to the invention,

[0457] - a kit according to the invention, or

[0458] - A combination according to the invention as described herein.

[0459] Dependence on CD8 + The immune response of response can be determined by evaluating inflammatory response, proinflammatory cytokine response, including that the expression of one or more of IFN-γ, TNF-α and IL-2 mRNA or protein is increased relative to the level before administering the compounds of this invention. It can also be measured by the increase in the frequency or absolute number of antigen-specific T cells after administering the compounds of this invention, which is measured by HLA-peptide polymer staining, ELISPOT determination and delayed-type hypersensitivity test. It can also be measured indirectly by the increase in antigen-specific serum antibodies that depend on antigen-specific T helper cells.

[0460] The present invention also provides a method for eliciting or enhancing an immune response in a subject to one or more antigens or antigenic epitopes restricted by a plurality of MHC class I molecules, wherein the method comprises administering to the subject any of the following:

[0461] - an antigenic peptide according to the present invention,

[0462] - an immunogenic compound according to the invention,

[0463] - nanoparticles according to the invention,

[0464] - a cell according to the invention,

[0465] - a nucleic acid according to the invention,

[0466] - a host cell according to the invention,

[0467] - a pharmaceutical composition according to the invention,

[0468] - a kit according to the invention, or

[0469] - A combination according to the invention as described herein.

[0470] The methods described herein for eliciting or improving an immune response to multiple epitopes by multiple MHC class I molecules in a subject can be determined by evaluating a cytokine response, including an increase in the expression of one or more of IFN-γ, TNF-α, and IL-2 mRNA or protein relative to the level before administration of the compounds of the invention after in vitro stimulation of T cells with individual peptides of discrete MHC class I molecules bound to antigen presenting cells. The restriction of MHC class I molecules can also be verified by utilizing antigen presenting cells expressing MHC class I molecules, or by utilizing MHC class I blocking antibodies. It can also be measured by an increase in the frequency or absolute number of antigen-specific T cells after administration of the compounds of the invention, measured by HLA-peptide multimer staining, utilizing multimers assembled with MHC class I molecules.

[0471] Therefore, in another aspect, the present invention also provides

[0472] - an antigenic peptide according to the present invention,

[0473] - an immunogenic compound according to the invention,

[0474] - nanoparticles according to the invention,

[0475] - a cell according to the invention,

[0476] - a nucleic acid according to the invention,

[0477] - a host cell according to the invention,

[0478] - a pharmaceutical composition according to the invention,

[0479] - a kit according to the invention, or

[0480] - a combination according to the invention, as described herein,

[0481] Used as medicine.

[0482] The present invention more particularly relates to a composition as defined above for use as a vaccine for immunotherapy.

[0483] - an antigenic peptide according to the present invention,

[0484] - an immunogenic compound according to the invention,

[0485] - nanoparticles according to the invention,

[0486] - a cell according to the invention,

[0487] - a nucleic acid according to the invention,

[0488] - a host cell according to the invention,

[0489] - a pharmaceutical composition according to the invention,

[0490] - a kit according to the invention, or

[0491] - a combination according to the invention, as described herein,

[0492] Can be used as a vaccine, in particular for (cancer) immunotherapy.

[0493] As described in the context of the present invention, the term "vaccine" refers to a (biological) preparation that provides innate and / or adaptive immunity, generally against a specific disease, preferably cancer. Thus, vaccines specifically support the innate and / or adaptive immune response of the immune system of the subject to be treated. For example, the antigenic peptides according to the present invention generally induce or support an adaptive immune response in the patient to be treated.

[0494] In the context of the present invention, vaccines (compositions) can induce a specific immune response against tumor antigens and are therefore preferably used to prevent or treat cancer. Vaccines used to prevent or treat cancer may also be referred to as "cancer vaccines."

[0495] Thus, in a preferred embodiment, the present invention relates to a composition as defined above for use in preventing and / or treating cancer in a subject in need thereof. More preferably, the present invention relates to the use of a composition according to the present invention for the preparation of a medicament for preventing or treating cancer in a subject in need thereof. In other words, the present invention relates to a method for preventing or treating cancer in a subject in need thereof, comprising administering to said subject an effective amount of a composition according to the present invention.

[0496] Preferably to be passed through the herein described

[0497] - an antigenic peptide according to the present invention,

[0498] - an immunogenic compound according to the invention,

[0499] - nanoparticles according to the invention,

[0500] - a cell according to the invention,

[0501] - a nucleic acid according to the invention,

[0502] - a host cell according to the invention,

[0503] - a pharmaceutical composition according to the invention,

[0504] - a kit according to the invention, or

[0505] - Combination according to the invention

[0506] The cancer to be prevented and / or treated involves a (reference) tumor antigen of the antigenic peptide described herein. That is, the appropriate antigenic peptide can be selected by: (i) selecting a tumor antigen known in the art and / or described in Table 1B (below) herein that is suitable for a certain cancer type; and (ii) selecting the antigenic peptide according to the present invention that is suitable for the selected tumor antigen as described above (e.g., Table 1A). It will be readily understood by those skilled in the art that the antigenic peptide of the present invention can be selected based on the properties of the cancer to be prevented or treated and / or the human gene / human tumor antigen involved in the cancer.

[0507] Therefore, preferred examples of cancer are shown in the following Table 1 B. Specifically, the antigenic peptides according to the present invention are sequence variants of fragments of tumor antigens shown in Table 1B and can be specifically used for the diseases outlined in Table 1B for the corresponding tumor antigens.

[0508] Table 1B: List of tumor antigens and associated therapeutic indications

[0509]

[0510]

[0511]

[0512]

[0513] In general, the antigenic peptides of the present invention can be administered "naked" or in the form of an immunogenic compound according to the present invention, a cell loaded therewith according to the present invention, a nanoparticle according to the present invention, a nucleic acid according to the present invention, a host cell according to the present invention and / or a pharmaceutical composition according to the present invention.

[0514] In a preferred embodiment, it can be given in the form of a microorganism such as an intestinal bacteria species. Complete intestinal bacteria species can also be advantageous because i...

Claims

1. An antigenic peptide, consisting of the amino acid sequence shown in SEQ ID NO:

32.

2. A nanoparticle loaded with the antigenic peptide according to claim 1.

3. The nanoparticle according to claim 2, wherein the nanoparticle is loaded with an adjuvant.

4. A cell loaded with the antigenic peptide according to claim 1.

5. The cell according to claim 4, wherein the cell is an antigen-presenting cell.

6. The cell according to claim 4, wherein the cell is a dendritic cell.

7. A nucleic acid encoding the antigenic peptide according to claim 1.

8. The nucleic acid according to claim 7, wherein the nucleic acid is a DNA molecule or an RNA molecule.

9. The nucleic acid according to claim 7, wherein the nucleic acid is selected from genomic DNA; cDNA or mRNA.

10. A host cell comprising the nucleic acid according to any one of claims 7-9.

11. The host cell according to claim 10, wherein the nucleic acid is a vector.

12. The host cell according to claim 10 or 11, wherein the host cell is a bacterial cell.

13. The host cell according to claim 10 or 11, wherein the host cell is an intestinal bacterial cell.

14. A pharmaceutical composition comprising - the antigenic peptide according to claim 1, - the nanoparticle according to claim 2 or 3, - the cell according to any one of claims 4-6, - the nucleic acid according to any one of claims 7-9, and / or - the host cell according to any one of claims 10-13, and one or more pharmaceutically acceptable excipients or carriers.

15. The pharmaceutical composition according to claim 14, further comprising one or more immunostimulants.

16. The pharmaceutical composition according to claim 15, wherein the immunostimulant is selected from immunoadjuvants and antigen-presenting cells.

17. The pharmaceutical composition according to claim 16, wherein the antigen-presenting cell is a dendritic cell.

18. A kit comprising - the antigenic peptide according to claim 1, - the nanoparticle according to claim 2 or 3, - the cell according to any one of claims 4-6, - the nucleic acid according to any one of claims 7-9, - the host cell according to any one of claims 10-13, and / or - the pharmaceutical composition according to any one of claims 14-17.

19. The kit according to claim 18, further comprising a package insert or instructions for using the antigenic peptide, the nanoparticle, the cell, the nucleic acid, the host cell, and / or the pharmaceutical composition for preventing or treating cancer.

20. A peptide-MHC (pMHC) multimer comprising the antigenic peptide according to claim 1.

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