Immunogenic Compounds for Cancer Treatment

Abstract

To provide antigenic peptides that can be used to induce a specific immune response against tumor cells.SOLUTION: An immunogenic compound comprises an antigenic peptide having amino acid similarity with a tumor antigen. The antigenic peptide is selected in the group consisting of specific amino acid sequences.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention is in the field of cancer treatment, more particularly, immunotherapeutic cancer treatment. [Background technology]

[0002] Cancer is one of the leading causes of death in the world. According to the World Health Organization, 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 about 70% within the next 20 years. So far, more than 60% of the total annual new cases worldwide occur in Africa, Asia, and Latin America. These regions also account for 70% of the world's cancer deaths. Among men, the five most common sites of cancer are lung, prostate, colorectal, stomach, and liver, while in women, they are breast, colorectal, lung, cervix, and stomach.

[0003] Cancer has been managed for many years by surgery, radiation therapy, cytotoxic chemotherapy, and endocrine manipulation, which are usually combined in sequence to best control the disease. However, the major limitations to the true effectiveness of these standard therapies lie in their imprecise specificity, which results in collateral damage of normal tissues with the treatment, low cure rates, and inherent drug resistance.

[0004] In recent years, significant progress has been made in the development of cancer treatments, especially due to major advances in expression profiling of tumor and normal cells, and recent research and first clinical results in immunotherapy or molecular targeted therapy are beginning to change our understanding of this disease.

[0005] Promising anti-cancer immunotherapy has become a reality, and evidence that the host immune system can recognize tumor antigens has led to the development of anti-cancer drugs that are currently approved by regulatory agencies, the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Various therapeutic approaches include, among others, adoptive transfer of ex vivo expanded tumor-infiltrating lymphocytes, cancer cell vaccines, immune stimulating cytokines and their variants, pattern recognition receptor (PRR) agonists, and immune-modulating monoclonal antibodies targeting tumor antigens or immune checkpoints (Non-Patent Document 1).

[0006] Unfortunately, a significant proportion of patients still exhibit inherent resistance to some of these immunotherapies or may even acquire resistance during the course of treatment. For example, the 3-year survival rate has been reported to be about 20% for the anti-CTLA-4 antibody ipilumumab in unresectable or metastatic melanoma (Non-Patent Document 2 and Non-Patent Document 3), while the 3-year survival rate for another checkpoint inhibitor targeting PD1, nivolumab, has been reported to be 44% for renal cell carcinoma (RCC) and 18% for NSCLC (Non-Patent Document 4 and Non-Patent Document 5). Thus, underlying drug resistance is a solid barrier to the efficacy of these immunotherapies. Therefore, it is clear that a different approach to cancer treatment is needed to overcome this barrier.

[0007] The lack of response in many subjects treated with these immunotherapies may be associated with a defective antitumor immune response (as a defect in antigen presentation by APCs or in antigen recognition by T cells). In other words, a positive response to immunotherapy correlates with the ability of the immune system to develop specific lymphocyte subsets capable of recognizing MHC class I-restricted antigens expressed by human cancer cells (Non-Patent Document 6). This hypothesis is supported by the fact that the response to adoptive transfer of tumor-infiltrating lymphocytes is dependent on the CD8 + This is strongly supported by data showing that the number of T cells directly correlates with the number of T cells (Non-Patent Document 7). Thus, a strong antitumor response depends on the presentation of immunoreactive peptides and the presence of sufficient numbers of reactive cells "trained" to recognize these antigens.

[0008] Tumor antigen-based vaccination is a unique approach to cancer therapy that has attracted great interest because it can mobilize the patient's own immune system to recognize, attack and destroy the tumor in a specific and durable way. Tumor cells are indeed known to express a large number of peptide antigens that are easily recognized by the immune system. Vaccines based on such antigens therefore not only improve the overall survival of patients, but also offer great opportunities for monitoring the immune response and preparation of GMP-grade products due to the low toxicity and low molecular weight of tumor antigens. Examples of tumor antigens include, in particular, protein by-products transcribed from normally silent or overexpressed genes, and proteins expressed by oncoviruses (Non-Patent Document 8), neo-antigens resulting from point mutations in cellular proteins. The latter are of particular interest since they have been shown to be directly associated with increased overall survival in patients treated with CTLA4 inhibitors (Non-Patent Document 9 and Non-Patent Document 10).

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

[0010] Thus, there is a need in the art to identify alternative cancer therapeutics that can overcome the limitations encountered in the art, particularly resistance to currently available immunotherapies.

[0011] The present invention aims to meet the aforementioned needs. [Prior art documents] [Non-patent literature]

[0012] [Non-Patent Document 1] Galuzzi et al., Classification of current anticancer immunotherapies. Oncotarget. 2014 Dec 30;5(24):12472-508

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Non-Patent Document 5

[0013] The present invention relates to an antigenic peptide having amino acid similarity with a tumor antigen, and the antigenic peptide is selected from the group consisting of SEQ ID NOs: 1 to 106. In other words, the present invention relates to an antigenic peptide having an amino acid sequence set forth in any one of SEQ ID NOs: 1 to 106. The antigenic peptide according to the present invention may be in the form of an immunogenic compound.

[0014] Thus, according to a particular embodiment, the present invention relates to an immunogenic compound comprising an antigenic peptide having amino acid similarity with a tumor antigen, the antigenic peptide being selected in the group consisting of SEQ ID NOs: 1 to 106, in particular SEQ ID NO: 71. In other words, the present invention relates to an immunogenic compound comprising an antigenic peptide having an amino acid sequence according to any one of SEQ ID NOs: 1 to 106.

[0015] More particularly, the present invention relates to an immunogenic compound as defined above, wherein said antigenic peptide is linked to a carrier protein.

[0016] The present invention also relates to nanoparticles loaded with at least an antigenic peptide according to the invention or at least one immunogenic compound according to the invention and, optionally, an adjuvant.

[0017] The present invention also relates to a composition comprising an antigenic peptide or an immunogenic compound as defined above, said composition preferably further comprising one or more pharma- ceutically acceptable excipients.

[0018] Thus, according to a particular embodiment, the present invention relates to an immunogenic composition comprising an antigenic peptide or an immunogenic compound as defined above and one or more pharma- ceutically acceptable excipients.

[0019] Preferably, the immunogenic composition may further comprise one or more immunostimulants.

[0020] The one or more immune stimulants may be selected in the group comprising (or consisting of) immune adjuvants and antigen presenting cells.

[0021] The antigen presenting cells may comprise dendritic cells.

[0022] According to another embodiment, the invention relates to an antigenic peptide as defined above or an immunogenic compound as defined above for use in the prevention or treatment of cancer.

[0023] According to a further embodiment, the present invention relates to an immunogenic composition for use in the prevention or treatment of cancer.

[0024] The present invention also relates to the use of an antigenic peptide as defined above or an immunogenic compound as defined above for preparing a medicament for treating or preventing cancer.

[0025] The present invention also relates to a method of preventing or treating cancer in an individual in need thereof, said method comprising the step of administering to said individual an antigenic peptide as defined above, or an immunogenic compound as defined above, or an immunogenic composition as defined above, or a nanoparticle according to the invention, or a nucleic acid according to the invention, or a combination according to the invention.

[0026] According to a further embodiment, the present invention relates to a nucleic acid encoding an antigenic peptide or an immunogenic compound as defined above.

[0027] Furthermore, the present invention also relates to a combination of two different immunogenic compounds according to the present invention for use in the prevention and / or treatment of cancer.Furthermore, the present invention also relates to a combination of two different antigenic peptides according to the present invention for use in the prevention and / or treatment of cancer.Furthermore, the present invention also relates to a combination of two different nanoparticles according to the present invention for use in the prevention and / or treatment of cancer.Furthermore, the present invention also relates to a combination of two different nucleic acids according to the present invention for use in the prevention and / or treatment of cancer.

[0028] In certain embodiments, the two different components of a combination for use according to the invention are contained in the same or different compositions.

[0029] In a specific embodiment, the two different components of a combination for use according to the invention are administered by the same or different routes of administration.

[0030] In certain embodiments, the two different components of a combination for use according to the invention are administered approximately simultaneously or sequentially.

[0031] Additionally, the present invention also relates to a kit comprising: an immunogenic compound according to the invention, - an antigenic peptide according to the invention, the nanoparticles according to the invention, a nucleic acid according to the invention, or - an immunogenic composition according to the invention. [Brief description of the drawings]

[0032] [Figure 1] FIG. 1 depicts the general protocol for proof-of-concept validation of tumor antigen-based immunotherapy targeting IL13RA2. [Diagram 2] FIG. 2 depicts a schematic diagram of the immunization scheme (d: day). [Diagram 3] Figure 3 shows the ELISPOT-IFNγ results for group 1 (IL13RA2-B) and group 2 (IL13RA2-A). The peptides used for vaccination (in brackets under each group) and the stimuli used for ELISPOT culture (X-axis) are shown on the graph. (A) Number of specific ELISPOT-IFNγ spots (subtracted media conditions). Each point represents the average value for one individual / mouse from the corresponding quadruplicate conditions. (B) For each individual, the level of specific ELISPOT-IFNγ response is compared to ConA stimulation (value: 100%). Statistical analysis: paired t-test for intragroup comparisons and unpaired t-test for intergroup comparisons. *p<0.05. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0033] The present inventors have identified a set of antigenic peptides that can be used to induce a specific immune response against tumor cells.

[0034] All of these antigenic peptides share the property of having amino acid similarity to the tumor antigens encoded by the set of genes disclosed in Tables 1A and 1B.

[0035] For example, interleukin-13 receptor subunit alpha-2 (IL-13Rα2 or IL13RA2) is a membrane-bound protein that is encoded by the IL13RA2 gene in humans. In a non-comprehensive manner, IL13RA2 has been reported as a potential immunotherapy target (see Beard et al.; Clin Cancer Res; 72(11);2012). High expression of IL13RA2 has further been associated with invasion, liver metastasis, and poor prognosis in colorectal cancer (Barderas et al.; Cancer Res; 72(11);2012).

[0036] Thus, the present invention relates to an antigenic peptide having amino acid similarity with a tumor antigen, the antigenic peptide being selected in the group consisting of SEQ ID NOs: 1-106.

[0037] As used herein, the phrase "having amino acid similarity to a tumor antigen" refers specifically to sequence variants of a fragment of a (reference) tumor antigen, such as IL13RA2.

[0038] A sequence variant shares at least 50% sequence identity with a reference sequence, i.e., a fragment of a (reference) tumor antigen, particularly over the entire length of the sequence. Preferably, a sequence variant shares at least 60%, preferably at least 70%, preferably at least 75%, more preferably at least 80%, even more preferably at least 85%, even more preferably at least 90%, particularly preferably at least 95%, and most preferably at least 99% sequence identity with a reference sequence, i.e., a fragment of a (reference) tumor antigen. Sequence identity can be calculated as follows. Preferably, a sequence variant preserves a specific function of the reference sequence, e.g., as an epitope. In particular, an amino acid sequence variant has an altered sequence in which one or more amino acids in the reference sequence are 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 that is at least 90% identical has no more than 10 changes per 100 amino acids of the reference sequence, i.e., any combination of deletions, insertions, or substitutions.

[0039] Methods for comparing the identity (similarity) of two or more sequences are well known in the art.The percentage of identity between two sequences can be determined, for example, by using mathematical algorithms.A preferred but non-limiting example of the mathematical algorithm that can be used is the algorithm of Karlin et al. (1993), PNAS USA, 90:5873-5877. Such algorithms are incorporated into the BLAST family of programs, e.g., the BLAST or NBLAST programs (see also Altschul et al., 1990, J. Mol. Biol. 215, 403-410 or Altschul et al. (1997), Nucleic Acids Res, 25:3389-3402), which are accessible through the NCBI home page at the World Wide Web (ncbi.nlm.nih.gov) and FASTA (Pearson (1990), Methods Enzymol. 183, 63-98; Pearson and Lipman (1988), Proc. Natl. Acad. Sci. 85, 2444-2448). Sequences that are identical to some degree to other sequences can be identified by these programs. In addition, programs available in the Wisconsin Sequence Analysis Package, version 9.1 (Devereux et al., 1984, Nucleic Acids Res., 387-395), such as the BESTFIT and GAP programs, can also be used to determine the percent identity between two polynucleotides and between two (poly)peptide sequences. BESTFIT uses the "local homology" algorithm of Smith and Waterman (1981), J. Mol. Biol. 147, 195-197, to find the best single region of similarity between two sequences.

[0040] Typically, a "fragment" of a reference tumor antigen sequence comprises at least 7, preferably at least 8, most preferably (at least) 9 amino acids, or 10 amino acids.

[0041] Advantageously, these antigenic peptides may be in the form of immunogenic compounds, particularly for use in the prevention or treatment of cancer.

[0042] Therefore, the present invention also relates to an immunogenic compound comprising an antigenic peptide having amino acid similarity with a tumor antigen, the antigenic peptide being selected from the group consisting of SEQ ID NOs: 1 to 106. In other words, the present invention provides an antigenic peptide having an amino acid sequence represented by any of SEQ ID NOs: 1 to 106. Preferably, the present invention provides an antigenic peptide (an immunogenic compound comprising) comprising or consisting of an amino acid sequence represented by any of SEQ ID NOs: 17, 31, 32, 51, 52, 55, 56, 59, 68, 89, 94, 100, 101, or 102. Also, the present invention preferably provides an antigenic peptide (an immunogenic compound comprising) comprising or consisting of an amino acid sequence represented by any of SEQ ID NOs: 26, 28, 47, 51, 52, 55, 56, 77, 93, 101, or 102. More preferably, the present invention provides an antigenic peptide (an immunogenic compound comprising) comprising or consisting of an amino acid sequence represented by any of SEQ ID NOs: 51, 52, 55, 56, 101, or 102. Even more preferably, the present invention provides an antigenic peptide (an immunogenic compound comprising the same) that comprises or consists of an amino acid sequence set forth in any one of SEQ ID NOs: 51, 52, 55, or 56. Furthermore, it is even more preferable that the present invention provides an antigenic peptide (an immunogenic compound comprising the same) that comprises or consists of an amino acid sequence set forth in any one of SEQ ID NOs: 101 or 102.

[0043] As shown in the examples of the present specification, the specific antigenic peptide of the present invention allows for the raising of a strong immune response against itself, and most importantly, while the peptide contained in the IL13RA2 tumor antigen is tolerogenic itself, it allows for the raising of a strong immune response against peptides that share amino acid similarity with it contained in the IL13RA2 tumor antigen.

[0044] Without wishing to be bound by any particular theory, the inventors believe that the high expression of gamma interferon measured following in vivo administration of an immunogenic composition comprising the antigenic peptides described herein explains the activation of antigenic peptide-specific T cells, and in particular the activation of antigenic peptide-specific CTLs, which are known in the art to be relevant immune effectors of anti-cancer immune responses.

[0045] Unless otherwise specified herein, scientific and technical terms used in connection with the present invention shall have the meanings commonly understood by those of ordinary skill in the art. Furthermore, unless the context requires otherwise, the nomenclature and cell and tissue culture techniques used herein are those commonly used and well known in the art.

[0046] Such techniques are fully explained in the literature, see, for example, 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).

[0047] Notwithstanding, the following definitions apply more specifically regarding the use of various terms herein.

[0048] As used herein, the terms "peptide", "polypeptide" and "protein" refer to a continuous chain of amino acids of any length that are linked together via peptide bonds (-NHCO-) ​​and can fulfill a structural and / or functional role in a cell in vitro and / or in vivo. This encompasses amino acid chains ranging in size from 2 to at least about 1000 amino acid residues. The term "peptide" as used herein preferably encompasses amino acid chains less than about 30 amino acids in size, and the terms "polypeptide" and "protein" preferably encompass amino acid chains at least 30 amino acids in size. The terms "polypeptide" and "protein" are used interchangeably herein. As is well known in the art, peptides, polypeptides and proteins can be encoded by nucleic acids.

[0049] The term "antigenic peptide" preferably means a peptide that has amino acid similarity with a tumor protein and that tends to induce or maintain an immunological response against said peptide in a subject to which it is administered.

[0050] The term "immunogenic compound" means a compound comprising an antigenic peptide as defined above, which is also capable of inducing or sustaining an immunological response against said peptide from a subject to which it is administered.

[0051] In some embodiments, the immunogenic compound comprises at least one antigenic peptide, or at least one compound comprising such an antigenic peptide, coupled to a protein, including a carrier protein.

[0052] A carrier protein is usually a protein capable of transporting a cargo, such as an antigenic peptide according to the invention. For example, a carrier protein can transport its cargo across a membrane. In the context of the present invention, a carrier protein also includes a peptide or polypeptide capable of inducing an immune response against an antigenic peptide bound thereto. Carrier proteins are known in the art.

[0053] In some embodiments, an antigenic peptide described herein, or a polypeptide comprising said antigenic peptide, may be linked, for example by covalent or non-covalent binding, to a protein with immune adjuvant properties, for example the HHD-DR3 peptide of sequence MAKTIAYDEEARRGLERGLN (SEQ ID NO: 144).

[0054] Alternatively, such carrier peptides or polypeptides can be co-administered in the form of an immune adjuvant.

[0055] Preferably, the antigenic peptides described herein or polypeptides comprising the antigenic peptides can be co-administered with or linked, such as by covalent or non-covalent binding, to proteins / peptides having immune adjuvant properties, such as stimulating CD4+ Th1 cells. The antigenic peptides described herein preferably bind to MHC class I, but CD4+ helper epitopes can also be used to provide an efficient immune response. Th1 helper cells can secrete interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), and interleukin-2 (IL-2) to maintain efficient DC cell activation and specific CTL activation by enhancing the expression of costimulatory signals in dendritic cells (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).

[0056] For example, the adjuvant peptide / protein may be a non-tumor antigen that preferably recalls immune memory or provides non-specific help, or may be a specific tumor-derived helper peptide. Several helper peptides for providing non-specific T cell help have been described in the literature, such as tetanus helper peptide, keyhole limpet hemocyanin peptide, or PADRE peptide (Adotevi 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 Sep-Oct;17(5):343-50). Thus, tetanus helper peptide, keyhole limpet hemocyanin peptide, and PADRE peptide are preferred examples of such adjuvant peptides / proteins. Furthermore, specific tumor-derived helper peptides are preferred. Specific tumor-derived helper peptides are typically represented by MHC class II, in particular 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 preferably have a length of at least 10 amino acids, more preferably at least 11 amino acids, even more preferably at least 12 amino acids, and most preferably at least 13 amino acids. In particular, 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 identified, for example, using the MHC class II binding prediction tool of the IEDB (Immune epitope database and analysis resource; Supported by a contract from the National Institute of Allergy and Infectious Diseases, a component of the National Institutes of Health in the Department of Health and Human Services; URL: http: / / www.iedb.org / ; http: / / tools.iedb.org / mhcii / ).

[0057] A composition as defined herein comprising an immunogenic compound as defined above and further comprising one or more immune adjuvant substances is also referred to herein as an "immunogenic composition" and in some embodiments as a "vaccine composition".

[0058] As used herein, the term "immunogenic composition" means a composition capable of inducing or maintaining an immune response, in particular capable of inducing an immune response, when administered to a mammal, in particular a human individual.

[0059] The terms "nucleic acid", "nucleic acid molecule", "nucleic acid sequence", "polynucleotide", "nucleotide sequence", as used interchangeably herein, refer to the exact contiguous natural nucleotides (e.g., A, T, G, C, and U) or synthetic nucleotides corresponding to single- or double-stranded DNA or RNA, e.g., cDNA, genomic DNA, ribosomal DNA, and the transcription products of said DNA, e.g., RNA, 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 skill of one of ordinary skill in the art to determine a nucleotide sequence capable of encoding a particular amino acid sequence.

[0060] The (poly)peptides and / or nucleic acids according to the invention may be prepared by any method known in the art, including but not limited to any synthetic method, any recombinant method, any ex vivo production method, etc., any combination thereof. Such techniques are fully explained in the literature as mentioned above.

[0061] In the context of the present invention, the antigenic peptide according to the present invention includes antigens having similarity to tumor antigens. As used herein, the term "tumor antigen" includes tumor-specific antigens and tumor-associated antigens. In general, the term "tumor antigen" or "tumor protein" as used herein refers to an antigenic substance that is produced in tumor cells, and sometimes also in normal cells, and can elicit an immune response upon administration in a subject. In humans, they have been classified according to their expression patterns, function, or genetic origin, and include, but are not limited to, overexpressed self antigens (e.g., HER2 / neu and its variant dHER2, p53, Wilms' tumor 1, ephrin receptors, proteinase 3, mucin-1, mesothelin, EGFR, CD20); cancer testis (CT) antigens (MAGE-1, BAGE, GAGE, NY-ESO-1, etc.); mutated antigens, also known as neoantigens (e.g., mutants derived from MUM-1, bcr-abl, ras, b-raf, p53, CDK-4, CDC27, beta-catenin, alpha-actenin-4); tissue-specific differentiation antigens (melanoma antigen Me ... A / MART-1, tyrosinase, TRP1 / pg75, TRP2, gp100, and gangliosides GM3, GM2, GD2, and GD3; prostate cancer antigens PSMA, PSA, and PAP, etc.; viral antigens expressed by oncoviruses (HPV, EBV, etc.); carcinoembryonic antigens (alpha-fetoprotein AFP and carcinoembryonic antigen CEA, etc.); and universal antigens (telomerase, 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).

[0062] According to various aspects and embodiments of the invention described herein, a "subject" or "host" refers preferably to a mammal, most preferably a human, suspected of having or likely to develop cancer, such as melanoma, colorectal cancer, or clear cell renal cell carcinoma.

[0063] By "pharmaceutical acceptable excipient" herein is meant a pharmaceutical grade compound that improves the delivery, stability, or bioavailability of an active agent, can be metabolized by the subject to which it is administered, and is non-toxic to said subject. Preferred excipients according to the present invention include any excipient normally used in pharmaceuticals, such as, for example, water, saline, phosphate buffered saline, dextrose, glycerol, ethanol, and combinations thereof. In many cases, it is preferred to include an isotonic agent in the composition, such as, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride. Pharmaceutically acceptable excipients may further include minor amounts of auxiliary substances, such as wetting or emulsifying agents, or preservatives.

[0064] By "vaccine" herein is meant a composition capable of stimulating the immune system of an organism so as to provide protection against harmful antigens, either prophylactically or therapeutically.

[0065] As used herein, the term "cancer" refers to a malignant neoplasm. In particular, the term "cancer" herein refers to any 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 direct growth into adjacent tissues by invasion or by transplantation to distant sites by metastasis. Metastasis is defined as the stage where cancer cells are transported through the bloodstream or lymphatic system. It includes, among others, esophageal cancer, stomach cancer, duodenal 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, oral cancer, skin cancer, blood cancer, lymphoma, eye cancer, bone cancer, bone marrow cancer, muscle cancer, etc. In the context of the present invention, melanoma, head and neck, breast, colorectal cancer, or clear cell renal cell carcinoma are preferred.

[0066] As used herein, the terms "preventing", "prevention", "prophylaxis", "prevent" generally mean avoiding or minimizing the onset of a disease or condition before onset, whereas the terms "treating", "treatment", "treat" include alleviating, ameliorating, or curing a disease or condition (or symptoms of a disease or condition) after onset. In the context of the present invention, prevention and / or treatment of cancer may result, for example, in non-proliferation, attenuated, reduced, or delayed proliferation of tumor cells in a subject, or complete or near-complete elimination of tumor cells in a subject. The term "preventing" includes "reducing the likelihood of occurrence of" or "reducing the likelihood of recurrence".

[0067] As used herein, an "effective amount" or "effective dose" is an amount that produces a desired effect. For therapeutic purposes, an effective amount is an amount sufficient to produce a beneficial or desired clinical result. A preferred effective amount for a given application can be easily determined by a person skilled in the art, taking into consideration, for example, the size, age, and weight of the subject, the type of cancer to be prevented or treated, and the time since the onset of the cancer. In the context of the present invention, an effective amount of the composition in terms of prevention or treatment is an amount sufficient to induce a humoral and / or cellular immune response against the cancer.

[0068] As used herein, the term "comprising" includes "consisting of."

[0069] Further definitions are provided throughout the specification.

[0070] The present invention may be understood more readily by reference to the following detailed description, including preferred embodiments of the invention and the examples contained therein.

[0071] Thus, the present invention relates to an immunogenic compound comprising an antigenic peptide having amino acid similarity to a tumor antigen, the antigenic peptide being selected from the group consisting of SEQ ID NOs: 1 to 106. In other words, the present invention provides an antigenic peptide (an immunogenic compound comprising) having an amino acid sequence represented by any one of SEQ ID NOs: 1 to 106. Preferably, the present invention provides an antigenic peptide (an immunogenic compound comprising) comprising or consisting of an amino acid sequence represented by any one of SEQ ID NOs: 17, 31, 32, 51, 52, 55, 56, 59, 68, 89, 94, 100, 101, or 102. The present invention also provides an antigenic peptide (an immunogenic compound comprising) comprising or consisting of an amino acid sequence represented by any one of SEQ ID NOs: 26, 28, 47, 51, 52, 55, 56, 77, 93, 101, or 102. More preferably, the present invention provides an antigenic peptide (an immunogenic compound comprising) comprising or consisting of an amino acid sequence represented by any one of SEQ ID NOs: 51, 52, 55, 56, 101, or 102. Even more preferably, the present invention provides an antigenic peptide (an immunogenic compound comprising the same) that comprises or consists of an amino acid sequence set forth in any one of SEQ ID NOs: 51, 52, 55, or 56. Furthermore, it is even more preferable that the present invention provides an antigenic peptide (an immunogenic compound comprising the same) that comprises or consists of an amino acid sequence set forth in any one of SEQ ID NOs: 101 or 102.

[0072] According to an exemplary embodiment, the antigenic peptide defined above is a peptide of sequence SEQ ID NO:71.

[0073] According to one embodiment, the antigenic peptide as defined above, or a polypeptide comprising said antigenic peptide, is bound to a carrier protein, for example by covalent or non-covalent bonds.

[0074] According to some embodiments, the present invention relates to an immunogenic compound as defined above, comprising an antigenic peptide of formula (I). PepNt-CORE-PepCt (I) where, - "PepNt" consists of a polypeptide having an amino acid length of 0 to 30 amino acid residues and is located at the N-terminus of the polypeptide of formula (I); -CORE is a polypeptide comprising or consisting of an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 106 (including SEQ ID NO: 71), in particular an amino acid sequence represented by any of SEQ ID NOs: 26, 28, 47, 51, 52, 55, 56, 77, 93, 101, or 102, or an amino acid sequence represented by any of SEQ ID NOs: 17, 31, 32, 51, 52, 55, 56, 59, 68, 89, 94, 100, 101, or 102, for example, an amino acid sequence represented by any of 51, 52, 55, 56, 101, or 102; and - "PepCt" consists of a polypeptide having an amino acid length of 0 to 30 amino acid residues and located at the C-terminus of the polypeptide of formula (I).

[0075] Preferably, the antigenic peptide of formula (I) is a fusion peptide or protein, in particular a recombinant fusion peptide or protein. The term "recombinant" means that it does not occur in nature.

[0076] The present invention further relates to nanoparticles loaded with: at least one immunogenic compound according to the invention, or - at least one antigenic peptide according to the invention, and optionally an adjuvant.

[0077] The present invention further relates to an immunogenic composition comprising: an immunogenic compound according to the invention, - an antigenic peptide according to the invention, the nanoparticles according to the invention, or - a nucleic acid according to the invention, one or more pharma- ceutically acceptable excipients.

[0078] The immunogenic composition can further comprise one or more immunostimulants.

[0079] In particular, said immune stimulant is selected in the group consisting of immune adjuvants and antigen presenting cells.

[0080] More specifically, the antigen-presenting cells may consist of dendritic cells.

[0081] In particular, the immunogenic composition may include: (i) two different immunogenic compounds according to the invention; (ii) two different antigenic peptides of the present invention; (iii) two different nanoparticles according to the invention; or (iv) two different nucleic acids according to the invention.

[0082] In this context, two different components in particular mean different antigenic peptides according to the invention, which are comprised in an immunogenic compound, a nanoparticle and / or a nucleic acid. Such two different components, in particular two different antigenic peptides according to the invention (comprised in two different components), are preferably directed to the same type of cancer, for example to the same or different antigens associated with this cancer and / or to the same or different (reference) epitopes within the antigens associated with this cancer. More preferably, the two different components, in particular the two different antigenic peptides according to the invention (comprised in two different components), are directed to the same tumor (associated or specific) antigen. The two different components, in particular the two different antigenic peptides according to the invention (comprised in two different components), may also be directed to the same or different (reference) tumor (associated or specific) antigens.

[0083] The present invention further relates to any of the following for use in the prevention or treatment of cancer: an immunogenic compound according to the invention, - an antigenic peptide according to the invention, - a (host) cell according to the invention, the nanoparticles according to the invention, a nucleic acid according to the invention, or - an immunogenic composition according to the invention.

[0084] Various types of cancer that are more specifically contemplated for treatment and / or prevention, particularly in terms of the tumor antigens that are targeted, are detailed below in Table 1B. [Table 1-1] [Table 1-2]

[0085] Thus, according to one embodiment, the invention relates to any of the antigenic peptides and immunogenic compounds described herein, and any of the immunogenic compositions described herein, for use in the prevention or treatment of a cancer selected from Table 1B.

[0086] The present invention further relates to a nucleic acid encoding an antigenic peptide having amino acid similarity to a tumor antigen, said peptide being selected in the group consisting of: - an antigenic peptide selected in the group consisting of SEQ ID NOs: 1 to 106; and / or - an antigenic peptide of formula (I), or (Ia), or (Ib) as described herein.

[0087] In particular, the above defined nucleic acid may encode an antigenic peptide selected in the group consisting of peptides having amino acid similarity to IL13RA2, including SEQ ID NO:71.

[0088] The present invention also relates to a method for the prevention or treatment of cancer or for initiating, enhancing or prolonging an anti-tumor response in a subject in need thereof, comprising administering to said subject an antigenic peptide according to the invention, or an immunogenic compound according to the invention, or an immunogenic composition according to the invention, or a nanoparticle according to the invention, or a nucleic acid according to the invention, or a combination according to the invention.

[0089] Furthermore, the present invention relates to a nucleic acid encoding an antigenic peptide or an immunogenic compound as defined above.

[0090] Furthermore, the present invention also relates to the combination of two different immunogenic compounds according to the invention for use in the prevention and / or treatment of cancer.

[0091] Furthermore, the present invention also relates to a combination of two different antigenic peptides according to the invention for use in the prevention and / or treatment of cancer.

[0092] Furthermore, the present invention also relates to the combination of two different nanoparticles according to the invention for use in the prevention and / or treatment of cancer.

[0093] Furthermore, the present invention also relates to the combination of two different nucleic acids according to the invention for use in the prevention and / or treatment of cancer.

[0094] In a particular embodiment, the two different components of a combination for use according to the invention are contained in the same or different compositions.

[0095] In a specific embodiment, the two different components of a combination for use according to the invention are administered by the same or different routes of administration.

[0096] In a specific embodiment, the two different components of a combination for use according to the invention are administered approximately simultaneously (concurrently) or sequentially.

[0097] Additionally, the present invention also relates to a kit comprising: an immunogenic compound according to the invention, - an antigenic peptide according to the invention, - a (host) cell according to the invention, the nanoparticles according to the invention, a nucleic acid according to the invention, or - an immunogenic composition according to the invention.

[0098] Antigenic peptides, immunogenic compounds, nucleic acids, nanoparticles, and cells Unless otherwise specified, all references to <<antigenic peptides>> can also apply to <<immunogenic compounds>>.

[0099] Antigenic peptides according to the invention are shown in Table 1A below, which also gives information on the corresponding "reference" human tumor antigens (epitopes) with the names of the genes that encode them, and their reported localization in tumors, but these are non-limiting. NA = not applicable. SEQ ID NOs: 1 to 106 refer to antigenic peptides. [Table 1-3] [Table 1-4] [Table 1-5]

[0100] These 106 antigenic peptide sequences can be further defined based on the sequence of a reference tumor antigen, for example a tumor antigen derived from IL13RA2.

[0101] Thus, the present invention relates to an immunogenic compound comprising an antigenic peptide having amino acid similarity with a tumor antigen, the antigenic peptide being selected in the group consisting of SEQ ID NOs: 1 to 106, including: - a peptide having amino acid similarity with a tumor antigen encoded by the gene PLIN2, said antigenic peptide being selected in the group consisting of SEQ ID NO: 1; - a peptide having amino acid similarity with a tumor antigen encoded by the gene ALDH1A1, said antigenic peptide being selected in the group consisting of SEQ ID NOs: 2-3; - a peptide having amino acid similarity with a tumor antigen encoded by the gene AFP, said antigenic peptide being selected in the group consisting of SEQ ID NOs: 4-5; - a peptide having amino acid similarity with a tumor antigen encoded by the gene PTPRC, said antigenic peptide being selected in the group consisting of SEQ ID NOs: 6 to 11; - a peptide having amino acid similarity with a tumor antigen encoded by the gene CEACAM5, said antigenic peptide being selected in the group consisting of SEQ ID NOs: 12 to 25; - a peptide having amino acid similarity with a tumor antigen encoded by the gene ENAH, said antigenic peptide being selected in the group consisting of SEQ ID NO: 26; - a peptide having amino acid similarity to a tumor antigen encoded by the gene EZH2, said antigenic peptide being selected in the group consisting of SEQ ID NO: 27; - a peptide having amino acid similarity with a tumor antigen encoded by the gene PMEL, said antigenic peptide being selected in the group consisting of SEQ ID NO: 28; - a peptide having amino acid similarity with a tumor antigen encoded by the gene ERBB2, said antigenic peptide being selected in the group consisting of SEQ ID NOs: 29 to 70; - a peptide having amino acid similarity with a tumor antigen encoded by the gene IL13RA2, said antigenic peptide being selected in the group consisting of SEQ ID NO: 71; - a peptide having amino acid similarity to a tumor antigen encoded by the gene MAGEA1, said antigenic peptide being selected in the group consisting of SEQ ID NO: 72; - a peptide having amino acid similarity with a tumor antigen encoded by the gene MAGEA3, said antigenic peptide being selected in the group consisting of SEQ ID NOs: 73 to 75; - a peptide having amino acid similarity to a tumor antigen encoded by the gene MAGEA4, said antigenic peptide being selected in the group consisting of SEQ ID NO: 76; - a peptide having amino acid similarity with a tumor antigen encoded by the gene MAGEC1, said antigenic peptide being selected in the group consisting of SEQ ID NOs: 77 to 80; - a peptide having amino acid similarity to a tumor antigen encoded by the gene MAGEC2, said antigenic peptide being selected from the group consisting of SEQ ID NOs: 81 to 85; - a peptide having amino acid similarity with a tumor antigen encoded by gene SCGB2A2, said antigenic peptide being selected in the group consisting of SEQ ID NOs: 86 to 87; - a peptide having amino acid similarity to a tumor antigen encoded by the gene MLANA, said antigenic peptide being selected in the group consisting of SEQ ID NOs: 88 to 89; - a peptide having amino acid similarity to a tumor antigen encoded by the gene MDK, said antigenic peptide being selected in the group consisting of SEQ ID NOs: 90 to 91; - a peptide having amino acid similarity with a tumor antigen encoded by the gene MMP2, said antigenic peptide being selected in the group consisting of SEQ ID NOs: 92-93; - a peptide having amino acid similarity to a tumor antigen encoded by the gene CTAG1B, said antigenic peptide being selected in the group consisting of SEQ ID NO: 94; - a peptide having amino acid similarity with a tumor antigen encoded by the gene ACPP, said antigenic peptide being selected in the group consisting of SEQ ID NOs: 95 to 99; - a peptide having amino acid similarity to a tumor antigen encoded by the gene STEAP1, said antigenic peptide being selected in the group consisting of SEQ ID NOs: 100 to 102; - a peptide having amino acid similarity with a tumor antigen encoded by the gene TAG1, said antigenic peptide being selected in the group consisting of SEQ ID NOs: 103 to 105; - a peptide having amino acid similarity with a tumor antigen encoded by the gene TYR, said antigenic peptide being selected in the group consisting of SEQ ID NO: 106.

[0102] Therefore, the 106 antigenic peptides can be further classified into several different families according to their reference peptides: - Family< <svastitgv>>(SEQ ID NO:107), this family comprises the amino acid sequence of SEQ ID NO:1; - Family< <llykladli>> (SEQ ID NO: 108), this family includes the amino acid sequences of SEQ ID NOs: 2 to 3; - Family< <qlavsvilrv>> (SEQ ID NO: 109), this family includes the amino acid sequences of SEQ ID NOs: 4 to 5; - Family< <kfldalisl>> (SEQ ID NO: 110), this family includes the amino acid sequences of SEQ ID NOs: 6 to 11; - Family< <gvlvgvali>> (SEQ ID NO: 111), this family includes the amino acid sequences of SEQ ID NOs: 12 to 24; - Family< <hlfgyswyk>>(SEQ ID NO:112), this family comprises the amino acid sequence of SEQ ID NO:25; - Family< <tmngskspv>>(SEQ ID NO:113), this family comprises the amino acid sequence of SEQ ID NO:26; - Family< <fmvedetvl>>(SEQ ID NO:114), this family comprises the amino acid sequence of SEQ ID NO:27; - Family< <itdqvpfsv>>(SEQ ID NO:115), this family comprises the amino acid sequence of SEQ ID NO:28; - Family< <iisavvgil>> (SEQ ID NO: 116), this family includes the amino acid sequences of SEQ ID NOs: 29 to 40; - Family< <ilhngaysl>>(SEQ ID NO:117), this family comprises the amino acid sequence of SEQ ID NO:41; - Family< <kifgslafl>> (SEQ ID NO: 118), this family includes the amino acid sequences of SEQ ID NOs: 42-43; - Family< <pltsiaisv>> (SEQ ID NO: 119), this family includes the amino acid sequences of SEQ ID NOs: 44 to 46; - Family< <rllqetelv>>(SEQ ID NO: 120), this family comprises the amino acid sequence of SEQ ID NO: 47; - Family< <tleeitgyl>> (SEQ ID NO: 121), this family includes the amino acid sequences of SEQ ID NOs: 48 to 50; - Family< <vvlgvvfgi>> (SEQ ID NO: 122), this family includes the amino acid sequences of SEQ ID NOs: 51 to 70; - Family containing SEQ ID NO: 71 <wlpfgfili>>(sequence number 123); - Family< <kvleyvikv>>(SEQ ID NO: 124), this family comprises the amino acid sequence of SEQ ID NO: 72; - Family< <evdpighly>> (SEQ ID NO: 125), this family includes the amino acid sequences of SEQ ID NOs: 73-74; - Family< <vaelvhfll>>(SEQ ID NO: 126), this family comprises the amino acid sequence of SEQ ID NO: 75; - Family< <evdpasnty>>(SEQ ID NO: 127), this family contains the amino acid sequence of SEQ ID NO: 76; - Family <<KVVEFLAML<<(SEQ ID NO: 128), this family contains the amino acid sequence of SEQ ID NO: 77; - Family <<SFSYTLLSL<<(SEQ ID NO: 129), this family contains the amino acid sequences of SEQ ID NOs: 78 - 79; - Family < <vssffsytl>>(SEQ ID NO:130), this family comprises the amino acid sequence of SEQ ID NO:80; - Family< <alkdveerv>> (SEQ ID NO: 131), this family includes the amino acid sequences of SEQ ID NOs: 81 to 83; - Family< <asstlylvf>> (SEQ ID NO: 132), this family includes the amino acid sequences of SEQ ID NOs: 84-85; - Family< <pllenvisk>> (SEQ ID NO: 133), this family includes the amino acid sequences of SEQ ID NOs: 86-87; - Family< <iltvilgvl>> (SEQ ID NO: 134). This family includes the amino acid sequences of SEQ ID NOs: 88-89; - Family< <allaltsav>> (SEQ ID NO: 135), this family includes the amino acid sequences of SEQ ID NOs: 90-91; - Family< <glppdvqrv>> (SEQ ID NO: 136), this family includes the amino acid sequences of SEQ ID NOs: 92-93; - Family< <lampfatpm>>(SEQ ID NO: 137), this family comprises the amino acid sequence of SEQ ID NO: 94; - Family< <aldvyngll>> (SEQ ID NO: 138), this family includes the amino acid sequences of SEQ ID NOs: 95 to 97; - Family< <flfllffwl>>(SEQ ID NO: 139), this family comprises the amino acid sequence of SEQ ID NO: 98; - Family< <tlmsamtnl>>(SEQ ID NO:140), this family comprises the amino acid sequence of SEQ ID NO:99; - Family< <miavflpiv>> (SEQ ID NO: 141), this family includes the amino acid sequences of SEQ ID NOs: 100 to 102; - Family< <slgwlflll>> (SEQ ID NO: 142), this family includes the amino acid sequences of SEQ ID NOs: 103 to 105; - Family< <mllavlycl>>(SEQ ID NO: 143), this family comprises the amino acid sequence of SEQ ID NO: 106.

[0103] According to a preferred embodiment, the antigenic peptide of the present invention is selected from the group consisting of peptides or polypeptides comprising or consisting of the amino acid sequence of SEQ ID NO:71.

[0104] According to an exemplary embodiment, an antigenic peptide of the invention is a peptide or polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO:71.

[0105] More preferably, the antigenic peptide of the present invention is selected from the group consisting of peptides or polypeptides comprising or consisting of the amino acid sequence according to any of SEQ ID NOs: 17, 31, 32, 51, 52, 55, 56, 59, 68, 89, 94, 100, 101, or 102. Also, it is more preferred that the antigenic peptide of the present invention is selected from the group consisting of peptides or polypeptides comprising or consisting of the amino acid sequence according to any of SEQ ID NOs: 26, 28, 47, 51, 52, 55, 56, 77, 93, 101, or 102. Even more preferably, the antigenic peptide of the present invention is selected from the group consisting of peptides or polypeptides comprising or consisting of the amino acid sequence according to any of SEQ ID NOs: 51, 52, 55, 56, 101, or 102. Even more preferably, the antigenic peptide of the present invention is selected from the group consisting of peptides or polypeptides comprising or consisting of the amino acid sequence according to any of SEQ ID NOs: 51, 52, 55, or 56. It is even more preferred that the antigenic peptide of the present invention is selected from the group consisting of peptides or polypeptides comprising or consisting of an amino acid sequence according to any of SEQ ID NOs: 101 or 102.

[0106] According to some embodiments, the immunogenic compound comprises or consists of an antigenic peptide of formula (I): PepNt-CORE-PepCt (I) where, - "PepNt" consists of a polypeptide having an amino acid length of 0 to 500 amino acid residues and is located at the N-terminus of the polypeptide of formula (I); -CORE is a polypeptide comprising or consisting of an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 106 (including SEQ ID NO: 71), in particular an amino acid sequence represented by any of SEQ ID NOs: 26, 28, 47, 51, 52, 55, 56, 77, 93, 101, or 102, or an amino acid sequence represented by any of SEQ ID NOs: 17, 31, 32, 51, 52, 55, 56, 59, 68, 89, 94, 100, 101, or 102, for example, an amino acid sequence represented by any of SEQ ID NOs: 51, 52, 55, 56, 101, or 102; and - "PepCt" consists of a polypeptide having an amino acid length of 0 to 500 amino acid residues and located at the C-terminus of the polypeptide of formula (I).

[0107] According to one particular embodiment, the immunogenic compound comprises or consists of an antigenic peptide of formula (Ia) or (Ib): PepNt-CORE(Ia); or CORE-PepCt(1b). where "PepNt" and "PepCt" and CORE are as defined above.

[0108] According to some even more specific embodiments, the antigenic peptide or immunogenic peptide as defined above comprises between 9 and 1000 amino acids, for example 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, 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, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, and 1000 amino acids.

[0109] According to said embodiment, where applicable, the lengths of "PepNt" and "PepCt" are defined as follows:

[0110] Thus, "PepNt" and "PepCt" can contain 0 to 500 amino acid residues as defined above, for example, 0, 1, 2, 3, 4, 5, 6, 7, 8, 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, 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, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 250, 300, 350, 400, 450, and 500 amino acid residues.

[0111] The type of carrier molecule used to generate the immunogenic compounds of the invention, such as those comprising or consisting of a peptide of formula (I) bound to a carrier molecule, is well within the general knowledge of the person skilled in the art. The function of the carrier molecule is to provide cytokine help (or T cell help) to enhance the immune response against tumor antigens.

[0112] Preferably, the antigenic peptide is bound to a carrier molecule, in particular a carrier protein, preferably by covalent or non-covalent binding. The carrier molecule to which the peptide is optionally bound can be selected from a wide variety of known carriers. Examples of carrier molecules for vaccine purposes include proteins such as human or bovine serum albumin and keyhole limpet hemocyanin (KLH), and fatty acids. Other embodiments of carrier molecules to which the antigenic peptides of formula (I) can be covalently attached include bacterial toxins or toxoids, such as diphtheria, cholera, E. coli heat labile or tetanus toxoids, meningococcal outer membrane proteins (European Patent Application No. EP0372501), synthetic peptides (European Patent Applications Nos. EP0378881 and EP0427347), heat shock proteins (PCT Application No. WO93 / 17712), pertussis proteins (PCT Application No. WO98 / 58668), protein D from H. influenzae (PCT Application No. WO00 / 56360), and toxins A or B from C. difficile (PCT Application No. WO00 / 61761).

[0113] According to one embodiment, the carrier protein or carrier peptide is the HHD-DR3 carrier peptide MAKTIAYDEEARRGLERGLN (SEQ ID NO: 144).

[0114] According to one embodiment, "PepNt" and / or "PepCt" may correspond to a carrier protein or carrier peptide, such as the HHD-DR3 carrier peptide MAKTIAYDEEARRGLERGLN (SEQ ID NO: 144).

[0115] According to one embodiment, the immunogenic compound comprises or consists of a carrier peptide of SEQ ID NO:144 covalently linked to the N-terminus of an antigenic peptide of SEQ ID NO:71.

[0116] More preferably, the carrier protein or carrier peptide is a protein / peptide with immune adjuvant properties, such as providing stimulation of CD4+Th1 cells as described herein. Preferred examples thereof can be non-tumor antigens that provide immune memory or non-specific help, or specific tumor-derived helper peptides, such as tetanus helper peptides, keyhole limpet hemocyanin peptides, or PADRE peptides. Another preferred example is a specific tumor-derived helper peptide that can be represented by MHC II, in particular HLA-DR, HLA-DP, or HLA-DQ, e.g., fragments of shared overexpressed tumor antigens, such as HER2, NY-ESO-1, hTERT, or IL13RA2, as described above.

[0117] Thus, "PepNt" and / or "PepCt" may preferably correspond to such proteins / peptides having immune adjuvant properties, such as providing stimulation of CD4+ Th1 cells as described herein.

[0118] Furthermore, the immunogenic compound comprises or consists of a protein / peptide having immune adjuvant properties, such as providing stimulation of CD4+ Th1 cells, covalently linked to the N-terminus of an antigenic peptide having an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 106 (including SEQ ID NO: 71), in particular the amino acid sequence represented by any of SEQ ID NOs: 26, 28, 47, 51, 52, 55, 56, 77, 93, 101, or 102, or any of SEQ ID NOs: 17, 31, 32, 51, 52, 55, 56, 59, 68, 89, 94, 100, 101, or 102, e.g., any of SEQ ID NOs: 51, 52, 55, 56, 101, or 102.

[0119] According to one embodiment, the antigenic peptide is covalently attached to the carrier molecule via a linker moiety.

[0120] The restricted family of linker agents includes or consists of linker agents designated GMBS, Sulfo-GMBS, SMPB, and Sulfo-SMPB.

[0121] In some embodiments of the immunogenic compounds defined above, the linker agent is selected from the group consisting of GMBS (N-[γ-maleimidobutyryloxy]succinimide ester), Sulfo-GMBS (N-[γ-maleimidobutyryloxy]sulfosuccinimide ester), SMPB (succinimidyl 4-[p-maleimidophenyl]butyrate), and Sulfo-SMPB (sulfosuccinimidyl 4-[p-maleimidophenyl]butyrate).

[0122] Methods for conjugating two proteins with a linker agent in general, and more specifically with a linker agent selected from the group consisting of GMBS, Sulfo-GMBS, SMPB, and Sulfo-SMPB, are well known to those skilled in the art. By way of illustration, such protocols are disclosed in a publicly available leaflet by Pierce Company (IL, USA). GMBS, Sulfo-GMBS, SMPB, and Sulfo-SMPB consist of heterobifunctional linker agents containing both an N-hydroxysuccinimide (NHS) ester group and a maleimide group. Conjugation with GMBS, Sulfo-GMBS, SMPB, or Sulfo-SMPB is usually carried out in a two-step procedure. In the first step, an amine-containing protein is reacted with a several-fold molar excess of the linker agent at pH 7-9 to form an amide bond, followed by removal of the excess unreacted linker agent, usually by desalting or dialysis. In the second step, a sulfhydryl-containing molecule (e.g., 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.

[0123] The use of SMPB or Sulfo-SMPB as a linker agent to covalently attach a peptide of formula (I) to an amine-containing carrier protein provides a conjugate of formula (II): [ka] (II) During the ceremony, -R1 consists of one reactive group of the amine-containing carrier protein, with the NH group attached to it coming from either (i) the alpha amino group located at the N-terminus of the amine-containing carrier protein, or (ii) the side chain amino group from a lysine (K) amino acid residue of the amine-containing carrier protein. -R2 consists of a peptide of formula (I) with the sulfur (S) atom attached thereto derived from the 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 can be part of an unnatural amino acid or any other molecule present at the terminus of a peptide of formula (I).

[0124] The use of GMBS or Sulfo-GMBS as a linker agent for covalently attaching a peptide of formula (I) to an amine-containing carrier protein, in particular CRM197 carrier protein, gives a conjugate of formula (III): [ka] (III) During the ceremony, -R1 consists of one reactive group of the amine-containing carrier protein, with the NH group attached to it coming from either (i) the alpha amino group located at the N-terminus of the amine-containing carrier protein, or (ii) the side chain amino group from a lysine (K) amino acid residue of the amine-containing carrier protein. -R2 consists of a peptide of formula (I) with the sulfur (S) atom attached thereto derived from the 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 can be part of an unnatural amino acid or any other molecule present at the terminus of a peptide of formula (I).

[0125] In a further aspect, the present invention provides a cell loaded with at least one immunogenic compound according to the invention or with at least one antigenic peptide according to the invention. Preferred antigenic peptides are peptides or polypeptides having an amino acid sequence as set forth in any of SEQ ID NOs: 26, 28, 47, 51, 52, 55, 56, 77, 93, 101 or 102, or an amino acid sequence as set forth in any of SEQ ID NOs: 17, 31, 32, 51, 52, 55, 56, 59, 68, 89, 94, 100, 101 or 102, such as an amino acid sequence as set forth in any of SEQ ID NOs: 51, 52, 55, 56, 101 or 102. Combinations thereof, i.e. cells loaded with different antigenic peptides (or respective immunogenic compounds) according to the invention, are also preferred.

[0126] A preferred cell is an antigen presenting cell (APC), more preferably a dendritic cell (DC).

[0127] Antigen-presenting cells (APCs) are of particular interest since their main function is to process antigens and present them on the cell surface to T cells of the immune system to initiate and modulate T cell responses in vivo. In the context of the present invention, it is preferred to load APCs with the antigenic peptides and / or immunogenic compounds according to the invention, which can be done by exposing APCs to the antigenic peptides and / or immunogenic compounds in vitro (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 Oct;11(4):311-8).

[0128] The preferred antigen-presenting cells according to the present invention are dendritic cells (DCs). As they are the most powerful antigen-presenting cells and are reported to be often functionally defective in cancer patients, it may be actually advantageous to combine at least one antigenic peptide or immunogenic compound according to the present invention with dendritic cells. Dendritic cells can be easily obtained by those skilled in the art from a healthy matched donor (i.e., the dendritic cells are HLA-associated) or from the patient himself (i.e., the dendritic cells are autologous) if they are functional, for example by direct isolation from peripheral blood or induction from peripheral blood cells such as 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). Dendritic cells can indeed be distinguished from other cells in peripheral blood by their surface markers, e.g., S100, p55, CD83, and / or OX62, and therefore can be isolated and purified based on said markers using cell culture techniques well known in the art.

[0129] In a further aspect, the invention provides a nucleic acid encoding an antigenic peptide according to the invention or an immunogenic compound according to the invention, wherein the immunogenic compound is a peptide or a protein. Preferably, the antigenic peptide is a peptide or polypeptide having an amino acid sequence as set forth in any of SEQ ID NOs: 26, 28, 47, 51, 52, 55, 56, 77, 93, 101 or 102, or a peptide or protein having an amino acid sequence as set forth in any of SEQ ID NOs: 17, 31, 32, 51, 52, 55, 56, 59, 68, 89, 94, 100, 101 or 102, such as a peptide or protein having an amino acid sequence as set forth in any of SEQ ID NOs: 51, 52, 55, 56, 101 or 102; and / or an antigenic peptide of formula (I) as hereinbefore described.

[0130] The nucleic acid preferably includes single-stranded, double-stranded or partially double-stranded nucleic acid, preferably selected from genomic DNA, 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, the nucleic acid (molecule) is preferably a DNA molecule or an RNA molecule, preferably selected from genomic DNA; 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.

[0131] Thus, the nucleic acid molecule may be a vector. The term "vector" as used in the context of the present invention means a nucleic acid molecule, preferably an artificial nucleic acid molecule, i.e. a nucleic acid molecule that does not occur in nature. A vector in the context of the present invention is suitable for incorporating or carrying a desired nucleic acid sequence. Such a vector may 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 a nucleic acid molecule. Thus, a vector may contain a sequence corresponding to a desired antigenic peptide according to the present invention, for example. An expression vector may be used for the production of an expression product, such as an RNA, such as an mRNA, or a peptide, polypeptide, or protein. For example, an expression vector may contain sequences necessary for transcription of a sequence range of the vector, such as a promoter sequence. A cloning vector is typically a vector that contains a cloning site, which may be used to incorporate a nucleic acid sequence into the vector. A cloning vector may be, for example, a plasmid vector or a bacteriophage vector. A transfer vector may be a vector suitable for introducing a nucleic acid molecule into a cell or organism, such as a viral vector. A vector in the context of the present invention may 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 comprises sequences suitable for the propagation of the vector, such as a cloning site, a selection marker, such as an antibiotic resistance factor, and an origin of replication. Preferably, a vector in the context of the present application is a plasmid vector. Preferably, a 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 is useful for expression in so-called "live bacterial vaccine vectors", where live bacterial cells (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.

[0132] The nucleic acid encoding the antigenic peptide of the present invention may be in the form of naked nucleic acid or nucleic acid cloned into a plasmid or viral vector (Tregoning and Kinnear, Using Plasmids as DNA Vaccines for Infectious Diseases. Microbiol Spectr. 2014 Dec;2(6). doi: 10.1128 / microbiolspec.PLAS-0028-2014), the latter being particularly preferred. Examples of suitable viral vectors according to the present invention include, but are not limited to, retrovirus, adenovirus, adeno-associated virus (AAV), herpes virus, and poxvirus vectors. It is within the skill of the art to clone the nucleic acid into a plasmid or viral vector using standard recombinant techniques in the art.

[0133] In a further aspect, the present invention also provides a host cell comprising a nucleic acid according to the present invention, where the nucleic acid is preferably a vector. Preferably, the host cell is a bacterial cell. Such a host cell can be preferably used for the production of an antigenic peptide according to the present invention or an immunogenic compound according to the present invention. Furthermore, such a host cell can also be an active ingredient in a vaccine.

[0134] Preferably, the host cell is a bacterial cell, preferably an enterobacterial cell. Such bacterial host cells can serve as "live bacterial vaccine vectors", where live bacterial cells (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.

[0135] Bacterial cells (bacteria or bacterial spores, e.g. endospores, exospores, or microbial cysts), in particular (pan)enteric bacterial species, may be advantageous as they may elicit a higher immune response than the (poly)peptides or nucleic acids they contain.

[0136] Alternatively, the bacterial cells, in particular the enterobacteria, according to the invention may be in the form of probiotics, i.e. live enterobacteria, and therefore may be used as a food additive for the health benefits they may provide. They may be freeze-dried, for example in granules, pills or capsules, or may be mixed directly with dairy products for consumption.

[0137] In a further aspect, the present invention provides nanoparticles loaded with: at least one immunogenic compound according to the invention, or - at least one antigenic peptide according to the invention, and optionally an adjuvant.

[0138] Nanoparticles, particularly 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 polypeptides / proteins / nucleic acids containing antigenic peptides), which may also act as adjuvants in some cases. Antigenic peptides (polypeptides / proteins / nucleic acids containing antigenic peptides) are typically encapsulated within the nanoparticles or linked / bound to (decorated on) the surface of the nanoparticles ("coated"). Compared with conventional approaches, nanoparticles can protect the payload (antigen / adjuvant) from the surrounding biological environment, extend half-life, minimize systemic toxicity, facilitate delivery to APCs, or even directly trigger the activation of TAA-specific T cells. Preferably, nanoparticles have a size (diameter) of 300 nm or less, more preferably 200 nm or less, and most preferably 100 nm or less. Such nanoparticles are adequately protected from phagocyte uptake, have high structural integrity and long circulation time in circulation, can accumulate at tumor growth sites, and can penetrate deep into the tumor mass.

[0139] Examples of nanoparticles include polymeric nanoparticles such as poly(ethylene glycol) (PEG) and poly(D,L-lactic-coglycolic 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; immune stimulating complexes (ISCOMs); virus-like particles (VLPs); and self-assembling proteins.

[0140] Polymeric nanoparticles are nanoparticles based on / comprising polymers such as poly(d,l-lactide-co-glycolide) (PLG), poly(d,l-lactic-co-glycolic acid) (PLGA), poly(g-glutamic acid) (g-PGA), poly(ethylene glycol) (PEG), and polystyrene. Polymeric nanoparticles can capture or bind / conjugate to antigens (e.g., antigenic peptides or (poly)peptides containing same). Polymeric nanoparticles can be used for delivery to specific cells and can sustain antigen release due to their slow biodegradation rate. For example, g-PGA nanoparticles can be used to encapsulate hydrophobic antigens. Polystyrene nanoparticles can be conjugated to various antigens since 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 type of nano-sized hydrophilic three-dimensional polymer network. Nanogels have favorable properties such as flexible mesh size, large surface area for multivalent conjugation, high water content, and high antigen loading capacity. Thus, preferred nanoparticles are nanogels such as chitosan nanogels. Preferred polymer nanoparticles are nanoparticles based on / comprising poly(ethylene glycol) (PEG) and poly(D,L-lactic-coglycolic acid) (PLGA).

[0141] Inorganic nanoparticles are inorganic particles based on / comprising inorganic substances, 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 offer rigid structures and controllable synthesis. For example, gold nanoparticles can be easily produced in various shapes such as spheres, rods, cubes, etc. Inorganic nanoparticles may be surface-modified, for example with carbohydrates. Carbon nanoparticles offer good biocompatibility and can be produced, for example, as nanotubes or (mesoporous) spheres. For example, multiple copies of the antigenic peptides (or (poly)peptides comprising same) according to the invention can be conjugated onto carbon nanoparticles such as carbon nanotubes. Mesoporous carbon nanoparticles are preferred for oral administration. Silica-based nanoparticles (SiNPs) are also preferred. SiNPs are biocompatible and show excellent properties in selective tumor targeting and vaccine delivery. The abundant silanol groups on the surface of SiNPs 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.

[0142] Liposomes are typically formed by phospholipids such as 1,2-dioleoyl-3-trimethylammoniumpropane (DOTAP). In general, cationic liposomes are preferred. Liposomes are self-assembled with a phospholipid bilayer shell and an aqueous core. Liposomes can be produced as unilamellar vesicles (with a single phospholipid bilayer) or as multilamellar vesicles (with several concentric phospholipid shells separated by layers of water). Thus, antigens can be encapsulated within the core or between the different layers / shells. Preferred liposome systems are those approved for human use, such as Inflexal® V and Epaxal®.

[0143] Immunostimulating complexes (ISCOMs) are cage-like particles of about 40 nm (diameter), e.g., colloidal saponin-containing micelles consisting of the saponin adjuvant Quil A, cholesterol, phospholipids, and (poly)peptide antigens (antigenic peptides or polypeptides containing same). These spherical particles are able to capture antigens by non-polar interactions. Two types of ISCOMs have been described, both consisting of cholesterol, phospholipids (typically phosphatidylethanolamine or phosphatidylcholine) and saponin (e.g., Quil A).

[0144] 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 repetitive structural order, VLPs can induce a strong immune response. VLPs can be derived from various viruses with sizes ranging from 20 nm to 800 nm, typically ranging from 20 to 150 nm. VLPs can be engineered to express additional peptides or proteins by fusing these peptides / proteins to the particle or by expressing multiple antigens. Additionally, antigens can be chemically coupled to the viral surface to generate bioconjugated VLPs.

[0145] Examples of self-assembling proteins include ferritin and major vault protein (MVP). Ferritin is a protein that can self-assemble into a roughly spherical 10 nm structure. 96 units of MVP can self-assemble into a barrel-shaped vault nanoparticle with a size of about 40 nm wide and 70 nm long. An antigen that is genetically fused to a minimal interaction domain can be packaged into the vault nanoparticle by a self-assembly process when mixed with MVP. Thus, an antigen (such as an antigenic peptide of the present invention of a polypeptide comprising it) can be fused to a self-assembling protein or a fragment / domain thereof (e.g., the minimal interaction domain of MVP). Thus, the present invention also provides a fusion protein comprising a self-assembling protein (or a fragment / domain thereof) and an antigenic peptide of the present invention.

[0146] In general, preferred examples of nanoparticles (NPs) include iron oxide beads, polystyrene microspheres, poly(γ-glutamic acid) (γ-PGA) NPs, iron oxide-zinc oxide NPs, cationized gelatin NPs, pluronic-stabilized poly(propylene sulfide) (PPS) NPs, PLGA NPs, (cationic) liposomes, (pH-responsive) polymeric micelles, PLGA, cancer cell membrane-coated PLGA, lipid-calcium-phosphate (LCP) NPs, liposome-protamine-hyaluronic acid (LPH) NPs, polystyrene latex beads, magnetic beads, iron-dextran particles, and quantum dot nanocrystals.

[0147] Preferably, the nanoparticle further comprises an adjuvant, such as a toll-like receptor (TLR) agonist. This allows the antigenic peptide (polypeptide / protein / nucleic acid containing the antigenic peptide) to be delivered together with the adjuvant to an antigen-presenting cell (APC), such as a dendritic cell (DC). The adjuvant, like the antigenic peptide, can be preferably encapsulated by the nanoparticle or bound / conjugated to the surface of the nanoparticle.

[0148] A particularly preferred adjuvant is polyinosinic:polycytidylic acid (also referred to 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 immunostimulant known to interact with Toll-like receptor 3 (TLR3). Poly I:C is structurally similar to double-stranded RNA, the "natural" stimulant of TLR3. Poly I:C can therefore be considered a synthetic analogue of double-stranded RNA. Poly-ICLC is a synthetic complex of carboxymethylcellulose, polyinosinic-polycytidylic acid, and poly-L-lysine double-stranded RNA. Like poly I:C, poly ICLC is also a ligand for TLR3. Poly I:C and poly ICLC typically stimulate the release of cytotoxic cytokines. A preferred example of poly ICLC is Hirutonol®.

[0149] Immunogenic Compositions and Kits The immunogenic composition of the present invention comprises at least one of the following: - an antigenic peptide according to the invention, an immunogenic compound according to the invention, the nanoparticles according to the invention, a cell according to the invention, a nucleic acid according to the invention, or - A host cell according to the invention.

[0150] Preferably, the immunogenic composition further comprises one or more pharma- ceutically acceptable excipients or carriers.

[0151] The immunogenic composition of the present invention can be in any form suitable for the purpose of the present invention. For example, the composition can 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 the art to select a suitable form of the composition for the intended purpose.

[0152] Indeed, in the context of the present invention, it may be particularly advantageous to use (poly)peptides or nucleic acids encoding same, due to their ease of production at low cost and their relative safety without the possibility of reassortment, infection or recombination.

[0153] The antigenic peptide of the invention may be administered in the form of an immunogenic compound according to the invention, a cell loaded therewith according to the invention, a nanoparticle according to the invention, a nucleic acid according to the invention, a host cell according to the invention, and / or an immunogenic composition according to the invention.

[0154] According to one embodiment, they may be administered in the form of microorganisms such as Enterobacteriaceae species.

[0155] Whole Enterobacterial species may also be advantageous, as they may elicit a greater immune response than the (poly)peptides or nucleic acids they contain.

[0156] Alternatively, the intestinal bacteria of the present invention may be in the form of probiotics, i.e. live intestinal bacteria, which can be used as a food additive for the health benefits they may provide. They can be freeze-dried, for example in granules, pills or capsules, or can be mixed directly with dairy products for consumption.

[0157] One skilled in the art will readily appreciate that one can select the antigenic peptides of the present invention based on the nature of the cancer to be prevented or treated and / or the human genes / human tumor antigens involved in said cancer. For example, if one wishes to prevent or treat melanoma involving glycoprotein 100 (gp100), TRP1, TRP2, tyrosinase, and / or Melan A / MART1 antigens, one can select any of the corresponding antigenic peptides listed in Table 1A.

[0158] It should be understood that co-administration of several antigenic peptides of the invention is particularly preferred to enhance the immune response.

[0159] Thus, according to a preferred embodiment, the composition of the invention comprises at least two antigenic peptides (which may be in the form of immunogenic compounds) as defined above, comprising at least 3 antigenic peptides, or at least 4 antigenic peptides, or at least 5 antigenic peptides, or at least 6 antigenic peptides, or at least 7 antigenic peptides, or at least 8 antigenic peptides, or at least 9 antigenic peptides, or at least 10 antigenic peptides, or at least 11 antigenic peptides, or at least 12 antigenic peptides, or at least 13 antigenic peptides, or at least 14 antigenic peptides, or at least 15 antigenic peptides, or at least 20 antigenic peptides, or at least 25 antigenic peptides, or at least 50 antigenic peptides, or at least 100 antigenic peptides, or at least 500 antigenic peptides, or at least 1000 antigenic peptides, or at least 1500 antigenic peptides. It is within the skill of the person skilled in the art to select a combination of antigenic peptides and / or immunogenic compounds suitable for the intended purpose. For example, if one desires to prevent or treat melanoma involving tumor antigens encoded by the genes listed in Table 1B, one can select any combination of the corresponding antigenic peptides listed in Table 1A.

[0160] In a particularly preferred embodiment, two different antigenic peptides according to the invention (e.g. relating to the same type of cancer and / or the same reference antigen) are combined. In other words, a composition according to the invention preferably comprises: (i) two different immunogenic compounds according to the invention; (ii) two different antigenic peptides of the present invention; (iii) two different nanoparticles according to the invention; or (iv) two different nucleic acids according to the invention.

[0161] The compositions of the present invention may further comprise other active agents that can, for example, enhance the effect of the antigenic peptide or immunogenic compound, or the compositions may not comprise other active agents (i.e., other than the antigenic peptide of the present invention, the immunogenic compound of the present invention, the nanoparticle of the present invention, the cell of the present invention, the nucleic acid of the present invention, or the host cell of the present invention).

[0162] According to a preferred embodiment, the composition further comprises at least one immunostimulatory agent, in particular to enhance the immune response mediated by the antigenic peptide. Preferred immunostimulatory agents according to the present invention include, but are not limited to, immune adjuvants, antigen presenting cells, and combinations thereof. Preferably, the immune stimulatory agent is an immune adjuvant or an antigen presenting cell (APC).

[0163] Some immune adjuvants can actually favor and extend the duration of the interaction between antigens and the immune system, while others can recruit and activate cells of the innate immune system to induce adaptive responses. Adjuvants belonging to the former category include, but are not limited to, mineral compounds such as alum, aluminum hydroxide, aluminum phosphate, calcium hydroxide, oil emulsions such as paraffin oil, starch oil, Freund's complete / incomplete adjuvant (FCA / FIA), saponins (e.g., from plants Quillaja, soybean, senega), etc. Adjuvants belonging to the latter category include, but are not limited to, immune stimulating complexes (ISCOMs) such as cytokines (e.g., GM-CSF; interleukins such as IL-1, IL-2, IL-6, IL-8, or IL-12; tumor necrosis factors (TNFs) such as TNFα or TNFβ; interferons IFNs such as IFNα, IFNβ, IFNγ, or IFNδ); ligands for toll-like receptors (TLRs) such as imiquimod, resiquimod, or MPL; exosomes such as exosomes derived from dendritic cells (DCs) or tumor cells; heat shock proteins (HSPs such as gp96, hsp90, hsp70, calreticulin, hsp110, hsp170), pathogen-associated molecular patterns (PAMPs), bacterial products such as trehalose dimycolate (TDM), muramyl dipeptide (MDP), polysaccharides (PLSs) (e.g., polysaccharide K).

[0164] According to one embodiment, the immune adjuvant may be the HHD-DR3 peptide MAKTIAYDEEARRGLERGLN (SEQ ID NO: 144).

[0165] More preferably, the immune adjuvant is a protein / peptide with immune adjuvant properties, such as providing stimulation of CD4+Th1 cells, as described herein. Preferred examples thereof may be non-tumor antigens that provide immune memory or non-specific help, or specific tumor-derived helper peptides, such as tetanus helper peptides, keyhole limpet hemocyanin peptides, or PADRE peptides, as described herein. Another preferred example is a specific tumor-derived helper peptide, such as a fragment of a shared overexpressed tumor antigen, such as HER2, NY-ESO-1, hTERT, or IL13RA2, as described above, that can be presented by MHCII, in particular by HLA-DR, HLA-DP, or HLA-DQ.

[0166] A particularly preferred adjuvant is polyinosinic:polycytidylic acid (also referred to 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 strand is a polymer of cytidylic acid. Poly I:C is an immunostimulant known to interact with toll-like receptor 3 (TLR3). Poly I:C is structurally similar to double-stranded RNA, the "natural" stimulant of TLR3. Poly I:C can therefore be considered a synthetic analogue of double-stranded RNA. Poly-ICLC is a synthetic complex of carboxymethylcellulose, polyinosinic-polycytidylic acid, and poly-L-lysine double-stranded RNA. Like poly I:C, poly ICLC is also a ligand for TLR3. Poly I:C and poly ICLC typically stimulate the release of cytotoxic cytokines. A preferred example of poly ICLC is Hirutonol®.

[0167] Antigen-presenting cells (APCs) are also of particular interest, since their main function is to process antigens and present them on the cell surface to T cells of the immune system to initiate and regulate T cell responses in vivo. In the composition of the invention, it is preferred to load APCs with the antigenic peptides and / or immunogenic compounds of the invention, which can be done by exposing APCs to the antigenic peptides and / or immunogenic compounds in vitro (Rizzo et al., Ex vivo loading of autologous dendritic cells with tumor antigens. Methods Mol Biol. 2014;1139:41-4; Rolinski and Hus, Breaking immunotolerance of tumors: a new perspective for dendritic cell therapy. J Immunotoxicol. 2014 Oct;11(4):311-8).

[0168] The preferred antigen-presenting cells according to the present invention are dendritic cells (DCs). As they are the most potent antigen-presenting cells and have been reported to be often functionally defective in cancer patients, it may be actually advantageous to combine at least one antigenic peptide or immunogenic compound according to the present invention with dendritic cells. Dendritic cells can be easily obtained by the skilled artisan from a healthy matched donor (i.e., the dendritic cells are HLA-associated) or from the patient himself (i.e., the dendritic cells are autologous) if they are functional, for example by direct isolation from peripheral blood or by derivation from peripheral blood cells such as CD14+ monocytes or CD34+ hematopoietic precursors (Emens et al., 2008). Dendritic cells can indeed 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 said markers using cell culture techniques well known in the art.

[0169] According to a preferred embodiment, the pharmaceutical composition may further comprise at least one anti-cancer therapeutic agent. Thus, said therapeutic agent is preferably capable of preventing and / or treating the same type of cancer for which the antigenic peptide of the present invention is used. Particularly preferred anti-cancer therapeutic agents according to the present invention include, but are not limited to, antibodies, tumor cell lysates, chemotherapeutic agents, radiotherapeutic agents, and combinations thereof. Most preferably, the anti-cancer therapeutic agent is selected from antibodies, tumor cell lysates, chemotherapeutic agents, radiotherapeutic agents, immune checkpoint modulators, and combinations thereof.

[0170] Antibodies are particularly advantageous in cancer therapy because they can bind to specific antigens on the surface of cancer cells, thereby directing therapy to the tumor (i.e., they are referred to as tumor-targeting antibodies) or block immune checkpoints that are dysregulated in cancer (i.e., they are referred to as immunomodulatory antibodies). The purpose of the latter type of antibody is to inhibit immune resistance of cancer, which can be seen especially for T cells specific for tumor antigens. Indeed, as is well known in the art, under normal physiological conditions, immune checkpoints are crucial for maintaining self-tolerance (i.e., preventing autoimmunity) and protect tissues from damage when the immune system is responding to pathogenic infections. However, in cancer, immune checkpoint expression can be dysregulated as a key mechanism of immune resistance. Said resistance is especially seen in melanoma, ovarian cancer, lung cancer, glioblastoma, breast cancer, and pancreatic cancer with respect to the PD-L1 checkpoint (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 for malignant melanoma. Cancer. 2010 Apr 14, 2013). 1;116(7):1757-66).Other examples of immune checkpoints include, but are not limited to, PD-L2, PD1, CD80, CD86, CTLA4, B7H3, B7H4, PVR, TIGIT, GAL9, LAG-3, GITR, CD137, TIM3, VISTA, VISTA-R (Pico de Coana 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 cancer immunotherapy. Nat Rev Cancer. 2012 Mar 22;12(4):252-64).

[0171] Antibodies are usually used for this purpose either in the form of naked monoclonal antibodies (i.e., unconjugated), or conjugated to another molecule, which may be toxic to cells or which may be radioactive.

[0172] 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, renal cancer), brentuximab / vedotin (lymphoma), blinatumumab (acute lymphoblastic leukemia), catumaxomab (EPCAM+ cancer malignancies). ascites), cetuximab (head and neck cancer, colorectal cancer), denosumab (breast cancer, prostate cancer, and bone cancer), gemtuzumab / ozogamicin (acute myeloid leukemia), ibritumomab / tiuxetan (non-Hodgkin's lymphoma), panitumumab (colorectal cancer), pertuzumab (breast cancer), obinutuzumab (chronic lymphocytic leukemia), ofatumumab (chronic lymphocytic leukemia), opilim Examples of immunomodulatory antibodies include, but are not limited to, ipilimumab (melanoma), which blocks the CTLA4-dependent immune checkpoint, nivolumab (melanoma, lung cancer) and prembrolizumab (melanoma), which all block the PDCD1-dependent immune checkpoint, and MPDL3280A, MEDI4736, MEDI0680, and MSB0010718C, which all block the PD-L1-dependent immune checkpoint (Sharma and Allison, The future of immune checkpoint therapy. Science. 2015 Apr 3;348(6230):56-61).

[0173] Other antibodies for cancer immunotherapy are described in: Buque 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(2 Pt A):28-45; Simpson and Caballero, Monoclonal antibodies for the therapy of cancer MC Proc. 2014; 8(Suppl 4): O6 as well as on the antibody society website (list of therapeutic monoclonal antibodies approved or in review in the European Union or United States available on the weblink http: / / www.antibodysociety.org / news / approved_mabs.php).

[0174] Tumor cell lysates can also be combined with the antigenic peptides of the present invention. Tumor cells can stimulate an immune response by presenting endogenous peptide-MHC complexes as well as through host dendritic cells (DCs) that can process and present antigens delivered by the lysate, thereby broadening the range of antigens that can induce an immune response. Tumor cell lysates can be easily obtained by treating tumor cells with heat shock and / or chemical treatment and can be autologous (i.e. isolated from the patient himself) or allogeneic (i.e. isolated from another subject).

[0175] Standard chemotherapy and radiotherapy agents are not further described herein, as they have been extensively described in Baskar et al., Cancer and radiation therapy: current advances and future directions. Int J Med Sci. 2012;9(3):193-9, Paci et al., Review of therapeutic drug monitoring of anticancer drugs part 1--cytotoxics. Eur J Cancer. 2014 Aug;50(12):2010-9, 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).

[0176] Preferably, the immune checkpoint modulator for combination with the antigenic peptides defined herein is an activator or inhibitor of one or more immune checkpoint molecules selected from 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 ligands thereof.

[0177] More preferably, the immune checkpoint modulator is an activator of a (co)stimulatory checkpoint molecule, or an inhibitor of an inhibitory checkpoint molecule, or a combination thereof. Thus, the immune checkpoint modulator is more preferably (i) an activator of CD27, CD28, CD40, CD122, CD137, OX40, GITR, and / or ICOS, or (ii) an inhibitor of 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.

[0178] Even more preferably, the immune checkpoint modulator is an inhibitor of an inhibitory checkpoint molecule (but preferably not an inhibitor of a stimulatory checkpoint molecule).Thus, the immune checkpoint modulator is even 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 ligands thereof.

[0179] Immune checkpoint modulators are also preferably activators of stimulatory or costimulatory checkpoint molecules (but preferably are not activators of inhibitory checkpoint molecules).Thus, immune checkpoint modulators are more preferably activators of CD27, CD28, CD40, CD122, CD137, OX40, GITR, and / or ICOS, or their ligands.

[0180] Even more preferably, the immune checkpoint modulator is a modulator of the CD40 pathway, the IDO pathway, the LAG3 pathway, the CTLA-4 pathway, and / or the PD-1 pathway. In particular, the immune checkpoint modulator is preferably a modulator of CD40, LAG3, CTLA-4, PD-L1, PD-L2, PD-1, and / or IDO, more preferably the immune checkpoint modulator is an inhibitor of CTLA-4, PD-L1, PD-L2, PD-1, LAG3, and / or IDO or an activator of CD40, even more preferably the immune checkpoint modulator is an inhibitor of CTLA-4, PD-L1, PD-1, LAG3, and / or IDO, even more preferably the immune checkpoint modulator is an inhibitor of LAG3, CTLA-4, and / or PD-1, and most preferably the immune checkpoint modulator is an inhibitor of CTLA-4 and / or PD-1.

[0181] Thus, checkpoint modulators for combination with the antigenic peptides may be selected from known modulators of the CTLA-4 or PD-1 pathways. Preferably, checkpoint modulators for combination with the antigenic peptides defined herein may be selected from known modulators of the CTLA-4 or PD-1 pathways. Particularly preferably, the immune checkpoint modulator is a PD-1 inhibitor. Preferred inhibitors of the CTLA-4 and PD-1 pathways include the monoclonal antibodies Yervoy® (ipilimumab; Bristol Myers Squibb), tremelimumab (Pfizer / MedImmune), and Opdivo® (nivolumab; Bristol Myers Squibb), Keytruda® (pembrolizumab; Merck), durvalumab (MedImmune / AstraZeneca), MEDI4736 (AstraZeneca; WO2011 / 066389). A1), MPDL3280A (Roche / Genentech; see US8,217,149B2), pidilizumab (CT-011; CureTech), MEDI0680 (AMP-514; AstraZeneca), MSB-0010718C (Merck), MIH1 (Affymetrix), and lambrolizumab (disclosed, e.g., as hPD109A and its humanized derivatives h409All, h409A16, and h409A17 in WO2008 / 156712; Hamid et al., 2013; N. Engl. J. Med. 369:134-144).More preferred checkpoint inhibitors include the CTLA-4 inhibitors Yervoy® (ipilimumab; Bristol Myers Squibb), tremelimumab (Pfizer / MedImmune), and the PD-1 inhibitors Opdivo® (nivolumab; Bristol Myers Squibb), Keytruda® (pembrolizumab; Merck), pidilizumab (CT-011; CureTech), MEDI0680 (AMP-514; Astrazeneca), AMP-224, and lambrolizumab (disclosed, e.g., as hPD109A and its humanized derivatives h409A11, h409A16, and h409A17 in WO2008 / 156712; Hamid O. et al., 2013; N. Engl. J. Med. 369:134-144).

[0182] Also preferably, the immune checkpoint modulator for combination with the antigenic peptides defined herein is selected from the group consisting of pembrolizumab, ipilimumab, nivolumab, MPDL3280A, MEDI4736, tremelimumab, avelumab, PDR001, LAG525, INCB24360, varlilumab, urelumab, AMP-224, and CM-24.

[0183] It is within the skill of the art to select an appropriate immunotherapeutic agent for the purposes of the present invention. For example, if prevention or treatment of melanoma is desired, lysates from melanoma cells and / or the antibody opilimumab can be preferably used with the corresponding antigenic peptides listed in Table 1A.

[0184] Anti-cancer therapeutic agents can also be administered simultaneously, separately or sequentially with the compositions of the invention. When the composition and the therapeutic agent are administered in a separate or sequential manner, they can be administered in different pharmaceutical forms.

[0185] Therefore, in another aspect, the present invention relates to the composition of the present invention and at least one anti-cancer therapeutic agent as described above as a combined preparation for simultaneous, separate or sequential administration. In other words, the present invention proposes the combined use of the composition of the present invention and at least one anti-cancer therapeutic agent as described above for simultaneous, separate or sequential administration.

[0186] In a further aspect, the present invention also relates to a kit-of-parts, preferably for use in the prevention and / or treatment of cancer, comprising at least one of the following: an immunogenic compound according to the invention, - an antigenic peptide according to the invention, the nanoparticles according to the invention, a cell according to the invention, - a nucleic acid according to the invention, a host cell according to the invention, or - an immunogenic composition according to the invention.

[0187] In particular, a kit-of-parts of the invention can comprise more than one of the above mentioned components. For example, a kit-of-parts according to the invention can comprise at least two different immunogenic compounds, at least two different antigenic peptides, 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 immunogenic compositions. Preferably, such different components comprised in said kit-of-parts differ in the antigenic peptide according to the invention, e.g. one component related to a first antigenic peptide and one component related to a second antigenic peptide (different from said first antigenic peptide).

[0188] For example, the kit may contain two different immunogenic compounds according to the invention.

[0189] For example, a kit can include two different antigenic peptides according to the invention.

[0190] For example, a kit can include two different nanoparticles according to the invention.

[0191] For example, the kit may contain two different nucleic acids according to the invention.

[0192] The various components of the kit-of-parts may be packaged in one or more containers. The components may be provided in lyophilized or dry form or may be dissolved in a suitable buffer. The kit may also contain further reagents such as, for example, preservatives, growth media, and / or buffers for storage and / or reconstitution of the components, washing solutions, etc. Furthermore, the kit-of-parts according to the invention may contain instructions for use.

[0193] Furthermore, the present invention provides a vaccination kit for treating, preventing and / or stabilizing cancer comprising an immunogenic composition as described herein or a vaccine as described herein and instructions for using said immunogenic composition or said vaccine in the prevention and / or treatment of cancer.

[0194] Preferably, such a kit further comprises a package insert or instruction leaflet comprising instructions for preventing or treating cancer by using the immunogenic compound of the invention, the antigenic peptide of the invention, the nanoparticle of the invention, the cell of the invention, the nucleic acid of the invention, the host cell of the invention, or the immunogenic composition of the invention.

[0195] In addition to any of the above components, the kit also preferably includes an anti-cancer therapeutic agent as described herein.

[0196] Medical Treatment and Use As mentioned above, the compositions of the invention may be particularly useful for therapeutic purposes, in particular for eliciting a specific immune response against a particular tumor antigen / protein to prevent or treat cancer in a patient in need thereof.

[0197] In a further aspect, the present invention provides an immunogenic compound according to the invention, an antigenic peptide according to the invention, a nanoparticle according to the invention, a cell according to the invention, a nucleic acid according to the invention, a host cell according to the invention or an immunogenic composition according to the invention for use in the prevention and / or treatment of cancer, preferably said cancer for which the (reference) antigen of such an antigenic peptide is directed.

[0198] Thus, the present invention provides a method for preventing and / or treating cancer, or initiating, enhancing or prolonging an anti-tumor response in a subject in need thereof, comprising administering to said subject: an immunogenic compound according to the invention, - an antigenic peptide according to the invention, the nanoparticles according to the invention, a cell according to the invention, - a nucleic acid according to the invention, a host cell according to the invention, an immunogenic composition according to the invention, or - a combination according to the invention as described herein.

[0199] Furthermore, the present invention relates to a method for detecting CD8 + Provided is a method for inducing or improving an immune response to one or more epitopes that is cytotoxic T cell dependent, the method comprising administering to the subject either: an immunogenic compound according to the invention, - an antigenic peptide according to the invention, the nanoparticles according to the invention, a cell according to the invention, - a nucleic acid according to the invention, a host cell according to the invention, an immunogenic composition according to the invention, or - a combination according to the invention as described herein.

[0200] CD8 + The immune response dependent response can be determined by evaluating inflammatory response, inflammatory cytokine response, such as an increase in expression of one or more of IFN-γ, TNF-α, and IL-2 mRNA or protein, relative to the level before administration of the compound of the present invention. It can also be measured by an increase in the frequency or absolute number of antigen-specific T cells after administration of the compound of the present invention, which can be measured by HLA-peptide multimer staining, ELISPOT assay, and delayed type hypersensitivity test. It can also be indirectly measured by an increase in antigen-specific serum antibodies dependent on antigen-specific T helper cells.

[0201] The present invention also provides a method for inducing or improving an immune response in a subject to one or more antigens or antigenic epitopes restricted by multiple MHC class I molecules, the method comprising: an immunogenic compound according to the invention, - an antigenic peptide according to the invention, the nanoparticles according to the invention, a cell according to the invention, - a nucleic acid according to the invention, a host cell according to the invention, an immunogenic composition according to the invention, or - combinations according to the invention as described herein The method includes administering

[0202] Methods for eliciting or improving immune responses in a subject against multiple epitopes described herein that are restricted by multiple MHC class I molecules can be determined by assessing cytokine responses, including an increase in expression of one or more of IFN-γ, TNF-α, and IL-2 mRNA or protein relative to levels prior to administration of the compound of the present invention after in vitro stimulation of T cells with individual peptides that bind to separate MHC class I molecules on antigen-presenting cells. Restriction to MHC class I molecules can also be assessed by using antigen-presenting cells expressing MHC class I molecules or by using MHC class I blocking antibodies. It can also be measured by an increase in the frequency or absolute number of antigen-specific T cells following administration of the compound of the present invention, as measured by HLA-peptide multimer staining, using multimers assembled with MHC class I molecules.

[0203] Therefore, in another aspect, the present invention relates to a composition as defined above for use as a medicament. an immunogenic compound according to the invention, - an antigenic peptide according to the invention, the nanoparticles according to the invention, a cell according to the invention, - a nucleic acid according to the invention, a host cell according to the invention, an immunogenic composition according to the invention, or - combinations according to the invention as described herein can be used as a medicine.

[0204] The present invention more particularly relates to a composition as defined above for use as a vaccine for immunotherapy. an immunogenic compound according to the invention, - an antigenic peptide according to the invention, the nanoparticles according to the invention, a cell according to the invention, - a nucleic acid according to the invention, a host cell according to the invention, an immunogenic composition according to the invention, or - combinations according to the invention as described herein can be used as a vaccine, especially for (cancer) immunotherapy.

[0205] When used in the context of the present invention, the term "vaccine" typically refers to a biological preparation that provides innate and / or adaptive immunity against a particular disease, preferably cancer. Thus, a vaccine specifically supports 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 typically induce or support an adaptive immune response in the patient to be treated.

[0206] In the context of the present invention, the vaccine (composition) is capable of inducing a specific immune response against tumor antigens and is therefore preferably used for the prevention or treatment of cancer, which may also be referred to herein as a cancer vaccine.

[0207] Thus, in a preferred embodiment, the present invention relates to a composition as defined above for use in the prevention and / or treatment of cancer in a subject in need thereof. More precisely, the present invention relates to the use of a composition of the present invention for the manufacture of a medicament for preventing or treating cancer in a subject in need thereof.

[0208] 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 the composition of the present invention.

[0209] Methods of administering pharmaceuticals are well known to those skilled in the art. With regard to the composition of the present invention, it can be administered to a subject directly to the affected organ (i.e., local administration) or to the whole body (i.e., enteral or parenteral administration), or it can be applied ex vivo to cells derived from the subject or human cell lines that are subsequently administered to the subject, and even used in vitro to select a subpopulation of immune cells derived from the subject that are subsequently re-administered to the subject. Enteral administration as used herein includes oral and rectal administration, as well as administration via a gastric feeding tube, duodenal feeding tube, or gastrostomy, while parenteral administration includes, inter alia, subcutaneous, intravenous, intramuscular, intraarterial, intradermal, intraosseous, intracerebral administration, and intrathecal injection. The method of administration often depends on the antigenic peptides and / or immunogenic compounds present in the composition, as well as the type of cancer to be treated and other active agents that may be included in said composition. For example, when the immunogenic compound is a nucleic acid as defined above, administration is preferably intramuscular or intradermal injection, and when said nucleic acid is cloned into a viral vector, oral / intranasal administration is particularly preferred. Alternatively, when the antigenic peptide and / or immunogenic compound is a (poly)peptide as defined above or when it is loaded into / onto a nanoparticle as described herein, administration is preferably intramuscular, intradermal or oral administration. Still alternatively, when the antigenic peptide and / or immunogenic compound is delivered in the form of an enterobacteria as defined above, particularly when the enterobacteria is in the form of a probiotic, administration is preferably oral administration.

[0210] To facilitate their administration to subjects in need thereof, the antigenic peptides and / or immunogenic compounds according to the invention can be further encapsulated, for example, in peptide nanocarriers (preferred when the immunogenic compound is a nucleic acid or (poly)peptide), virosomes (preferred when the immunogenic compound is a nucleic acid or (poly)peptide), or lipid-based carrier systems such as liposome-polycation-DNA complexes (preferred when the immunogen is a nucleic acid or (poly)peptide) (Trovato M, De Berardinis P. Novel antigen delivery systems. World J Virol. 2015 Aug 12;4(3):156-68; Saade F, Petrovsky N. Technologies for enhanced efficacy of DNA vaccines. Expert Rev Vaccines. 2012 Feb;11(2):189-209; Li et al., Peptide Vaccine: Progress and Challenges. Vaccines (Basel). 2014 Jul 2;2(3):515-36).

[0211] The composition can be administered more than once to achieve the desired effect. In a preferred embodiment, the composition is administered repeatedly, at least twice, preferably more than twice. This can be done after the first administration, for an extended period of time, such as weekly, biweekly, monthly, yearly, or even several years, to ensure that the subject is adequately immunized.

[0212] According to one embodiment, the antigenic peptides or immunogenic compounds of the present invention can be used for the preparation of a composition and / or an immunogenic composition for preventing or treating cancer in a subject in need thereof.

[0213] Combination Therapy In particular, in the methods and uses according to the invention, the administration of the antigenic peptides according to the invention, the immunogenic compounds according to the invention, the nanoparticles according to the invention, the cells according to the invention, the nucleic acids according to the invention, the host cells according to the invention and the immunogenic compositions according to the invention can be performed alone or in combination with adjuvants useful in the treatment and / or prevention of cancer, such as anti-cancer therapeutic agents.

[0214] Thus, the therapeutic agent is preferably capable of preventing and / or treating the same type of cancer for which the antigenic peptide of the present invention is used. Particularly preferred anti-cancer therapeutic agents of the present invention include, but are not limited to, antibodies, tumor cell lysates, chemotherapeutic agents, radiotherapeutic agents, immune checkpoint modulators, and combinations thereof.

[0215] Antibodies are particularly advantageous in cancer therapy because they can bind to specific antigens on the surface of cancer cells, thereby directing therapy to the tumor (i.e., they are referred to as tumor-targeting antibodies) or block immune checkpoints that are dysregulated in cancer (i.e., they are referred to as immunomodulatory antibodies). The purpose of the latter type of antibody is to inhibit immune resistance of cancer, which can be seen especially for T cells specific for tumor antigens. Indeed, as is well known in the art, under normal physiological conditions, immune checkpoints are crucial for maintaining self-tolerance (i.e., preventing autoimmunity) and protect tissues from damage when the immune system is responding to pathogenic infections. However, in cancer, immune checkpoint expression can be dysregulated as a key mechanism of immune resistance. Said resistance is especially seen in melanoma, ovarian cancer, lung cancer, glioblastoma, breast cancer, and pancreatic cancer with respect to the PD-L1 checkpoint (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 for malignant melanoma. Cancer. 2010 Apr 14, 2013). 1;116(7):1757-66).Other examples of immune checkpoints include, but are not limited to, PD-L2, PD1, CD80, CD86, CTLA4, B7H3, B7H4, PVR, TIGIT, GAL9, LAG-3, GITR, CD137, TIM3, VISTA, VISTA-R (Pico de Coana et al., Checkpoint blockade for cancer therapy: revitalizing a suppressed immune system. Trends Mol Med. 2015 Aug;21(8):482-91; Pardoll DM1. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012 Mar 22;12(4):252-64).

[0216] Antibodies are usually used for this purpose either in the form of naked monoclonal antibodies (i.e., unconjugated), or conjugated to another molecule, which may be toxic to cells or which may be radioactive.

[0217] 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, renal cancer), brentuximab / vedotin (lymphoma), blinatumumab (acute lymphoblastic leukemia), catumaxomab (EPCAM+ cancer malignancies). ascites), cetuximab (head and neck cancer, colorectal cancer), denosumab (breast cancer, prostate cancer, and bone cancer), gemtuzumab / ozogamicin (acute myeloid leukemia), ibritumomab / tiuxetan (non-Hodgkin's lymphoma), panitumumab (colorectal cancer), pertuzumab (breast cancer), obinutuzumab (chronic lymphocytic leukemia), ofatumumab (chronic lymphocytic leukemia), opilim Examples of immunomodulatory antibodies include, but are not limited to, ipilimumab (melanoma), which blocks the CTLA4-dependent immune checkpoint, nivolumab (melanoma, lung cancer) and prembrolizumab (melanoma), which all block the PDCD1-dependent immune checkpoint, and MPDL3280A, MEDI4736, MEDI0680, and MSB0010718C, which all block the PD-L1-dependent immune checkpoint (Sharma and Allison, The future of immune checkpoint therapy. Science. 2015 Apr 3;348(6230):56-61).

[0218] Other antibodies for cancer immunotherapy are described in: Buque et al. (Buque et al., Trial Watch: Immunomodulatory monoclonal antibodies for oncological indications. Oncoimmunology. 2015 Mar 2;4(4):e1008814. eCollection 2015 Apr) Redman et al. (Redman et al., Mechanisms of action of therapeutic antibodies for cancer. Mol Immunol. 2015 Oct;67(2 Pt A):28-45) and Simpson and Caballero, Monoclonal antibodies for the therapy of cancer MC Proc. 2014; 8(Suppl 4): O6 as well as on the antibody society website (list of therapeutic monoclonal antibodies approved or in review in the European Union or United States available on the weblink http: / / www.antibodysociety.org / news / approved_mabs.php).

[0219] Tumor cell lysates can also be combined with the antigenic peptides of the present invention. Tumor cells can stimulate an immune response by presenting endogenous peptide-MHC complexes as well as through host dendritic cells (DCs) that can process and present antigens delivered by the lysate, thereby broadening the range of antigens that can induce an immune response. Tumor cell lysates can be easily obtained by treating tumor cells with heat shock and / or chemical treatment and can be autologous (i.e. isolated from the patient himself) or allogeneic (i.e. isolated from another subject).

[0220] Standard chemotherapy and radiotherapy agents are not further described herein, as they have been extensively described in Baskar et al., Cancer and radiation therapy: current advances and future directions. Int J Med Sci. 2012;9(3):193-9, Paci et al., Review of therapeutic drug monitoring of anticancer drugs part 1--cytotoxics. Eur J Cancer. 2014 Aug;50(12):2010-9, 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).

[0221] Preferably, the immune checkpoint modulator for combination with the antigenic peptides defined herein is an activator or inhibitor of one or more immune checkpoint molecules selected from 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 ligands thereof.

[0222] More preferably, the immune checkpoint modulator is an activator of a (co)stimulatory checkpoint molecule, or an inhibitor of an inhibitory checkpoint molecule, or a combination thereof. Thus, the immune checkpoint modulator is more preferably (i) an activator of CD27, CD28, CD40, CD122, CD137, OX40, GITR, and / or ICOS, or (ii) an inhibitor of 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.

[0223] Even more preferably, the immune checkpoint modulator is an inhibitor of an inhibitory checkpoint molecule (but preferably not an inhibitor of a stimulatory checkpoint molecule).Thus, the immune checkpoint modulator is even 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 ligands thereof.

[0224] Immune checkpoint modulators are also preferably activators of stimulatory or costimulatory checkpoint molecules (but preferably are not activators of inhibitory checkpoint molecules).Thus, immune checkpoint modulators are more preferably activators of CD27, CD28, CD40, CD122, CD137, OX40, GITR, and / or ICOS, or their ligands.

[0225] Even more preferably, the immune checkpoint modulator is a modulator of the CD40 pathway, the IDO pathway, the LAG3 pathway, the CTLA-4 pathway, and / or the PD-1 pathway. In particular, the immune checkpoint modulator is preferably a modulator of CD40, LAG3, CTLA-4, PD-L1, PD-L2, PD-1, and / or IDO, more preferably the immune checkpoint modulator is an inhibitor of CTLA-4, PD-L1, PD-L2, PD-1, LAG3, and / or IDO or an activator of CD40, even more preferably the immune checkpoint modulator is an inhibitor of CTLA-4, PD-L1, PD-1, LAG3, and / or IDO, even more preferably the immune checkpoint modulator is an inhibitor of LAG3, CTLA-4, and / or PD-1, and most preferably the immune checkpoint modulator is an inhibitor of CTLA-4 and / or PD-1.

[0226] Thus, checkpoint modulators for combination with the antigenic peptides may be selected from known modulators of the CTLA-4 or PD-1 pathways. Preferably, checkpoint modulators for combination with the antigenic peptides defined herein may be selected from known modulators of the CTLA-4 or PD-1 pathways. Particularly preferably, the immune checkpoint modulator is a PD-1 inhibitor. Preferred inhibitors of the CTLA-4 and PD-1 pathways include the monoclonal antibodies Yervoy® (ipilimumab; Bristol Myers Squibb), tremelimumab (Pfizer / MedImmune), and Opdivo® (nivolumab; Bristol Myers Squibb), Keytruda® (pembrolizumab; Merck), durvalumab (MedImmune / AstraZeneca), MEDI4736 (AstraZeneca; WO2011 / 066389). A1), MPDL3280A (Roche / Genentech; see US8,217,149B2), pidilizumab (CT-011; CureTech), MEDI0680 (AMP-514; AstraZeneca), MSB-0010718C (Merck), MIH1 (Affymetrix), and lambrolizumab (disclosed, e.g., as hPD109A and its humanized derivatives h409All, h409A16, and h409A17 in WO2008 / 156712; Hamid et al., 2013; N. Engl. J. Med. 369:134-144).More preferred checkpoint inhibitors include the CTLA-4 inhibitors Yervoy® (ipilimumab; Bristol Myers Squibb), tremelimumab (Pfizer / MedImmune), and the PD-1 inhibitors Opdivo® (nivolumab; Bristol Myers Squibb), Keytruda® (pembrolizumab; Merck), pidilizumab (CT-011; CureTech), MEDI0680 (AMP-514; Astrazeneca), AMP-224, and lambrolizumab (disclosed, e.g., as hPD109A and its humanized derivatives h409A11, h409A16, and h409A17 in WO2008 / 156712; Hamid O. et al., 2013; N. Engl. J. Med. 369:134-144).

[0227] Also preferably, the immune checkpoint modulator for combination with the antigenic peptides defined herein is selected from the group consisting of pembrolizumab, ipilimumab, nivolumab, MPDL3280A, MEDI4736, tremelimumab, avelumab, PDR001, LAG525, INCB24360, varlilumab, urelumab, AMP-224, and CM-24.

[0228] It is within the skill of the art to select an appropriate immunological anti-cancer therapeutic agent for the purposes of the present invention. For example, if prevention or treatment of melanoma is desired, lysates from melanoma cells and / or the antibody opilimumab may be preferably used together with the corresponding antigenic peptides according to the present invention as described herein.

[0229] The anti-cancer therapeutic agent can also be administered together with the antigenic peptide of the present invention, the immunogenic compound of the present invention, the nanoparticle of the present invention, the cell of the present invention, the nucleic acid of the present invention, the host cell of the present invention, or the immunogenic composition of the present invention, approximately simultaneously or sequentially as described herein, in the same or different pharmaceutical forms.

[0230] Therefore, in another aspect, the present invention relates to the composition of the present invention and at least one anti-cancer therapeutic agent as described above as a combined preparation for simultaneous, separate or sequential administration. In other words, the present invention proposes the combined use of the composition of the present invention and at least one anti-cancer therapeutic agent as described above for simultaneous, separate or sequential administration.

[0231] Furthermore, the present invention also provides a combination of (at least) two different antigenic peptides according to the present invention as described herein. In this context, the (at least) two different antigenic peptides can be in any form, for example "naked", contained in an immunogenic compound, a nanoparticle, an (immunogenic) composition, or in a cell loaded with them, or encoded by a nucleic acid (for example a vector). Thus, the (at least) two different antigenic peptides can be contained in (at least) two different components (to be combined). Thus, two different components of a combination according to the present invention particularly refer to different antigenic peptides according to the present invention (contained in an immunogenic compound, a nanoparticle, encoded by a nucleic acid, etc.). Such two different components, in particular two different antigenic peptides according to the present invention (contained in two different components), preferably refer to the same type of cancer, for example the same or different antigens associated with this cancer, and / or different (reference) epitopes within an antigen associated with this cancer. More preferably, the two different components, in particular the two different antigenic peptides according to the present invention (contained in two different components), relate to the same tumor (associated or specific) antigen. The two different components, in particular the two different antigenic peptides according to the invention (contained in the two different components), may also be related to the same or different (reference) tumor (associated or specific) antigens.

[0232] Furthermore, the antigenic peptides according to the invention can also be combined with the corresponding (human) tumor antigen epitopes (as described above for peptide "families"). Thereby, a highly efficient selection of T cell clones against tumors is obtained / supported. In particular, the antigenic peptides according to the invention and the corresponding (human) tumor antigen epitopes can be co-administered. Such co-administration can be approximately simultaneous (concurrent) or sequential, whereby the antigenic peptides according to the invention are preferably administered first and then the corresponding (human) tumor antigen epitopes. In particular, the antigenic peptides according to the invention can be administered first and the corresponding (human) tumor antigen epitopes can be used as a (re)boost. For example, the antigenic peptide of SEQ ID NO: 47 can be combined with the reference peptide of SEQ ID NO: 120. In another example, the antigenic peptides of SEQ ID NO: 51, 52, 55 or 56 can be combined with the reference peptide of SEQ ID NO: 122. In another example, the antigenic peptide of SEQ ID NO: 77 can be combined with the reference peptide of SEQ ID NO: 128. In another example, the antigenic peptide of SEQ ID NO: 93 can be combined with the reference peptide of SEQ ID NO: 136. In another example, an antigenic peptide of SEQ ID NO:28 can be combined with a reference peptide of SEQ ID NO:115. In another example, an antigenic peptide of SEQ ID NO:101 or 102 can be combined with a reference peptide of SEQ ID NO:141. In another example, an antigenic peptide of SEQ ID NO:26 can be combined with a reference peptide of SEQ ID NO:113.

[0233] (a) an antigenic peptide according to the invention and a corresponding (human) tumor antigen epitope, or (b) both peptides to be combined, such as two different antigenic peptides according to the invention. - in the same immunogenic compound according to the invention or in different immunogenic compounds according to the invention, - (loaded) in the same nanoparticle according to the invention or in different nanoparticles according to the invention, - (loaded) in the same cell according to the invention or in different cells according to the invention, - by the same nucleic acid according to the invention or (encoded by) different nucleic acids according to the invention, - (expressed by) the same host cell according to the invention or by different host cells according to the invention, - (contained in) the same immunogenic composition according to the invention or a different immunogenic composition according to the invention, It can be administered.

[0234] For example, the present invention provides the following combinations for use in the prevention and / or treatment of cancer: (i) an immunogenic compound of the invention comprising a first antigenic peptide of the invention; and (ii) An immunogenic compound of the invention comprising a second antigenic peptide of the invention.

[0235] For example, the present invention provides the following combinations for use in the prevention and / or treatment of cancer: (i) a first antigenic peptide of the present invention, and (ii) A second antigenic peptide of the present invention.

[0236] For example, the present invention provides the following combinations for use in the prevention and / or treatment of cancer: (i) a nanoparticle according to the invention comprising a first antigenic peptide according to the invention, and (ii) A nanoparticle according to the invention comprising a second antigenic peptide according to the invention.

[0237] For example, the present invention provides the following combinations for use in the prevention and / or treatment of cancer: (i) a nucleic acid according to the invention, comprising a polynucleotide encoding a first antigenic peptide according to the invention; and (ii) A nucleic acid according to the present invention, comprising a polynucleotide encoding a first antigenic peptide according to the present invention.

[0238] Preferably, both peptides to be combined, such as (a) an antigenic peptide according to the invention and a corresponding (human) tumor antigen epitope, or (b) two different antigenic peptides according to the invention, in particular components (i) and (ii), are administered at approximately the same time. More generally, a first (antigenic) peptide of any formulation (e.g. in the form of an immunogenic compound according to the invention, a nanoparticle according to the invention, a cell according to the invention, a nucleic acid according to the invention, a host cell according to the invention, or an immunogenic composition according to the invention; referred to herein as the "first (antigenic) peptide component") is preferably administered at approximately the same time as a second (antigenic) peptide of any formulation (e.g. in the form of an immunogenic compound according to the invention, a nanoparticle according to the invention, a cell according to the invention, a nucleic acid according to the invention, a host cell according to the invention, or an immunogenic composition according to the invention; referred to herein as the "second (antigenic) peptide component"), both (antigenic) peptides being preferably administered in the same form (i.e. in the same type of formulation, e.g. both as nanoparticles, both as immunogenic compositions, etc.).

[0239] As used herein, "approximately simultaneously" refers in particular to simultaneous administration, or administration of (i) a first (antigenic) peptide component immediately followed by administration of (ii) a second (antigenic) peptide component, or administration of (ii) a second (antigenic) peptide component immediately followed by administration of (i) a first (antigenic) peptide component. Those skilled in the art will appreciate that "immediately" includes the time required to prepare the second administration, in particular the time required to expose and disinfect the site for the second administration, and the time required for proper preparation of the "administration device" (e.g., syringe, pump, etc.). Simultaneous administration also includes cases where the administration periods of (i) the first (antigenic) peptide component and (ii) the second (antigenic) peptide component overlap, or where, for example, one component is administered, such as by infusion, over a longer period of time (e.g., 30 minutes, 1 hour, 2 hours, or more), and the other component is administered at some point during such longer period. When different routes of administration and / or different sites of administration are used, near simultaneous administration of (i) the first (antigenic) peptide component and (ii) the second (antigenic) peptide component is particularly preferred.

[0240] It is also preferred that both peptides to be combined, such as (a) an antigenic peptide according to the invention and a corresponding (human) tumor antigen epitope, or (b) two different antigenic peptides according to the invention, in particular components (i) and (ii), are administered sequentially. More generally, it is preferred that a first (antigenic) peptide of any formulation (e.g. in the form of an immunogenic compound according to the invention, a nanoparticle according to the invention, a cell according to the invention, a nucleic acid according to the invention, a host cell according to the invention, or an immunogenic composition according to the invention; referred to herein as the "first (antigenic) peptide component") and a second (antigenic) peptide of any formulation (e.g. in the form of an immunogenic compound according to the invention, a nanoparticle according to the invention, a cell according to the invention, a nucleic acid according to the invention, a host cell according to the invention, or an immunogenic composition according to the invention; referred to herein as the "second (antigenic) peptide component") are administered sequentially, with both (antigenic) peptides preferably being administered in the same form (i.e. in the same type of formulation, e.g. both as nanoparticles, both as immunogenic compositions, etc.).

[0241] This means that (i) the first (antigenic) peptide component is administered before or after (ii) the second (antigenic) peptide component. In sequential administration, the time between administration of the first component and administration of the second component is preferably within one week, more preferably within three days, even more preferably within two days, and most preferably within 24 hours. It is particularly preferred that (i) the first (antigenic) peptide component and (ii) the second (antigenic) peptide component are administered on the same day, and the time between administration of the first component (the first or second (antigenic)) and administration of the second component (the other of the first or second (antigenic) peptide) is preferably within 6 hours, more preferably within 3 hours, even more preferably within 2 hours, and most preferably within 1 hour.

[0242] Preferably, (i) the first (antigenic) peptide component and (ii) the second (antigenic) peptide component are administered by the same route of administration. More generally, the first (antigenic) peptide of any formulation (e.g. in the form of an immunogenic compound according to the invention, a nanoparticle according to the invention, a cell according to the invention, a nucleic acid according to the invention, a host cell according to the invention, or an immunogenic composition according to the invention; referred to herein as the "first (antigenic) peptide component") and the second (antigenic) peptide of any formulation (e.g. in the form of an immunogenic compound according to the invention, a nanoparticle according to the invention, a cell according to the invention, a nucleic acid according to the invention, a host cell according to the invention, or an immunogenic composition according to the invention; referred to herein as the "second (antigenic) peptide component") are preferably administered by the same route of administration, and both (antigenic) peptides are preferably administered in the same form (i.e. in the same type of formulation, e.g. both as nanoparticles, both as immunogenic compositions, etc.).

[0243] It is also preferred that components (i) and (ii) are administered by different routes of administration. More generally, a first (antigenic) peptide of any formulation (e.g. in the form of an immunogenic compound according to the invention, a nanoparticle according to the invention, a cell according to the invention, a nucleic acid according to the invention, a host cell according to the invention, or an immunogenic composition according to the invention; referred to herein as the "first (antigenic) peptide component") and a second (antigenic) peptide of any formulation (e.g. in the form of an immunogenic compound according to the invention, a nanoparticle according to the invention, a cell according to the invention, a nucleic acid according to the invention, a host cell according to the invention, or an immunogenic composition according to the invention; referred to herein as the "second (antigenic) peptide component") are preferably administered by different routes of administration, with both (antigenic) peptides preferably being administered in the same form (i.e. in the same type of formulation, e.g. both as nanoparticles, both as immunogenic compositions, etc.).

[0244] Preferably, components (i) and (ii) are contained in the same composition. More generally, a first (antigenic) peptide of any formulation (e.g. an immunogenic compound according to the invention, a nanoparticle according to the invention, a cell according to the invention, a nucleic acid according to the invention, or a host cell according to the invention; referred to herein as the "first (antigenic) peptide component") and a second (antigenic) peptide of any formulation (e.g. an immunogenic compound according to the invention, a nanoparticle according to the invention, a cell according to the invention, a nucleic acid according to the invention, or a host cell according to the invention; referred to herein as the "second (antigenic) peptide component") are preferably contained in the same composition, and both (antigenic) peptides are preferably administered in the same form (i.e. the same type of formulation, e.g. both as nanoparticles, etc.).

[0245] It is also preferred that components (i) and (ii) are contained in different compositions. More generally, a first (antigenic) peptide of any formulation (e.g. an immunogenic compound according to the invention, a nanoparticle according to the invention, a cell according to the invention, a nucleic acid according to the invention, or a host cell according to the invention; referred to herein as the "first (antigenic) peptide component") and a second (antigenic) peptide of any formulation (e.g. an immunogenic compound according to the invention, a nanoparticle according to the invention, a cell according to the invention, a nucleic acid according to the invention, or a host cell according to the invention; referred to herein as the "second (antigenic) peptide component") are preferably contained in different compositions, with both (antigenic) peptides being preferably administered in the same form (i.e. the same type of formulation, e.g. both as nanoparticles, etc.).

[0246] Working Example Both Examples 1 and 2 relate to the general protocol depicted in FIG. Example 1: HLA-A * Identification of candidate antigenic peptides with superior affinity for the 0201 allele

[0247] This example illustrates the antigenic peptide of SEQ ID NO: 71 ( <flpfgfilv>>, also referred to herein as IL13RA2-B) is associated with HLA-A * 0201 allele, whereas the corresponding reference human peptide from IL13RA2 (< <wlpfgfili>>, SEQ ID NO: 123, also referred to herein as IL13RA2-H) is shown to have low affinity.

[0248] A. Materials and Methods A1. Measurement of peptide affinity for the T2 cell line The experimental protocol was HLA-A * This is similar to that validated for peptides presented by HLA-A2.1.0201 (Tourdot et al., A general strategy to enhance immunogenicity of low-affinity HLA-A2.1-associated peptides: implication in the identification of cryptic tumor epitopes. Eur J Immunol. 2000 Dec; 30(12):3411-21). Peptide affinity measurements were performed using HLA-A * This is achieved using the human tumor cell line T2, which expresses the 0201 molecule but is TAP1 / 2 negative and unable to present the endogenous peptide.

[0249] T2 cells (2.10 5 Cells / well) are incubated with decreasing concentrations of peptide from 100 μM to 0.1 μM in AIMV medium supplemented with 100 ng / μl human β2m for 16 h at 37° C. Cells are then washed twice and labeled with an anti-HLA-A2 antibody conjugated to PE (clone BB7.2, BD Pharmagen).

[0250] Analysis is accomplished by FACS (Guava Easy Cyte).

[0251] For each peptide concentration, the geometric mean of the label associated with the peptide of interest was subtracted from the background noise and the HLA-A concentration obtained with the reference peptide HIV pol 589-597 at a concentration of 100 μM. * The results are reported as a percentage of the geometric mean of the 0202 label. Relative affinities are then determined as follows:

[0252] Relative affinity = HLA-A * Concentration of each peptide that induces 20% of expression of 0201 / HLA-A * Concentration of reference peptide that induces 20% of 0201 expression

[0253] A2. Solubilization of peptides Each peptide is solubilized by considering its amino acid composition. For peptides that do not contain cysteine, methionine, or tryptophan, DMSO can be added up to 10% of the total volume. Other peptides are resuspended in water or PBS pH 7.4.

[0254] B. Results For T2 ATCC cells: Mean fluorescence intensity for variable peptide concentrations: For paired IL13RA2 peptides (IL13RA2-H and IL13RA2-B), the human peptides were * Candidate peptide IL13RA2-B strongly binds to 0201, whereas HLA-A * Does not appear to bind to 0201: 112.03 vs. 18.64 at 100 μM; 40.77 vs. 11.61 at 10 μM; 12.18 vs. 9.41 at 1 μM; 9.9 vs. 7.46 at 0.1 μM.

[0255] In addition, IL13RA2-B at 4.4 μM inhibited HLA-A * Induces 20% of 0201 expression (versus 100 μM for IL13RA2-H).

[0256] Similar results were obtained from a second, different T2 cell clone.

[0257] Example 2: Vaccination of mice with candidate antigenic peptides induces improved T cell responses in ELISPOT-IFNγ assays.

[0258] A. Materials and Methods A.1 Mouse model The characteristics of the models used are outlined in Table 2. [Table 2]

[0259] A.2 Immunization schemes The immunization scheme is shown in Figure 2. Briefly, 14 β / A2 / DR3 mice were randomly assigned (based on the sex and age of the mice) into two experimental groups, each of which was immunized with a specific vaccinating peptide (vacc-pAg) combined with a common helper peptide (h-pAg) (outlined in Table 3 below). The vacc-pAgs were compared pairwise (group 1 vs. group 2), allowing both the native and optimized versions of a single peptide to be compared in each group. [Table 3]

[0260] Peptides were provided as follows: · vacc-pAg pairs: IL13RA2-H and IL13RA2-B; both were manufactured and provided at a concentration of 4mg / ml (4mM). · h-pAg: HHD-DR3; lyophilized (50.6 mg; Eurogentec batch 1611166) and resuspended in pure distilled water at a concentration of 10 mg / mL.

[0261] Animals were immunized with a prime injection on day 0 (d0) and a boost injection on d14. Each mouse was injected subcutaneously in the tail with 100 μL of an oil emulsion containing: 100 μg vacc-pAg (25 μL of 4 mg / mL stock per mouse). 150 μg h-pAg (15 μL of 10 mg / mL stock per mouse). · 10 μL of PBS (per mouse) to bring the total volume to 50 μL. Incomplete Freund's adjuvant (IFA) added in a 1:1 (v:v) ratio (50 μL per mouse)

[0262] Separate emulsions were prepared for each vac-pAg as follows: IFA reagent was added to the vac-pAg / h-pAg / PBS mixture in a 15 mL tube and vortexed for repeated cycles of 1 min until a thick emulsion was formed.

[0263] A.3 Mouse analysis Seven days after the booster injection (i.e., d21), the animals were euthanized and the spleens were removed. Splenocytes were prepared by mechanical disruption of the organ followed by 70 μm filtered Ficoll density gradient purification.

[0264] Splenocytes were immediately used for ELISPOT-IFNγ assay (Table 4). 2 × 10 per well 5 Total splenocytes were used in quadruplicate experimental conditions and cultured in the presence of vacc-pAg (10 μM), concanavalin A (ConA, 2.5 μg / mL), or medium alone to assess their IFNγ secretion capacity. A commercially available ELISPOT-IFNγ kit (Diaclone Kit Mujrine IFNγ ELISpot) was used according to the manufacturer's instructions, and the assay was performed after approximately 16 hours of incubation. [Table 4]

[0265] Spots were counted with a Grand ImmunoSpot® S6 Ultimate UV Image Analyzer interfaced with ImmunoSpot 5.4 software (CTL-Europe). Data plotting and statistical analysis were performed with Prism-5 software (GraphPad Software Inc.).

[0266] Cell suspensions were also analyzed by flow cytometry for normalization of T cell numbers. Monoclonal antibody cocktails (data not shown) were applied to purified leukocytes in the presence of Fc-blocking reagents targeting mouse (1:10 dilution "anti-mCD16 / CD32 CF11 clone" - internally supplied) Fc receptors. Incubations were performed for 15-20 min at 4 °C in the dark in 96-well plates. After staining, cells were washed by centrifugation to remove excess monoclonal antibody cocktail and resuspended in PBS for data acquisition.

[0267] All data acquisition was performed using an LSR-II Fortessa flow cytometer interfaced with FACS-Diva software (BD Bioscience). Data analysis was performed using FlowJo-9 software (TreeStar Inc.) with gating strategies (not shown). [Table 5]

[0268] B. Results A total of 14 β / A2 / DR3 mice were used in this experiment (see Table 6). At the time of sacrifice, splenic T cell populations were analyzed by flow cytometry and showed that the majority belonged to the CD4+ T cell subset.

[0269] [Table 6]

[0270] After plating and incubation with appropriate stimuli, IFNγ producing cells appeared and were counted. The data were then analyzed using a 10 6 Normalized as the number of specific spots per total T cells (minus the average number obtained in the "medium only" condition).

[0271] Individual means (from quadruplicates) were then used to plot group means (see Figure 3A). Because the functional capacity of T cells may vary from individual to individual, data were also expressed as the percentage of ConA response per individual (see Figure 3B).

[0272] Overall, vaccination with IL13RA2-B pAg (candidate) peptide induced improved T cell responses in ELISPOT-IFNγ assays compared to IL13RA2-H pA (reference human)-vaccinated animals (group 2). In group 1 (IL13RA2-B), ex vivo restimulation with IL13RA2-B pAg prompted higher responses than IL13RA2-H pAg, but not in group 2 (IL13RA2-H). The percentage of ConA-induced responses for each condition (mean + / - SEM) was as follows: ·Group 1 (IL13RA2-B) / IL13RA2-B pAg:56.3%+ / -18.1 ·Group 1 (IL13RA2-B) / IL13RA2-H pAg:32.3%+ / -11.8 ·Group 2 (IL13RA2-H) / IL13RA2-B pAg:2.0%+ / -0.8 ·Group 2 (IL13RA2-H) / IL13RA2-H pAg:1.1%+ / -0.8

[0273] Thus, these results provide experimental evidence that tumor antigen immunotherapy targeting IL13RA2 can improve T cell responses in vivo, and that the IL13RA2-B candidate peptide (SEQ ID NO: 71) is particularly effective for that purpose.

[0274] Example 3: HLA-A * Identification of additional candidate antigenic peptides with superior affinity for the 0201 allele

[0275] This example illustrates the antigenic peptide of SEQ ID NO: 47 ( <rlleetdlv>>, also referred to herein as ERBB2-1B; the antigenic peptide of SEQ ID NO:51 (< <vmlgvvfgv>>, also referred to herein as ERBB2-3B1; the antigenic peptide of SEQ ID NO:52 (< <vllgvvfgv>>, also referred to herein as ERBB2-3B2; the antigenic peptide of SEQ ID NO:55 (< <vmlgvvfgi>>, also referred to herein as ERBB2-3B3); and the antigenic peptide of SEQ ID NO:56 (< <illgvvfgi>>, also referred to herein as ERBB2-3B4) inhibits ERBB2 (< <rllqetelv>>, SEQ ID NO: 120, also referred to herein as ERBB2-1H);(< <vvlgvvfgi>>, SEQ ID NO: 122, also referred to herein as ERBB2-3H), rather than the corresponding reference human peptide derived from HLA-A * It is shown that it has high affinity for the 0201 allele.

[0276] A. Materials and Methods A1. Measurement of peptide affinity for the T2 cell line The experimental protocol was HLA-A * This is similar to that validated for peptides presented by HLA-A2.1.0201 (Tourdot et al., A general strategy to enhance immunogenicity of low-affinity HLA-A2.1-associated peptides: implication in the identification of cryptic tumor epitopes. Eur J Immunol. 2000 Dec; 30(12):3411-21). Peptide affinity measurements were performed using HLA-A * This is achieved using the human tumor cell line T2, which expresses the 0201 molecule but is TAP1 / 2 negative and unable to present the endogenous peptide.

[0277] T2 cells (2.10 5 Cells / well) are incubated with decreasing concentrations of peptide from 100 μM to 0.1 μM in AIMV medium supplemented with 100 ng / μl human β2m for 16 h at 37° C. Cells are then washed twice and labeled with an anti-HLA-A2 antibody conjugated to PE (clone BB7.2, BD Pharmagen).

[0278] Analysis is accomplished by FACS (Guava Easy Cyte).

[0279] For each peptide concentration, the geometric mean of the label associated with the peptide of interest was subtracted from the background noise and the HLA-A concentration obtained with the reference peptide HIV pol 589-597 at a concentration of 100 μM. * The results are reported as a percentage of the geometric mean of the 0202 label. Relative affinities are then determined as follows:

[0280] Relative affinity = HLA-A * Concentration of each peptide that induces 20% of expression of 0201 / HLA-A * Concentration of reference peptide that induces 20% of 0201 expression

[0281] A2. Solubilization of peptides Each peptide is solubilized by considering its amino acid composition. For peptides that do not contain cysteine, methionine, or tryptophan, DMSO can be added up to 10% of the total volume. Other peptides are resuspended in water or PBS pH 7.4.

[0282] B. Results The results are shown in Table 7. [Table 7]

[0283] As shown in Table 7 (see in particular "Relative Affinity" calculated as above), antigenic peptide ERBB2-1B exhibits higher affinity (lower value) than the corresponding human peptide ERBB2-1H. Furthermore, antigenic peptides ERBB2-3B1, ERBB2-3B2, ERBB2-3B3, and ERBB2-3B4 exhibit higher affinity (lower value) than the corresponding human peptide ERBB2-1B. Furthermore, antigenic peptides ERBB2-1B, ERBB2-3B1, ERBB2-3B2, ERBB2-3B3, and ERBB2-3B4 bind to HLA-A. * Lower concentrations are required to induce 20% of 0201 expression (compared to their human reference peptides).

[0284] Similar results were obtained with a second, different T2 cell clone.

[0285] Example 4: HLA-A * Identification of additional candidate antigenic peptides with superior affinity for the 0201 allele

[0286] This example illustrates the antigenic peptide of SEQ ID NO: 77 ( <klvewlaml>>, also referred to herein as MAGE C1B; the antigenic peptide of SEQ ID NO: 93 (< <slppdvqqv>>, also referred to herein as MMP2-B; the antigenic peptide of SEQ ID NO:28 (< <itsdvpfsv>>, also referred to herein as PMEL-B; the antigenic peptide of SEQ ID NO: 101 (< <mlavflplv>>, also referred to herein as STEAP-B1); and the antigenic peptide of SEQ ID NO: 102 (< <ylavflpiv>>, also referred to herein as STEAP-B2) was identified as MAGE C1 (< <kvveflaml>>, SEQ ID NO: 128, also referred to herein as MAGE C1H), MMP2 (< <glppdvqrv>>, SEQ ID NO: 136, also referred to herein as MMP2-H), PMEL (< <itdqvpfsv>>, SEQ ID NO: 115, also referred to herein as PMEL-H), and STEAP (< <miavflpiv>>, SEQ ID NO: 141, also referred to herein as STEAP-H) than the corresponding reference human peptide derived from HLA-A * It is shown that it has high affinity for the 0201 allele.

[0287] A. Materials and Methods A1. Measurement of peptide affinity for the T2 cell line The experimental protocol was HLA-A * This is similar to that validated for peptides presented by HLA-A2.1.0201 (Tourdot et al., A general strategy to enhance immunogenicity of low-affinity HLA-A2.1-associated peptides: implication in the identification of cryptic tumor epitopes. Eur J Immunol. 2000 Dec; 30(12):3411-21). Peptide affinity measurements were performed using HLA-A * This is achieved using the human tumor cell line T2, which expresses the 0201 molecule but is TAP1 / 2 negative and unable to present the endogenous peptide.

[0288] T2 cells (2.10 5 Cells / well) are incubated with decreasing concentrations of peptide from 100 μM to 0.1 μM in AIMV medium supplemented with 100 ng / μl human β2m for 16 h at 37° C. Cells are then washed twice and labeled with an anti-HLA-A2 antibody conjugated to PE (clone BB7.2, BD Pharmagen).

[0289] Analysis is accomplished by FACS (Guava Easy Cyte).

[0290] For each peptide concentration, the geometric mean of the label associated with the peptide of interest was subtracted from the background noise and the HLA-A concentration obtained with the reference peptide HIV pol 589-597 at a concentration of 100 μM. * The results are reported as a percentage of the geometric mean of the 0202 label. Relative affinities are then determined as follows:

[0291] Relative affinity = HLA-A * Concentration of each peptide that induces 20% of expression of 0201 / HLA-A * Concentration of reference peptide that induces 20% of 0201 expression

[0292] A2. Solubilization of peptides Each peptide is solubilized by considering its amino acid composition. For peptides that do not contain cysteine, methionine, or tryptophan, DMSO can be added up to 10% of the total volume. Other peptides are resuspended in water or PBS pH 7.4.

[0293] B. Results The results are shown in Table 8. [Table 8]

[0294] As shown in Table 8 (see in particular "Relative Affinity" calculated as above), antigenic peptide MAGE C1B exhibits a higher affinity (lower value) than the corresponding human peptide MAGE C1H. Furthermore, antigenic peptide MMP2-B exhibits a higher affinity (lower value) than the corresponding human peptide MMP2-H. Furthermore, antigenic peptide PMEL-B exhibits a higher affinity (lower value) than the corresponding human peptide PMEL-H. Furthermore, antigenic peptides STEAP-B1 and STEAP-B2 exhibit a higher affinity (lower value) than the corresponding human peptide STEAP-H. Furthermore, antigenic peptides MAGE C1B, MMP2-B, PMEL-B, STEAP-B1, and STEAP-B2 are shown to bind to HLA-A. * Lower concentrations are required to induce 20% of 0201 expression (compared to their human reference peptides).

[0295] Similar results were obtained with a second, different T2 cell clone.

[0296] Example 5: HLA-A * Identification of additional candidate antigenic peptides with superior affinity for the 0201 allele

[0297] This example illustrates the antigenic peptide of SEQ ID NO:26 ( <tmngksspv>>, also referred to herein as ENAH-B) is HLA-A * 0201 allele, whereas the corresponding reference human peptide from ENAH (< <tmngskspv>>, SEQ ID NO: 113, also referred to herein as ENAH-H) is shown to have low affinity.

[0298] A. Materials and Methods A1. Measurement of peptide affinity for the T2 cell line The experimental protocol was HLA-A * This is similar to that validated for peptides presented by HLA-A2.1.0201 (Tourdot et al., A general strategy to enhance immunogenicity of low-affinity HLA-A2.1-associated peptides: implication in the identification of cryptic tumor epitopes. Eur J Immunol. 2000 Dec; 30(12):3411-21). Peptide affinity measurements were performed using HLA-A * This is achieved using the human tumor cell line T2, which expresses the 0201 molecule but is TAP1 / 2 negative and unable to present the endogenous peptide.

[0299] T2 cells (2.10 5 Cells / well) are incubated with decreasing concentrations of peptide from 100 μM to 0.1 μM in AIMV medium supplemented with 100 ng / μl human β2m for 16 h at 37° C. Cells are then washed twice and labeled with an anti-HLA-A2 antibody conjugated to PE (clone BB7.2, BD Pharmagen).

[0300] Analysis is accomplished by FACS (Guava Easy Cyte).

[0301] For each peptide concentration, the geometric mean of the label associated with the peptide of interest was subtracted from the background noise and the HLA-A concentration obtained with the reference peptide HIV pol 589-597 at a concentration of 100 μM. * The results are reported as a percentage of the geometric mean of the 0202 label. Relative affinities are then determined as follows:

[0302] Relative affinity = HLA-A * Concentration of each peptide that induces 20% of expression of 0201 / HLA-A * Concentration of reference peptide that induces 20% of 0201 expression

[0303] A2. Solubilization of peptides Each peptide is solubilized by considering its amino acid composition. For peptides that do not contain cysteine, methionine, or tryptophan, DMSO can be added up to 10% of the total volume. Other peptides are resuspended in water or PBS pH 7.4.

[0304] B. Results The results are shown in Table 9. [Table 9]

[0305] As shown in Table 9 (see in particular the "Relative Affinity" calculated as above), the antigenic peptide ENAH-B exhibits a higher affinity (lower value) than the corresponding human peptide ENAH-H. In particular, the human peptide ENAH-H binds to HLA-A * Does not appear to bind to 0201 (ND: not determined).

[0306] Furthermore, the antigenic peptide ENAH-B binds to HLA-A * Lower concentrations are required (compared to the human reference peptide ENAH-H) to induce 20% of 0201 expression.

[0307] Similar results were obtained with a second, different T2 cell clone.< / tmngskspv> < / tmngksspv> < / miavflpiv> < / itdqvpfsv> < / glppdvqrv> < / kvveflaml> < / ylavflpiv> < / mlavflplv> < / itsdvpfsv> < / slppdvqqv> < / klvewlaml> < / vvlgvvfgi> < / rllqetelv> < / illgvvfgi> < / vmlgvvfgi> < / vllgvvfgv> < / vmlgvvfgv> < / rlleetdlv> < / wlpfgfili> < / flpfgfilv> < / mllavlycl> < / slgwlflll> < / miavflpiv> < / tlmsamtnl> < / flfllffwl> < / aldvyngll> < / lampfatpm> < / glppdvqrv> < / allaltsav> < / iltvilgvl> < / pllenvisk> < / asstlylvf> < / alkdveerv> < / vssffsytl> < / evdpasnty> < / vaelvhfll> < / evdpighly> < / kvleyvikv> < / wlpfgfili> < / vvlgvvfgi> < / tleeitgyl> < / rllqetelv> < / pltsiaisv> < / kifgslafl> < / ilhngaysl> < / iisavvgil> < / itdqvpfsv> < / fmvedetvl> < / tmngskspv> < / hlfgyswyk> < / gvlvgvali> < / kfldalisl> < / qlavsvilrv> < / llykladli> < / svastitgv>

Claims

1. An antigenic peptide consisting of the amino acid sequence represented by SEQ ID NO:51, 52, 55, or 56.

2. An immunogenic compound, characterized in that it comprises or consists of an antigenic peptide of formula (I): The immunogenic compound is an immunogenic compound that induces an immune response against ERBB2: PepNt-CORE-PepCt (I) where, - "PepNt" consists of a polypeptide having an amino acid length of 0 to 50 amino acid residues and is located at the N-terminus of the polypeptide of formula (I); - CORE consists of a polypeptide consisting of an amino acid sequence selected from the group consisting of SEQ ID NOs: 51, 52, 55, and 56; and "PepCt" consists of a polypeptide having an amino acid length of 1 to 50 amino acid residues and is located at the C-terminus of a polypeptide of formula (I).

3. - at least one of the antigenic peptides according to claim 1; or - at least one immunogenic compound according to claim 2; and optionally loaded with an adjuvant.

4. A cell loaded with an antigenic peptide according to claim 1 or an immunogenic compound according to claim 2.

5. A nucleic acid comprising a polynucleotide encoding: - an antigenic peptide according to claim 1; or - An immunogenic compound according to claim 2.

6. The nucleic acid according to claim 5, wherein the nucleic acid is a DNA molecule or an RNA molecule, preferably selected from the group consisting of genomic DNA; cDNA; mRNA; RNA and / or DNA sequences with or without expression elements, regulatory elements, and / or promoters; and combinations thereof.

7. A vector comprising a sequence encoding the antigenic peptide of claim 1 and capable of expressing said antigenic peptide.

8. A host cell comprising a nucleic acid according to any one of claims 5 to 6 or a vector according to claim 7, characterized in that said host cell preferably comprises a vector.

9. - an antigenic peptide according to claim 1, - an immunogenic compound according to claim 2, - nanoparticles according to claim 3, - a cell according to claim 4, - a nucleic acid according to any one of claims 5 to 6, - a vector according to claim 7, or - a host cell according to claim 8, and one or more pharma- ceutically acceptable excipients.

10. The immunogenic composition of claim 9 further comprising one or more immunostimulants.

11. An antigenic peptide according to claim 1, an immunogenic compound according to claim 2, a nanoparticle according to claim 3, a cell according to claim 4, a nucleic acid according to any one of claims 5 to 6, a vector according to claim 7, a host cell according to claim 8, or an immunogenic composition according to any one of claims 9 to 10, for use as a drug.

12. An antigenic peptide according to claim 1, an immunogenic compound according to claim 2, a nanoparticle according to claim 3, a cell according to claim 4, a nucleic acid according to any one of claims 5 to 6, a vector according to claim 7, a host cell according to claim 8, or an immunogenic composition according to any one of claims 9 to 10, for use in the prevention or treatment of cancer.

13. A combination of two different antigenic peptides, characterized in that the combination comprises: (i) The antigenic peptide of claim 1. (ii) An antigenic peptide comprising or consisting of an amino acid sequence represented by any one of SEQ ID NOs: 1 to 50, 53, 54, and 57 to 106.

14. - an antigenic peptide according to claim 1, - an immunogenic compound according to claim 2, - nanoparticles according to claim 3, - a cell according to claim 4, - a nucleic acid according to any one of claims 5 to 6, - a vector according to claim 7, - a host cell according to claim 8, or - A kit, characterized in that it comprises an immunogenic composition according to any one of claims 9 to 10.

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