NEW PEPTIDES AND PEPTIDE COMBINATIONS FOR USE IN IMMUNOTHERAPY AGAINST OVARIAN CANCER AND OTHER CANCERS

Abstract

The present invention relates to peptides, proteins, nucleic acids, and cells for use in immunotherapeutic processes. In particular, the invention relates to cancer immunotherapy. The invention further relates to tumor peptide epitopes of T cells, alone or in combination with other tumor peptides, which can, for example, serve as active pharmaceutical ingredients in vaccine compositions that stimulate antitumor immune responses, or for the ex vivo stimulation of T cells and their transfer to patients. Peptides bound to major histocompatibility complex (MHC) molecules, or peptides as such, can also serve as targets for antibodies, soluble T cell receptors, and other binding molecules.

Description

[0001] The present invention relates to peptides, proteins, nucleic acids and cells for use in immunotherapeutic methods. In particular, the present invention relates to the immunotherapy of cancer. The present invention furthermore discloses tumor-associated T-cell peptide epitopes, alone or in combination with other tumor-associated peptides that can for example serve as active pharmaceutical ingredients of vaccine compositions that stimulate anti-tumor immune responses, or to stimulate T cells ex vivo and transfer into patients. Peptides bound to molecules of the major histocompatibility complex (MHC), or peptides as such, can also be targets of antibodies, soluble T-cell receptors, and other binding molecules.

[0002] The present invention relates to a peptide sequence derived from an HLA class I molecule of human tumor cells that can be used in vaccine compositions for eliciting anti-tumor immune responses, or as targets for the development of pharmaceutically / immunologically active compounds and cells.BACKGROUND OF THE INVENTION Ovarian cancer

[0003] With an estimated 239 000 new cases in 2012, ovarian cancer is the seventh most common cancer in women, representing 4% of all cancers in women. The fatality rate of ovarian cancer tends to be rather high relative to other cancers of the female reproductive organs, and case fatality is higher in lower-resource settings. As a consequence, ovarian cancer is the eighth most frequent cause of cancer death among women, with 152 000 deaths. In 2012, almost 55% of all new cases occurred in countries with high or very high levels of human development; 37% of the new cases and 39% of the deaths occurred in Europe and North America. Incidence rates are highest in northern and Eastern Europe, North America, and Oceania, and tend to be relatively low in Africa and much of Asia. Incidence rates have been declining in certain countries with very high levels of human development, notably in Europe and North America.

[0004] The most common ovarian cancers are ovarian carcinomas, which are also the most lethal gynecological malignancies. Based on histopathology and molecular genetics, ovarian carcinomas are divided into five main types: high-grade serous (70%), endometrioid (10%), clear cell (10%), mucinous (3%), and low-grade serous carcinomas (< 5%), which together account for more than 95% of cases. Much less common are malignant germ cell tumours (dysgerminomas, yolk sac tumours, and immature teratomas) (3% of ovarian cancers) and potentially malignant sex cord stromal tumours (1-2%), the most common of which are granulosa cell tumours.

[0005] Family history of ovarian cancer accounts for 10% of cases; the risk is increased 3-fold when two or more first-degree relatives have been affected. Women with germline mutations in BRCA1 or BRCA2 have a 30-70% risk of developing ovarian cancer, mainly high-grade serous carcinomas, by age 70 (Risch et al., 2006).

[0006] Surgical resection is the primary therapy in early as well as advanced stage ovarian carcinoma. Surgical removal is followed by systemic chemotherapy with platinum analogs, except for very low grade ovarian cancers (stage IA, grade 1), where postoperative chemotherapy is not indicated. In advanced stage ovarian cancer, the first line chemotherapy comprises a combination of carboplatin with paclitaxel, which can be supplemented with bevacizumab. The standard treatment for platinum-resistant ovarian cancers consists of a monotherapy with one of the following chemotherapeutics: pegylated liposomal doxorubicin, topotecane, gemcitabine or paclitaxel (S3-Leitlinie maligne Ovarialtumore, 2013).

[0007] Immunotherapy appears to be a promising strategy to ameliorate the treatment of ovarian cancer patients, as the presence of pro-inflammatory tumor infiltrating lymphocytes, especially CD8-positive T cells, correlates with good prognosis and T cells specific for tumor-associated antigens can be isolated from cancer tissue.

[0008] Therefore, a lot of scientific effort is put into the investigation of different immunotherapies in ovarian cancer. A considerable number of pre-clinical and clinical studies has already been performed and further studies are currently ongoing. Clinical data are available for cytokine therapy, vaccination, monoclonal antibody treatment, adoptive cell transfer and immunomodulation.

[0009] Cytokine therapy with interleukin-2, interferon-alpha, interferon-gamma or granulocyte-macrophage colony stimulating factor aims at boosting the patient's own anti-tumor immune response and these treatments have already shown promising results in small study cohorts.

[0010] Phase I and II vaccination studies, using single or multiple peptides, derived from several tumor-associated proteins (Her2 / neu, NY-ESO-1, p53, Wilms tumor-1) or whole tumor antigens, derived from autologous tumor cells revealed good safety and tolerability profiles, but only low to moderate clinical effects.

[0011] Monoclonal antibodies that specifically recognize tumor-associated proteins are thought to enhance immune cell-mediated killing of tumor cells. The anti-CA-125 antibodies oregovomab and abagovomab as well as the anti-EpCAM antibody catumaxomab achieved promising results in phase II and III studies. In contrast, the anti-MUC1 antibody HMFG1 failed to clearly enhance survival in a phase III study.

[0012] An alternative approach uses monoclonal antibodies to target and block growth factor and survival receptors on tumor cells. While administration of trastuzumab (anti-HER2 / neu antibody) and MOv18 and MORAb-003 (anti-folate receptor alpha antibodies) only conferred limited clinical benefit to ovarian cancer patients, addition of bevacizumab (anti-VEGF antibody) to the standard chemotherapy in advanced ovarian cancer appears to be advantageous.

[0013] Adoptive transfer of immune cells achieved heterogeneous results in clinical trials. Adoptive transfer of autologous, in vitro expanded tumor infiltrating T cells was shown to be a promising approach in a pilot trial. In contrast, transfer of T cells harboring a chimeric antigen receptor specific for folate receptor alpha did not induce a significant clinical response in a phase I trial. Dendritic cells pulsed with tumor cell lysate or tumor-associated proteins in vitro were shown to enhance the anti-tumor T cell response upon transfer, but the extent of T cell activation did not correlate with clinical effects. Transfer of natural killer cells caused significant toxicities in a phase II study.

[0014] Intrinsic anti-tumor immunity as well as immunotherapy are hampered by an immunosuppressive tumor microenvironment. To overcome this obstacle immunomodulatory drugs, like cyclophosphamide, anti-CD25 antibodies and pegylated liposomal doxorubicin are tested in combination with immunotherapy. Most reliable data are currently available for ipilimumab, an anti-CTLA4 antibody, which enhances T cell activity. Ipilimumab was shown to exert significant anti-tumor effects in ovarian cancer patients (Mantia-Smaldone et al., 2012).

[0015] Considering the severe side-effects and expense associated with treating cancer, there is a need to identify factors that can be used in the treatment of cancer in general and ovarian cancer in particular. There is also a need to identify factors representing biomarkers for cancer in general and ovarian cancer in particular, leading to better diagnosis of cancer, assessment of prognosis, and prediction of treatment success.

[0016] Immunotherapy of cancer represents an option of specific targeting of cancer cells while minimizing side effects. Cancer immunotherapy makes use of the existence of tumor associated antigens.

[0017] The current classification of tumor associated antigens (TAAs) comprises the following major groups: a) Cancer-testis antigens: The first TAAs ever identified that can be recognized by T cells belong to this class, which was originally called cancer-testis (CT) antigens because of the expression of its members in histologically different human tumors and, among normal tissues, only in spermatocytes / spermatogonia of testis and, occasionally, in placenta. Since the cells of testis do not express class I and II HLA molecules, these antigens cannot be recognized by T cells in normal tissues and can therefore be considered as immunologically tumor-specific. Well-known examples for CT antigens are the MAGE family members and NY-ESO-1. b) Differentiation antigens: These TAAs are shared between tumors and the normal tissue from which the tumor arose. Most of the known differentiation antigens are found in melanomas and normal melanocytes. Many of these melanocyte lineage-related proteins are involved in biosynthesis of melanin and are therefore not tumor specific but nevertheless are widely used for cancer immunotherapy. Examples include, but are not limited to, tyrosinase and Melan-A / MART-1 for melanoma or PSA for prostate cancer. c) Over-expressed TAAs: Genes encoding widely expressed TAAs have been detected in histologically different types of tumors as well as in many normal tissues, generally with lower expression levels. It is possible that many of the epitopes processed and potentially presented by normal tissues are below the threshold level for T-cell recognition, while their over-expression in tumor cells can trigger an anticancer response by breaking previously established tolerance. Prominent examples for this class of TAAs are Her-2 / neu, survivin, telomerase, or WT1. d) Tumor-specific antigens: These unique TAAs arise from mutations of normal genes (such as β-catenin, CDK4, etc.). Some of these molecular changes are associated with neoplastic transformation and / or progression. Tumor-specific antigens are generally able to induce strong immune responses without bearing the risk for autoimmune reactions against normal tissues. On the other hand, these TAAs are in most cases only relevant to the exact tumor on which they were identified and are usually not shared between many individual tumors. Tumor-specificity (or -association) of a peptide may also arise if the peptide originates from a tumor- (-associated) exon in case of proteins with tumor-specific (-associated) isoforms. e) TAAs arising from abnormal post-translational modifications: Such TAAs may arise from proteins which are neither specific nor overexpressed in tumors but nevertheless become tumor associated by posttranslational processes primarily active in tumors. Examples for this class arise from altered glycosylation patterns leading to novel epitopes in tumors as for MUC1 or events like protein splicing during degradation which may or may not be tumor specific. f) Oncoviral proteins: These TAAs are viral proteins that may play a critical role in the oncogenic process and, because they are foreign (not of human origin), they can evoke a T-cell response. Examples of such proteins are the human papilloma type 16 virus proteins, E6 and E7, which are expressed in cervical carcinoma.

[0018] T-cell based immunotherapy targets peptide epitopes derived from tumor-associated or tumor-specific proteins, which are presented by molecules of the major histocompatibility complex (MHC). The antigens that are recognized by the tumor specific T lymphocytes, that is, the epitopes thereof, can be molecules derived from all protein classes, such as enzymes, receptors, transcription factors, etc. which are expressed and, as compared to unaltered cells of the same origin, usually up-regulated in cells of the respective tumor.

[0019] There are two classes of MHC-molecules, MHC class I and MHC class II. MHC class I molecules are composed of an alpha heavy chain and beta-2-microglobulin, MHC class II molecules of an alpha and a beta chain. Their three-dimensional conformation results in a binding groove, which is used for non-covalent interaction with peptides.

[0020] MHC class I molecules can be found on most nucleated cells. They present peptides that result from proteolytic cleavage of predominantly endogenous proteins, defective ribosomal products (DRIPs) and larger peptides. However, peptides derived from endosomal compartments or exogenous sources are also frequently found on MHC class I molecules. This non-classical way of class I presentation is referred to as cross-presentation in the literature (Brossart and Bevan, 1997; Rock et al., 1990). MHC class II molecules can be found predominantly on professional antigen presenting cells (APCs), and primarily present peptides of exogenous or transmembrane proteins that are taken up by APCs e.g. during endocytosis, and are subsequently processed.

[0021] Complexes of peptide and MHC class I are recognized by CD8-positive T cells bearing the appropriate T-cell receptor (TCR), whereas complexes of peptide and MHC class II molecules are recognized by CD4-positive-helper-T cells bearing the appropriate TCR. It is well known that the TCR, the peptide and the MHC are thereby present in a stoichiometric amount of 1:1:1.

[0022] CD4-positive helper T cells play an important role in inducing and sustaining effective responses by CD8-positive cytotoxic T cells. The identification of CD4-positive T-cell epitopes derived from tumor associated antigens (TAA) is of great importance for the development of pharmaceutical products for triggering anti-tumor immune responses (Gnjatic et al., 2003). At the tumor site, T helper cells, support a cytotoxic T cell- (CTL-) friendly cytokine milieu (Mortara et al., 2006) and attract effector cells, e.g. CTLs, natural killer (NK) cells, macrophages, and granulocytes (Hwang et al., 2007).

[0023] In the absence of inflammation, expression of MHC class II molecules is mainly restricted to cells of the immune system, especially professional antigen-presenting cells (APC), e.g., monocytes, monocyte-derived cells, macrophages, dendritic cells. In cancer patients, cells of the tumor have been found to express MHC class II molecules (Dengjel et al., 2006).

[0024] Elongated (longer) peptides of the invention can act as MHC class II active epitopes. T-helper cells, activated by MHC class II epitopes, play an important role in orchestrating the effector function of CTLs in anti-tumor immunity. T-helper cell epitopes that trigger a T-helper cell response of the TH1 type support effector functions of CD8-positive killer T cells, which include cytotoxic functions directed against tumor cells displaying tumor-associated peptide / MHC complexes on their cell surfaces. In this way tumor-associated T-helper cell peptide epitopes, alone or in combination with other tumor-associated peptides, can serve as active pharmaceutical ingredients of vaccine compositions that stimulate anti-tumor immune responses.

[0025] It was shown in mammalian animal models, e.g., mice, that even in the absence of CD8-positive T lymphocytes, CD4-positive T cells are sufficient for inhibiting manifestation of tumors via inhibition of angiogenesis by secretion of interferon-gamma (IFNγ) (Beatty and Paterson, 2001; Mumberg et al., 1999). There is evidence for CD4 T cells as direct anti-tumor effectors (Braumuller et al., 2013; Tran et al., 2014).

[0026] Since the constitutive expression of HLA class II molecules is usually limited to immune cells, the possibility of isolating class II peptides directly from primary tumors was previously not considered possible. However, Dengjel et al. were successful in identifying a number of MHC Class II epitopes directly from tumors (WO 2007 / 028574, EP 1 760 088 B1).

[0027] Since both types of response, CD8 and CD4 dependent, contribute jointly and synergistically to the anti-tumor effect, the identification and characterization of tumor-associated antigens recognized by either CD8+ T cells (ligand: MHC class I molecule + peptide epitope) or by CD4-positive T-helper cells (ligand: MHC class II molecule + peptide epitope) is important in the development of tumor vaccines.

[0028] For an MHC class I peptide to trigger (elicit) a cellular immune response, it also must bind to an MHC-molecule. This process is dependent on the allele of the MHC-molecule and specific polymorphisms of the amino acid sequence of the peptide. MHC-class-I-binding peptides are usually 8-12 amino acid residues in length and usually contain two conserved residues ("anchors") in their sequence that interact with the corresponding binding groove of the MHC-molecule. In this way each MHC allele has a "binding motif" determining which peptides can bind specifically to the binding groove.

[0029] In the MHC class I dependent immune reaction, peptides not only have to be able to bind to certain MHC class I molecules expressed by tumor cells, they subsequently also have to be recognized by T cells bearing specific T cell receptors (TCR).

[0030] For proteins to be recognized by T-lymphocytes as tumor-specific or -associated antigens, and to be used in a therapy, particular prerequisites must be fulfilled. The antigen should be expressed mainly by tumor cells and not, or in comparably small amounts, by normal healthy tissues. In a preferred embodiment, the peptide should be over-presented by tumor cells as compared to normal healthy tissues. It is furthermore desirable that the respective antigen is not only present in a type of tumor, but also in high concentrations (i.e. copy numbers of the respective peptide per cell). Tumor-specific and tumor-associated antigens are often derived from proteins directly involved in transformation of a normal cell to a tumor cell due to their function, e.g. in cell cycle control or suppression of apoptosis. Additionally, downstream targets of the proteins directly causative for a transformation may be up-regulated und thus may be indirectly tumor-associated. Such indirect tumor-associated antigens may also be targets of a vaccination approach (Singh-Jasuja et al., 2004). It is essential that epitopes are present in the amino acid sequence of the antigen, in order to ensure that such a peptide ("immunogenic peptide"), being derived from a tumor associated antigen, leads to an in vitro or in vivo T-cell-response.

[0031] Basically, any peptide able to bind an MHC molecule may function as a T-cell epitope. A prerequisite for the induction of an in vitro or in vivo T-cell-response is the presence of a T cell having a corresponding TCR and the absence of immunological tolerance for this particular epitope.

[0032] Therefore, TAAs are a starting point for the development of a T cell based therapy including but not limited to tumor vaccines. The methods for identifying and characterizing the TAAs are usually based on the use of T-cells that can be isolated from patients or healthy subjects, or they are based on the generation of differential transcription profiles or differential peptide expression patterns between tumors and normal tissues. However, the identification of genes over-expressed in tumor tissues or human tumor cell lines, or selectively expressed in such tissues or cell lines, does not provide precise information as to the use of the antigens being transcribed from these genes in an immune therapy. This is because only an individual subpopulation of epitopes of these antigens are suitable for such an application since a T cell with a corresponding TCR has to be present and the immunological tolerance for this particular epitope needs to be absent or minimal. In a very preferred embodiment of the invention it is therefore important to select only those over- or selectively presented peptides against which a functional and / or a proliferating T cell can be found. Such a functional T cell is defined as a T cell, which upon stimulation with a specific antigen can be clonally expanded and is able to execute effector functions ("effector T cell").

[0033] WO2006 / 029176 discloses a 69 aa peptide (SEQ ID NO:6) derived from the testis specific protein CT45 and comprising SEQ ID NO:11 (KIFEMLEGV) of the present invention. WO2006 / 029176 relates to any kind of antigenic molecules derived from CT45 that are primarily used to generate antibodies or antigen-binding fragments thereof that are used in therapy. WO2006 / 029176 mentions T cells that recognize epitopes of an isolated polypeptide presented by MHC molecules, but lacks any specific data regarding this.

[0034] In case of targeting peptide-MHC by specific TCRs (e.g. soluble TCRs) and antibodies according to the invention, the immunogenicity of the underlying peptides is secondary. In these cases, the presentation is the determining factor.SUMMARY OF THE INVENTION

[0035] In a first aspect of the present invention, the present invention relates to a peptide consisting of the amino acid sequence according to SEQ ID No. 11; or a pharmaceutical acceptable salt thereof.

[0036] The following tables show the peptides as disclosed, their respective SEQ ID NOs, and the prospective source (underlying) genes for these peptides. All peptides in Table 1 and Table 2 bind to HLA-A*02. The peptides in Table 2 have been disclosed before, e.g. in large listings as results of high-throughput screenings with high error rates or calculated using algorithms, but have not been associated with cancer at all before. The peptides in Table 3 are additional peptides that may be useful in combination with the other peptides as disclosed. The peptides in Table 4 are furthermore useful in the diagnosis and / or treatment of various other malignancies that involve an over-expression or over-presentation of the respective underlying polypeptide. Table 1: Peptides as disclosed, SEQ ID NO: 11 is according to the present invention. J = phospho-serine.SEQ ID NO.SequenceGene ID(s)Official Gene Symbol(s)1SLMEPPAVLLL8900CCNA12SLLEADPFL8900CCNA13SLASKLTTL94025MUC164GIMEHITKI94025MUC165HLTEVYPEL94025MUC166VLVSDGVHSV1952CELSR27SLVGLLLYL100101267,9883POM121C, POM1218FTLGNVVGMYL100287425,647087C7orf739GAAKDLPGV100534599,57461ISY1-RAB43, ISY110FLATFPLAAV10076PTPRU11KIFEMLEGV101060208,1010602 10,101060211,4415 19,441520,441521,5 41465,541466,7289 11CT45A3, CT45A4, CT45A5, CT45A6, CT45A1, CT45A212SLWPDPMEV101060557,146177VWA3A13YLMDESLNL101060756,115948CCDC15114AAYGGLNEKSFV10140TOB115VLLTFKIFL10149GPR6416VLFQGQASL10154PLXNC117GLLPGDRLVSV10207INADL18YLVAKLVEV10277UBE4B19FMVDNEAIYDI10376,112714,113457, 51807,7277,7278,7846 ,84790TUBA1B, TUBA3E, TUBA3D, TUBA8, TUBA4A, TUBA3C, TUBA1A, TUBA1C20RMIEYFIDV10396,153020ATP8A1, RASGEF1B21VLDELDMEL10437IFI3022IMEENPGIFAV10558SPTLC123VLLDDIFAQL10565ARFGEF124SLSDGLEEV10651MTX225FLPDEPYIKV10686CLDN1626ALLELAEEL10694,644131CCT8, CCT8P127ILADIVISA10797MTHFD228QLLDETSAITL10915TCERG129KMLGIPISNILMV10964IFI44L30LILDWVPYI10975UQCR1131YLAPELFVNV11035RIPK332KLDDLTQDLTV11116FGFR10P33VLLSLLEKV1130LYST34ILVEADSLWVV11329STK3835KINDTIYEV113510HELQ36YVLEDLEVTV114960,22820,26958TSGA13, COPG1, COPG237LLWDVVTGQSV114987WDR3138FLLEDDIHVS116461TSEN1539SVAPNLPAV120114FAT340TLLVKVFSV122402TDRD941SLMPHIPGL122402TDRD942VLLQKIVSA122402TDRD943VLSSLEINI1233CCR444ILDPISSGFLL127795C1orf8745SLWQDIPDV128272ARHGEF1946ILTEENIHL130540ALS2CR1247ILLSVPLLVV1314COPA48ALAELYEDEV137886UBXN2B49YLPAVFEEV9961MVP50SLSELEALM143686SESN351LLPDLEFYV143888KDELC252FLLAHGLGFLL144110TMEM86A53KMIETDILQKV146562C16orf7154SLLEQGKEPWMV147949,163087,34289 2,374899,84503ZNF583, ZNF383, ZNF850, ZNF829, ZNF52755SLLDLETLSL148137C19orf5556KLYEGIPVLL152110NEK1057TLAELQPPVQL157922CAMSAP158FLDTLKDLI162AP1B159IMEDIILTL1656DDX660SLTIDGIYYV1659DHX861FLQGYQLHL19ABCA162VLLDVSAGQLLM196463PLBD263YLLPSGGSVTL196483,286042,34892 6,55199,692099FAM86A, FAM86B3P, FAM86EP, FAM86C1, FAM86DP64YAAPGGLIGV1968,255308EIF2S365LKVNQGLESL197358NLRC366FLDENIGGVAV200424TET367TLLAEALVTV200958MUC2068SLMELPRGLFL219527LRRC5569FQLDPSSGVLVTV2196FAT270GLLDYPVGV219736STOX171GILARIASV221322C6orf17072SLLELDGINL221806VWDE73NIFDLQIYV222256CDHR374ALLDPEVLSIFV22898DENND375GLLEVMVNL23001WDFY376ILIDSIYKV23007PLCH177ILVEADGAWVV23012STK38L78SLFSSLEPQIQPV23029RBM3479SLFIGEKAVLL23029RBM3480FLYDNLVESL23132RAD54L281FLFSQLQYL23165NUP20582FLSSVTYNL23312DMXL283ILAPTVMMI23312DMXL284VTFGEKLLGV23428SLC7A885KMSELRVTL23499MACF186NLIGKIENV23639LRRC687ALPEAPAPLLPHIT23786BCL2L1388FLLVGDLMAV23787MTCH189YILPTETIYV254956MORN590TLLQIIETV256309CCDC11091IMQDFPAEIFL25914RTTN92YLIPFTGIVGL26001RNF16793LLQAIKLYL260293CYP4X194YLIDIKTIAI26160IFT17295SVIPQIQKV26272FBX0496YIFTDNPAAV26301GBGT197SLINGSFLV27ABL298LIIDQADIYL27042DIEXF99ALVSKGLATV27044SND1100YLLSTNAQL27285TEKT2101ILVGGGALATV2820GPD2102YLFESEGLVL283431GAS2L3103TLAEEVVAL283755,400322,8924HERC2P3, HERC2P2, HERC2104STMEQNFLL284110GSDMA105LLLEHSFEI284361EMC10106LLYDAVHIVSV2899GRIK3107FLQPVDDTQHL2906GRIN2D108ALFPGVALLLA2923PDIA3109IILSILEQA2953,653689GSTT2, GSTT2B110FLSQVDFEL2968GTF2H4111YVWGFYPAEV3109HLA-DMB112FLITSNNQL353497,79441POLN, HAUS3113GLLPTPLFGV359710BPIFB3114SLVGEPILQNV359710BPIFB3115AIAGAGILYGV362AQP5116YHIDEEVGF3620IDO1117ILPDGEDFLAV3636INPPL1118KLIDNNINV3696ITGB8119FLYIGDIVSL3709ITPR2120ALLGIPLTLV3777,60598KCNK3, KCNK15121GVVDPRAISVL387522,7335TMEM189-UBE2V1, UBE2V1122FLLAEDDIYL389677RBM12B123NLWDLTDASVV3959LGALS3BP124ALYETELADA4001LMNB1125VQIHQVAQV4053LTBP2126VLAYFLPEA4171MCM2127KIGDEPPKV4291MLF1128YLFDDPLSAV4363ABCC1129GLLDGGVDILL4548MTR130FLWNGEDSALL4586,727897MUC5AC, MUC5B131FVPPVTVFPSL4586,727897MUC5AC, MUC5B132LLVEQPPLAGV4773NFATC2133KVLSNIHTV4867NPHP1134YLQELIFSV51000SLC35B3135ALSEVDFQL51059FAM135B136YLADPSNLFVV51072,728556MEMO1, MEMO1P1137TLVLTLPTV51073MRPL4138YQYPRAILSV51105PHF20L1139SVMEVNSGIYRV51182HSPA14140YMDAPKAAL51246SHISA5141YLDFSNNRL51284TLR7142FLFATPVFI51296SLC15A3143LLLDITPEI51430SUCO144YIMEPSIFNTL51497TH1L145FLATSGTLAGI51522TMEM14C146SLATAGDGLIEL5245PHB147SLLEAVSFL5261PHKG2148ALNPEIVSV5277PIGA149NLLELFVQL5297PI4KA150RLWEEGEELEL5329PLAUR151KILQQLVTL541468LURAP1152ILFEDIFDV5437POLR2H153FLIANVLYL5476CTSA154ALDDGTPAL54798DCHS2155RVANLHFPSV54809SAMD9156AISQGITLPSL54856GON4L157SLNDEVPEV54919HEATR2158KLFDVDEDGYI54947LPCAT2159GLVGNPLPSV55127HEATR1160FLFDEEIEQI55132LARP1B161ALLEGVNTV55211DPPA4162YQQAQVPSV55217TMLHE163ALDEMGDLLQL55304SPTLC3164ALLPQPKNLTV5546PRCC165SLLDEIRAV55567DNAH3166YLNHLEPPV55666NPLOC4167KVLEVTEEFGV55705IPO9168KILDADIQL55779WDR52169NLPEYLPFV55832,91689CAND1, C22orf32170RLQETLSAA5591PRKDC171LLLPLQILL5650KLK7172VLYSYTIITV56941C3orf37173LLDSASAGLYL56992KIF15174ALAQYLITA57060PCBP4175YLFENISQL57115PGLYRP4176YLMEGSYNKVFL5714PSMD8177YLLPEEYTSTL57143ADCK1178ALTEIAFVV57148RALGAPB179KVLNELYTV57522SRGAP1180FQIDPHSGLVTV57526PCDH19181LLWAGTAFQV57535KIAA1324182MLLEAPGIFL57570TRMT5183FGLDLVTEL57674RNF213184YLMDINGKMWL57674RNF213185FLI DDKGYTL57685CACHD1186TLFFQQNAL5771PTPN2187RQISIRGIVGV5836PYGL188GLFPVTPEAV59352LGR6189ALQRKLPYV60598KCNK15190FLSSLTETI629CFB191LLQEGQALEYV629CFB192KMLDGASFTL63941NECAB3193QLLDADGFLNV63967CLSPN194ALPLFVITV64078SLC28A3195GLFADLLPRL642475MROH6196YLYSVEIKL642987TMEM232197ALGPEGGRV64321SOX17198KTINKVPTV6498SKIL199ALQDVPLSSV65003MRPL11200LLFGSVQEV65250C5orf42201RLVDYLEGI65260SELRC1202ALLDQQGSRWTL6565SLC15A2203VLLEDAHSHTL6614SIGLEC1204KIAENVEEV6804STX1A205SLYPGTETMGL6840SVIL206VLQEGKLQKLAQL6891TAP2207GLTSTNAEV7029TFDP2208KISPVTFSV728661,9906SLC35E2B, SLC35E2209KLIESKHEV7328UBE2H210LLLNAVLTV7374UNG211LLWPGAALL7462LAT2212ALWDQDNLSV7464CORO2A213VTAAYMDTVSL7498XDH214FLLDLDPLLL7915ALDH5A1215QLINHLHAV79365BHLHE41216NLWEDPYYL79659DYNC2H1217ALIHPVSTV79690GAL3ST4218SALEELVNV79707NOL9219KLSDIGITV79725THAP9220LLQKFVPEI79832QSER1221ALYEEGLLL80311KLHL15222NLIENVQRL8195MKKS223ALLENIALYL833CARS224TLIDAQWVL84000TMPRSS13225SLLKVLPAL84125LRRIQ1226MLYVVPIYL84187TMEM164227ALMNTLLYL84197228AMQEYIAVV84320ACBD6229RLPGPLGTV84875PARP10230ILVDWLVEV85417,890,8900CCNB3, CCNA2, CCNA1231FLSPQQPPLLL8621CDK13232ALLEAQDVELYL8701DNAH11233VLSETLYEL8914TIMELESS234ALMEDTGRQML89782LMLN235YLNDLHEVLL898CCNE1236GLLEAKVSL89845ABCC10237ALLEASGTLLL90580C19orf52238YLISFQTHI90592ZNF700239AAFAGKLLSV91543RSAD2240ILLEQAFYL92255LMBRD2241SLVEVNPAYSV92305TMEM129242AIAYILQGV92335STRADA243LLLNELPSV92345NAF1244SLFGGTEITI93035PKHD1L1245SMIDDLLGV93233CCDC114246LLWEVVSQL9462RASAL2247VLLPNDLLEKV9472AKAP6248FLFPNQYVDV9632SEC24C249LLDGFLVNV9632SEC24C250ALSEEGLLVYL9690UBE3C251ALYTGFSILV972CD74252LLIGTDVSL9730VPRBP253GLDAATATV9869SETDB1254TLLAFIMEL987LRBA255VLASYNLTV987LRBA256FLPPEHTIVYI9896FIG4257SIFSAFLSV9918NCAPD2258ELAERVPAI9918NCAPD2259TLMRQLQQV140680C20orf96260TLLEGPDPAELLL100101267,9883POM121C, POM121261YVLEFLEEI10026PIGK262LLWGDLIWL101060729,548593,79 008SLX1A, SLX1B263LLVSNLDFGV10189ALYREF264SLQEQLHSV133584EGFLAM265LLFGGTKTV1572CYP2F1266KITDTLIHL2099ESR1267ALQDFLLSV2189FANCG268IAGPGLPDL220074LRTOMT269RVLEVGALQAV25885POLR1A270LLLDEEGTFSL27013CNPPD1271LVYPLELYPA29956CERS2272ALGNTVPAV352909DNAAF3273NLFQSVREV367AR274SLLFSLFEA3938LCT275YLVYILNEL51202DDX47276ALFTFSPLTV54665RSBN1277LLPPLESLATV5518PPP2R1A278QLLDVVLTI55295KLHL26279ALWGGTQPLL56063TMEM234280VLPDPEVLEAV57326PBXIP1281ILRESTEEL57639CCDC146282LLADVVPTT57661PHRF1283ALYIGDGYVIHLA5920RARRES3284ILLSQTTGV7175TPR285QLLHVGVTV79598CEP97286YLFPGIPEL80308FLAD1287FLNEFFLNV833CARS288NLINEINGV8672EIF4G3289VLLEIEDLQV8826IQGAP1290GLLDLNNAILQL2104ESRRG291GLDSNLKYILV23269MGA292LLWEAGSEA26167PCDHB5293GLGELQELYL2811GP1BA294ILDPFQYQL9420CYP7B1295VLDRESPNV1000CDH2296FMEGAIIYV10006ABI1297VLADIELAQA10039PARP3298VMITKLVEV10076PTPRU299YLLETSGNL10135NAMPT300ALLGQTFSL10147SUGP2301FLVEDLVDSL10313,6253RTN3, RTN2302ALLQEGEVYSA10594PRPF8303AILPQLFMV10945KDELR1304MTLGQIYYL10959TMED2305SIANFSEFYV111,112ADCY5, ADCY6306ALVNVQIPL11194ABCB8307ALPVSLPQI11218DDX20308SQYSGQLHEV114884OSBPL10309GLFDGVPTTA122618PLD4310FLVDTPLARA124975GGT6311RLYTGMHTV130367SGPP2312IISDLTIAL144110TMEM86A313VLFDDELLMV1687DFNA5314ALIAEGIALV1778DYNC1H1315YLQDVVEQA19ABCA1316ILLERLWYV215ABCD1317SLAALVVHV2196FAT2318GLINTGVLSV221656KDM1B319SLEPQIQPV23029RBM34320KMFEFVEPLL23092ARHGAP26321GLFEDVTQPGILL23140ZZEF1322TLMTSLPAL23154NCDN323IQIGEETVITV2316FLNA324FLYDEIEAEV23191,26999CYFIP1, CYFIP2325FIMPATVADATAV23352UBR4326FLPEALDFV23511NUP188327GLAPFTEGISFV23780APOL2328ALNDQVFEI2475MTOR329FLVTLNNVEV25839COG4330QLALKVEGV25896INTS7331KVDTVWVNV25917THUMPD3332YLISELEAA25940FAM98A333FLPDANSSV25942SIN3A334TLTKVLVAL26292MYCBP335YSLSSVVTV28396,3500,3501,3502 ,3503,3507IGHV4-31, IGHG1, IGHG2, IGHG3, IGHG4, IGHM336ILLTAIVQV29100TMEM208337HLLSELEAAPYL2976GTF3C2338SVLEDPVHAV29927SEC61A1339GLWEIENNPTVKA3068HDGF340ALLSMTFPL3094HINT1341SQIALNEKLVNL339799,8665EIF3FP3, EIF3F342HIYDKVMTV340706VWA2343SLLEVNEESTV3428IFI16344YLQDQHLLLTV3636INPPL1345VIWKALIHL3689ITGB2346LLDSKVPSV3691ITGB4347SLFKHDPAAWEA3728JUP348ILLDVKTRL3728,3861,3868,3872JUP, KRT14, KRT16, KRT17349SLTEYLQNV3799KIF5B350ALLDVTHSELTV3911LAMA5351SLIPNLRNV3949LDLR352SLLELLHIYV401494PTPLAD2353YLFEMDSSL4074M6PR354LILEGVDTV4126MANBA355SIQQSIERLLV4809NHP2L1356KLLGKLPEL4929NR4A2357SMHDLVLQV51435SCARA3358ALDEYTSEL51477ISYNA1359YLLPESVDL51657STYXL1360ALDJGASLLHL54101RIPK4361ALYELEGTTV54625PARP14362TLYGLSVLL54896PQLC2363KVLDVSDLESV54961SSH3364LLQNEQFEL55329MNS1365YVIDQGETDVYV5573PRKAR1A366RLLDMGETDLML55898UNC45A367SLQNHNHQL56254,9810RNF20, RNF40368ILLEEVSPEL5660PSAP369GLFPEHLIDV56997ADCK3370SLLQDLVSV57169ZNFX1371FLQAHLHTA57674RNF213372TMLLNIPLV57674RNF213373SLLEDKGLAEV59342SCPEP1374FLLQQHLISA5993RFX5375SLTETIEGV629CFB376AMFESSQNVLL64328XP04377FLLDSSASV64856VWA1378ALGYFVPYV6567SLC16A2379IMEGTLTRV6654SOS1380TLIEDEIATI6788STK3381FIDEAYVEV6873TAF2382ALQNYIKEA7022TFAP2C383ALLELENSVTL715,83481C1R,EPPK1384ILFANPNIFV728689,8663EIF3CL, EIF3C385SLLEQGLVEA7468WHSC1386ILFRYPLTI767CA8387ALFQATAEV7840ALMS1388SLTIDGIRYV79665DHX40389LLADVTHLL79699ZYG11B390ALFMKQIYL79781IQCA1391YVYPQRLNFV81704DOCK8392ALLHPQGFEV8269TMEM187393GLLDTQTSQVLTA83481EPPK1394LLAVIGGLVYL84061MAGT1395ALALGGIAVV84159ARID5B396ALLPDLPAL84273NOA1397YLFGERLLEC84365MK1671P398KLLEEDGTIITL84612PARD6B399YLFEPLYHV8534CHST1400SLLTEQDLWTV90806ANGEL2401ILLDDTGLAYI9125RQCD1402VLFSGALLGL968CD68403KLYDRILRV9746CLSTN3404AIDIJGRDPAV100288805,54768HYDIN2, HYDIN405ALYDVFLEV1774DNASE1 L1406SVQGEDLYLV2880GPX5407YLMDLINFL54536EXOC6408VLDDSIYLV57565KLHL14409LLDAMNYHL57565KLHL14410VLSDVIPJI139231FAM199X411LLAHLSPEL57194ATP10A412YLDDLNEGVYI9897KIAA0196413TLLEKVEGC149371EXOC8414YVDDIFLRV19ABCA1415LLDKVYSSV221960,51622CCZ1B, CCZ1416VLSDIIQNLSV3071NCKAP1L417NLQDTEYNL472ATM418ALAELENIEV55561CDC42BPG419GQYEGKVSSV55705IPO9420FMYDTPQEV629CFB421RLPETLPSL6337SCNN1A422FLPKLLLLA6614SIGLEC1423GLDGPPPTV7127TNFAIP2424TLLDAL YEI8690JRKL425FLYEKSSQV89876MAATS1426RLADKSVLV9918NCAPD2 Table 2: Additional peptides as disclosed with no prior known cancer association. J = phospho-serine. SEQ ID NO.SequenceGene ID(s)Official Gene Symbol(s)427ALLPLSPYL79679VTCN1428KLGHTDILVGV23016EXOSC7429GLVNDLARV10075HUWE1430HLYSSIEHLTT10075HUWE1431SLVNVVPKL1020CDK5432TLIEESAKV10257ABCC4433AMLNEPWAV10379,55072IRF9, RNF31434KVSNSGITRV10575CCT4435WLMPVIPAL10809,134266, 26259,30820,5 4906,56260,57 461,57619,901 6,91133,91574STARD10, GRPEL2, FBXW8, KCNIP1, FAM208B, C8orf44, ISY1, SHROOM3, SLC25A14, L3MBTL4, C12orf65436HLAEVSAEV11130ZWINT437SMAPGLVIQAV11160ERLIN2438KLLPLAGLYL113655MFSD3439YLLQEIYGI114804,23295RNF157, MGRN1440ALADGVTMQV114960,26958TSGA13, COPG2441ALLENPKMEL140901,14942 0STK35, PDIK1L442149954BPIFB4443GLWEIENNPTV154150,3068HDGFL1, HDGF444GLLRDEALAEV1663,440081,6 42846DDX11, DDX12P445GLYQDPVTL201292TRIM65446QLI PALAKV2070,2138,213 9EYA4, EYA1, EYA2447QLVPALAKV2140EYA3448NLLETKLQL219988PATL1449KLAEGLDIQL221656KDM1B450FMIDASVHPTL221960,51622CCZ1B, CCZ1451LLLLDTVTMQV22820COPG1452ILLEHGADPNL22852ANKRD26453KLLEATSAV100129478,20 1725C4orf46454KLPPPPPQA23028KDM1A455SLLKEPQKVQL23154NCDN456LLIGHLERV23165NUP205457SLLPGNLVEKV23341DNAJC16458SLIDKLYNI25885POLR1A459ALITEVVRL26005C2CD3460AMLEKNYKL26160IFT172461VMFRTPLASV26271FBX05462KLAKQPETV27085MTBP463284361EMC10464ALNDCIYSV3652IPP465QLCDLNAEL3833KIFC1466VLIANLEKL440590ZYG11A467FLAKDFNFL4600MX24684904,8531YBX1, CSDA469YLASDEITTV4976OPA1470MLQDSIHVV4999ORC2471YLYNNMIAKI51284TLR7472KLLEVSDDPQV51606ATP6V1H473AMATESILHFA5297PI4KA474537ATP6AP1475LLLNEEALAQI54497HEATR5B47654502RBM47477ALLPASGQIAL54512EXOSC4478YLLHEKLNL55010PARPBP47955125CEP192480ALLEDSCHYL55161TMEM33481GLIEDYEALL55755CDK5RAP2482SLAPAGIADA55839CENPN483ALTDIVSQV56924PAK6484SLIEKVTQL56992KIF15485NVPDSFNEV57508INTS2486AVMESIQGV57646USP28487LLINSVFHV57655GRAMD1A488FLAEDPKVTL60489APOBEC3G489KMWEELPEVV622BDH1490FLLQHVQEL64127NOD2491GLNDRSDAV64151NCAPG49264219,9867PJA1, PJA24936522SLC4A2494ALQPEPIKV6653SORL1495FIFSEKPVFV6653SORL1496FLVEKQPPQV6778STAT6497GLLEKLTAI6875TAF4B4987088,7090,709 1TLE1, TLE3, TLE4499KIFDIDEAEEGV728350,8894EIF2S2P4, EIF2S2500SLMEDQVLQL7486WRN501LLDPNVKSIFV79033ERI3502RLLAQVPGL79096C11orf49503SLNHFTHSV79670ZCCHC6504GLSDGNPSL79684MSANTD250579729SH3D21506KLLGKVETA80185TTI2507KLIDDQDISISL80208SPG11508ILAQEQLVVGV80347COASY509FLFDTKPLIV821CANX510KLYSVVSQL8239,8287USP9X, USP9Y511FLDPYCSASV85415RHPN2512SLSEIVPCL8900CCNA1513SLWPSPEQL90480GADD45GIP1514ILVDWLVQV9133CCNB2515LLQELVLFL93589CACNA2D4516AVGPASILKEV9406ZRANB2517LLMPIPEGLTL9540TP53I3518KLNAEVACV9569GTF21RD1519GLLHLTLLL9603NFE2L3520LAVHPSGVAL9636ISG15521MLLTKLPTI9804TOMM20522TLWYRSPEV983CDK1523YQIPRTFTL9846GAB2524ALIENLTHQI100508782,96 77PPIP5K152510072,582DPP3, BBS152623019CNOT1527FLLEPGNLEV23218NBEAL252851428DDX41529LLADELITV56904SH3GLB2530VMYADIGGMDI5704PSMC4531YTLPIASSIRL7249TSC2532ALNNLLHSL101060416,10 1060589,2304 9,440345,4403 54,552900,641 298SMG1, BOLA2, SMG1P1533RMVAEIQNV11262SP140534HLANIVERL117854,44537 2,53840TRIM6, TRIM6-TRIM34, TRIM34535KLIAQNLEL3832KIF11536YLVEGRFSV55125CEP192537TLAPGEVLRSV3996LLGL1538LLLAHIIAL9415FADS2539ALFDAQAQV7297TYK2540ALIPETTTLTV100529251,51 192CKLF-CMTM1, CKLF541SMLEPVPEL10277UBE4B542RVWDISTVSSV11137PWP1543133619PRRC1544LLWDVPAPSL1388,7148ATF6B, TNXB545LLADLLHNV1677DFFB546VMIAGKVAVV191AHCY547TLDITPHTV2177FANCD254822893BAHD1549AMLENASDIKL23ABCF155023191,26999CYFIP1, CYFIP2551KLYESLLPFA23310NCAPD3552GLLDLPFRVGV23347SMCHD155323355VPS8554LLMPSSEDLLL26046LTN1555YVLEGLKSV26098C10orf137556FLTDLEDLTL26151NAT9557KLYDDMIRL26160IFT172558GLLENIPRV2618GART559VTVPPGPSL266971,5710PIPSL, PSMD45602782GNB1561YLQLTQSEL283237TTC9C562YLEELPEKLKL2944,2949GSTM1, GSTM5563WLLPYNGVTV2976GTF3C2564TVTNAVVTV3312HSPA8565ALQETPTSV3434IFIT1566VIADGGIQNV3615IMPDH2567SLLPLDDIVRV3708,3709ITPR1, ITPR2568TLYDIAHTPGV4191MDH2569KLVDRTWTL441733,5613,5 616PRKXP1, PRKX, PRKY570ALANQIPTV4436MSH2571LLLTTIPQI4507MTAP572ALADLIEKELSV4850CNOT4573ILVANAIVGV488,489ATP2A2, ATP2A3574YLLQEPPRTV5074PAWR575YLISQVEGHQV51002TPRKB576ILLNNSGQIKL51755CDK12577545ATR57855627SMPD4579NLMEMVAQL55636CHD7580LLMENAERV55726ASUN581RLWNETVEL55789DEPDC1B582TLCDVILMV55975KLHL7583ILANDGVLLAA5685PSMA458456987BBX5855701PSMC2586KLKPGDLVGV5702PSMC3587VMNDRLYAI57565KLHL14588SLLPLSHLV57674RNF213589KLYPQLPAEI57724EPG5590SLIEKLWQT5991RFX3591SMAELDIKL60561RINT1592RLLJAAENFL64092SAMSN1593GLPRFGIEMV64397ZFP106594IMLKGDNITL6635SNRPE595VLLSIYPRV6890TAP15967094TLN1597KLLEGQVIQL7629ZNF76598FLFPHSVLV79022TMEM106C599YLLNDASLISV79145CHCHD7600ALAAPDIVPAL79886CAAP1601SAFPFPVTV79939SLC35E1602YLLEQIKLIEV79956ERMP1603FLIEPEHVNTV80124VCPIP1604SILDRDDIFV8237USP11605KLYEAVPQL8317CDC7606ALWETEVYI8398PLA2G6607RLYSGISGLEL84172POLR1B608SLLSVSHAL84219WDR24609ALWKQLLEL85441HELZ2610LLAPTPYIIGV8567MADD611YLLDDGTL VV8872CDC123612YLYNEGLSV899CCNF613RLLPPGAVVAV90353CTU1614LLLPDQPPYHL9246UBE2L6615VLPPDTDPA93100NAPRT1616VLIDEVESL9319TRIP136179342SNAP29618VLFDSESIGIYV9555H2AFY619ALQDRVPLA9636ISG15620KLLNKIYEA9875URB1621VLMDRLPSLL9875URB16229894TELO2623YLVEDIQHI9985REC8624FLQEEPGQLL101060729,54 8593,79008SLX1A, SLX1B625VVLEGASLETV10436EMG1626LLMATILHL1315COPB1627KLLETELLQEI151636DTX3L628KLWEFFQVDV178AGL629HLLNESPML23165NUP205630LLSHVIVAL545ATR631FLDVFLPRV5591PRKDC632YLIPDIDLKL6599SMARCC1633ALSRVSVNV80746TSEN2634VVAEFVPLI8295TRRAP635SLDSTLHAV85444LRRCC1636LLTEIRAVV9263STK17A637SIYGGFLLGV9276COPB2638KLIQESPTV9702CEP57639SLFQNCFEL9716AQR640YLFSEALNAA987LRBA Table 3: Peptides useful for cancer therapy, e.g. personalized cancer therapies SEQ ID NO.SequenceGene ID(s)Official Gene Symbol(s)641VLLPVEVATHYL10568SLC34A2642FLHDISDVQL10715CERS1643ALFPHLLQPV1434CSE1 L644LTFGDVVAV2173FABP7645LLYDAVHIV2899GRIK3646ILSPTVVSI3832KIF11647SLGLFLAQV51435SCARA3648LLWGNAIFL547KIF1A649ALAFKLDEV201780SLC10A4650AIMGFIGFFV23480SEC61G651ILQDRLNQV990CDC6652TLWYRAPEV1019,1021CDK4, CDK6653TLISRLPAV1104RCC1654KILEDVVGV22974TPX2655ALMDKEGLTAL26115TANC2656KLLEYIEEI3161HMMR657SLAERLFFQV339983NAT8L658LLQDRLVSV57664PLEKHA4659ILFPDIIARA64110MAGEF1660AILDTLYEV84725PLEKHA8661SLIDADPYL890CCNA2662KIQEILTQV10643IGF2BP3663KIQEMQHFL4321MMP12

[0037] The present invention furthermore generally relates to the peptide according to the present invention for use in the treatment of proliferative diseases, such as, for example non-small cell lung cancer, small cell lung cancer, kidney cancer, brain cancer, colon or rectum cancer, stomach cancer, liver cancer, pancreatic cancer, prostate cancer, leukemia, breast cancer, Merkel cell carcinoma, melanoma, esophageal cancer, urinary bladder cancer, uterine cancer, gallbladder cancer, bile duct cancer.

[0038] Disclosed are the peptides - alone or in combination - wherein SEQ ID NO: 11 is according to the present invention selected from the group consisting of SEQ ID NO: 1, 11, 427, 408, 198, 512, 519, and 587 and their uses in the immunotherapy of ovarian cancer, non-small cell lung cancer, small cell lung cancer, kidney cancer, brain cancer, colon or rectum cancer, stomach cancer, liver cancer, pancreatic cancer, prostate cancer, leukemia, breast cancer, Merkel cell carcinoma, melanoma, esophageal cancer, urinary bladder cancer, uterine cancer, gallbladder cancer, bile duct cancer, and preferably ovarian cancer.

[0039] As shown in the following Table 4A and B, many of the peptides as disclosed are also found on other tumor types and can, thus, also be used in the immunotherapy of other indications. Also refer to Figures 1 and Example 1. Table 4A: Peptides as disclosed, SEQ ID NO: 11 is according to the present invention and their specific uses in other proliferative diseases, especially in other cancerous diseases. The table shows for selected peptides on which additional tumor types they were found and either over-presented on more than 5% of the measured tumor samples, or presented on more than 5% of the measured tumor samples with a ratio of geometric means tumor vs normal tissues being larger than 3. Over-presentation is defined as higher presentation on the tumor sample as compared to the normal sample with highest presentation. Normal tissues against which over-presentation was tested were: adipose tissue, adrenal gland, artery, bone marrow, brain, central nerve, colon, duodenum, esophagus, gallbladder, heart, kidney, liver, lung, lymph node, mononuclear white blood cells, pancreas, peripheral nerve, peritoneum, pituitary, pleura, rectum, salivary gland, skeletal muscle, skin, small intestine, spleen, stomach, thymus, thyroid gland, trachea, ureter, urinary bladder, vein. J = phospho-serineSEQ ID NoSequenceOther relevant organs / cancerous diseases1SLMEPPAVLLLNSCLC, SCLC, Esophageal Cancer2SLLEADPFLEsophageal Cancer6VLVSDGVHSVSCLC, Brain Cancer, BrCa, MCC, Esophageal Cancer7SLVGLLLYLRCC, PC, BrCa9GAAKDLPGVRCC, GC, HCC, Urinary bladder Cancer10FLATFPLAAVUrinary bladder Cancer11KIFEMLEGVNSCLC14AAYGGLNEKSFVHCC, Urinary bladder Cancer17GLLPGDRLVSVNSCLC, SCLC, BrCa19FMVDNEAIYDISCLC, CRC, HCC, Leukemia, Melanoma, Esophageal Cancer, Urinary bladder Cancer20RMIEYFIDVSCLC, HCC, MCC22IMEENPGIFAVCRC, Leukemia, Melanoma24SLSDGLEEVCRC, PC, Urinary bladder Cancer26ALLELAEELLeukemia, Esophageal Cancer27ILADIVISANSCLC, SCLC, PC, BrCa, Esophageal Cancer28QLLDETSAITLSCLC, HCC, Leukemia, Urinary bladder Cancer31YLAPELFVNVSCLC, GC, Leukemia, Melanoma32KLDDLTQDLTVHCC,33VLLSLLEKVLeukemia34ILVEADSLWVVSCLC, PrC, Leukemia, Melanoma36YVLEDLEVTVSCLC, HCC, Leukemia38FLLEDDIHVSSCLC, Leukemia, Melanoma45SLWQDIPDVNSCLC, SCLC47ILLSVPLLVVSCLC, Leukemia, Gallbladder Cancer, Bile Duct Cancer48ALAELYEDEVSCLC, Brain Cancer, HCC, Leukemia, Melanoma, Uterine Cancer49YLPAVFEEVLeukemia51LLPDLEFYVSCLC, PrC, Gallbladder Cancer, Bile Duct Cancer54SLLEQGKEPWMVSCLC, HCC, Gallbladder Cancer, Bile Duct Cancer55SLLDLETLSLSCLC56KLYEGIPVLLBrCa57TLAELQPPVQLNSCLC, SCLC, HCC, Leukemia, Melanoma, Esophageal Cancer58FLDTLKDLINSCLC, SCLC, GC, CRC, HCC, Leukemia, Melanoma, Esophageal Cancer, Gallbladder Cancer, Bile Duct Cancer59IMEDIILTLSCLC, Leukemia, BrCa60SLTIDGIYYVSCLC, Prostate, Leukemia61FLQGYQLHLNSCLC, SCLC, BrCa, Melanoma, Esophageal Cancer62VLLDVSAGQLLMNSCLC, Melanoma63YLLPSGGSVTLHCC, Melanoma, Esophageal Cancer64YAAPGGLIGVHCC, PC, Melanoma, Esophageal Cancer, Gallbladder Cancer, Bile Duct Cancer65LKVNQGLESLNSCLC, SCLC, PC, Leukemia, BrCa, Esophageal Cancer66FLDENIGGVAVSCLC, HCC68SLMELPRGLFLBrain Cancer69FQLDPSSGVLVTVEsophageal Cancer72SLLELDGINLNSCLC, SCLC, Prostate74ALLDPEVLSIFVNSCLC, Leukemia, Melanoma75GLLEVMVNLSCLC76ILIDSIYKVSCLC, CRC, BrCa77ILVEADGAWVVMelanoma, Esophageal Cancer79SLFIGEKAVLLNSCLC, SCLC, CRC, Leukemia, Esophageal Cancer, Urinary bladder Cancer80FLYDNLVESLLeukemia82FLSSVTYNLSCLC,84VTFGEKLLGVNSCLC, CRC, PC, PrC, Gallbladder Cancer, Bile Duct Cancer85KMSELRVTLSCLC, Esophageal Cancer86NLIGKIENVColon, Rectum87ALPEAPAPLLPHITHCC, PC, Urinary bladder Cancer, Gallbladder Cancer, Bile Duct Cancer88FLLVGDLMAVSCLC91IMQDFPAEIFLSCLC92YLIPFTGIVGLSCLC, HCC, Leukemia, Melanoma93LLQAIKLYLBrCa94YLIDIKTIAIHCC95SVIPQIQKVPC, Esophageal Cancer97SLINGSFLVNSCLC, RCC, CRC, HCC, PC, Melanoma, Esophageal Cancer98LIIDQADIYLNSCLC, SCLC, RCC, CRC, HCC, Leukemia, Melanoma, Esophageal Cancer101ILVGGGALATVMelanoma, Urinary bladder Cancer103TLAEEVVALSCLC, BrCa, Esophageal Cancer104STMEQNFLLNSCLC,105LLLEHSFEINSCLC, Melanoma106LLYDAVHIVSVBrain Cancer107FLQPVDDTQHLMelanoma, Esophageal Cancer108ALFPGVALLLASCLC, HCC, Endometrium110FLSQVDFELBrCa117ILPDGEDFLAVSCLC118KLIDNNINVBrain Cancer119FLYIGDIVSLLeukemia121GVVDPRAISVLEsophageal Cancer123NLWDLTDASVVSCLC, Prostate125VQIHQVAQVNSCLC, SCLC, HCC, PC, Esophageal Cancer, Gallbladder Cancer, Bile Duct Cancer126VLAYFLPEANSCLC, SCLC, CRC, PC, Leukemia, Esophageal Cancer, Uterine Cancer127KIGDEPPKVNSCLC, SCLC, Brain Cancer, PC, Esophageal Cancer, Uterine Cancer128YLFDDPLSAVLeukemia, Esophageal Cancer129GLLDGGVDILLHCC, Leukemia, Esophageal Cancer, Uterine Cancer130FLWNGEDSALLPC131FVPPVTVFPSLBrCa132LLVEQPPLAGVLeukemia134YLQELIFSVEndometrium135ALSEVDFQLSCLC, Brain Cancer137TLVLTLPTVPC139SVMEVNSGIYRVHCC, MCC141YLDFSNNRLSCLC, BrCa142FLFATPVFISCLC143LLLDITPEINSCLC, Brain Cancer, HCC, PC, BrCa, Melanoma, Esophageal Cancer144YIMEPSIFNTLHCC, Leukemia, Melanoma, Urinary bladder Cancer145FLATSGTLAGIProstate146SLATAGDGLIELUrinary bladder, Endometrium148ALNPEIVSVEsophageal Cancer, Urinary bladder Cancer149NLLELFVQLSCLC, Leukemia, BrCa, Urinary bladder Cancer, Uterine Cancer150RLWEEGEELELNSCLC, Melanoma, Esophageal Cancer151KILQQLVTLEndometrium152ILFEDIFDVSCLC, Endometrium153FLIANVLYLSCLC, Urinary bladder Cancer, Uterine Cancer154ALDDGTPALHCC155RVANLHFPSVMelanoma, Esophageal Cancer157SLNDEVPEVNSCLC, Brain Cancer, HCC, Esophageal Cancer, Uterine Cancer159GLVGNPLPSVHCC, Leukemia161ALLEGVNTVNSCLC, Leukemia163ALDEMGDLLQLHCC166YLNHLEPPVSCLC, HCC, Leukemia, Esophageal Cancer167KVLEVTEEFGVNSCLC, HCC, Melanoma169NLPEYLPFVSCLC, BrCa, Urinary bladder Cancer170RLQETLSAAHCC, Esophageal Cancer171LLLPLQILLSCLC174ALAQYLITABrain Cancer, HCC, PrC, Esophageal Cancer, Urinary bladder Cancer176YLMEGSYNKVFLNSCLC, SCLC, CRC, HCC, Melanoma177YLLPEEYTSTLMelanoma, Esophageal Cancer178ALTEIAFVVCRC, HCC, PrC179KVLNELYTVNSCLC183FGLDLVTELNSCLC, SCLC, RCC, GC, PC, Leukemia, BrCa, Melanoma184YLMDINGKMWLNSCLC, SCLC, Melanoma186TLFFQQNALProstate,188GLFPVTPEAVColon, Rectum, HCC190FLSSLTETIUrinary bladder Cancer195GLFADLLPRLNSCLC197ALGPEGGRVHCC198KTINKVPTVNSCLC, HCC199ALQDVPLSSVMelanoma200LLFGSVQEVSCLC, PC, PrC, Esophageal Cancer, Gallbladder Cancer, Bile Duct Cancer201RLVDYLEGINSCLC, HCC, Esophageal Cancer204KIAENVEEVNSCLC, HCC, PC, Leukemia, BrCa, Esophageal Cancer205SLYPGTETMGLSCLC, Gallbladder, Bile duct207GLTSTNAEVHCC, PrC, Esophageal Cancer, Uterine Cancer208KISPVTFSVHCC209KLIESKHEVBrain Cancer, HCC210LLLNAVLTVUrinary bladder Cancer212ALWDQDNLSVHCC, PrC, BrCa, Urinary bladder Cancer213VTAAYMDTVSLNSCLC, SCLC, HCC, Melanoma, Esophageal Cancer, Gallbladder Cancer, Bile Duct Cancer214FLLDLDPLLLSCLC, HCC, Leukemia, Uterine Cancer216NLWEDPYYLSCLC, PrC, BrCa, Urinary bladder Cancer217ALIHPVSTVNSCLC, RCC, HCC, Melanoma, Esophageal Cancer218SALEELVNVRCC222NLIENVQRLNSCLC, RCC, CRC, HCC, Melanoma, Esophageal Cancer, Urinary bladder Cancer223ALLENIALYLEsophageal Cancer, Urinary bladder Cancer226MLYVVPIYLBrCa228AMQEYIAVVNSCLC, SCLC, Uterine Cancer, Gallbladder Cancer, Bile Duct Cancer229RLPGPLGTVHCC, Esophageal Cancer, Endometrium230ILVDWLVEVMelanoma, Endometrium233VLSETLYELSCLC, Endometrium234ALMEDTGRQMLNSCLC, SCLC, HCC, Esophageal Cancer235YLNDLHEVLLEsophageal Cancer, Uterine Cancer, Gallbladder Cancer, Bile Duct Cancer237ALLEASGTLLLSCLC, HCC, PrC, Leukemia, Uterine Cancer, Gallbladder Cancer, Bile Duct Cancer240ILLEQAFYLSCLC241SLVEVNPAYSVProstate, Gallbladder, Bile duct242AIAYILQGVSCLC, Leukemia, BrCa, Esophageal Cancer, Urinary bladder Cancer243LLLNELPSVColon, Rectum, Esophageal Cancer247VLLPNDLLEKVBrain Cancer248FLFPNQYVDVNSCLC, SCLC, HCC, Leukemia, Melanoma249LLDGFLVNVSCLC251ALYTGFSILVSCLC, Leukemia, Melanoma252LLIGTDVSLPrC, Leukemia, Esophageal Cancer, Urinary bladder Cancer253GLDAATATVProstate, Leukemia255VLASYNLTVBrCa256FLPPEHTIVYISCLC, HCC, Leukemia, Melanoma257SIFSAFLSVStomach, Urinary bladder Cancer258ELAERVPAIEsophageal Cancer262LLWGDLIWLLeukemia263LLVSNLDFGVNSCLC, SCLC, RCC, Leukemia264SLQEQLHSVNSCLC, SCLC, PrC, BrCa, Melanoma, Esophageal Cancer266KITDTLIHLBrCa267ALQDFLLSVHCC, Esophageal Cancer, Endometrium268IAGPGLPDLNSCLC, RCC, BrCa269RVLEVGALQAVHCC270LLLDEEGTFSLLeukemia271LVYPLEL YPARCC, HCC, Leukemia, BrCa, Esophageal Cancer, Urinary bladder Cancer272ALGNTVPAVPC, Leukemia, Endometrium273NLFQSVREVHCC, BrCa275YLVYILNELRCC, GC, HCC, PC, Leukemia, Esophageal Cancer276ALFTFSPLTVLeukemia277LLPPLESLATVSCLC, Leukemia, Melanoma279ALWGGTQPLLSCLC, Brain Cancer, Esophageal Cancer280VLPDPEVLEAVProstate, Leukemia282LLADVVPTTLeukemia, Melanoma283ALYIGDGYVIHLASCLC, BrCa, MCC, Melanoma284ILLSQTTGVProstate, Leukemia285QLLHVGVTVNSCLC, RCC, CRC, Leukemia, Esophageal Cancer286YLFPGIPELSCLC, HCC287FLNEFFLNVNSCLC, Leukemia, Melanoma, Esophageal Cancer288NLINEINGVSCLC, PrC, Esophageal Cancer, Urinary bladder Cancer, Uterine Cancer289VLLEIEDLQVLeukemia, BrCa290GLLDLNNAILQLHCC291GLDSNLKYILVPC, Melanoma292LLWEAGSEABrain Cancer, PC294ILDPFQYQLHCC, Esophageal Cancer296FMEGAIIYVSCLC, Leukemia298VMITKLVEVUrinary bladder Cancer299YLLETSGNLLeukemia, Urinary bladder Cancer300ALLGQTFSLSCLC, Brain Cancer, CRC301FLVEDLVDSLSCLC, HCC, Leukemia303AILPQLFMVNSCLC, RCC, CRC, BrCa, Esophageal Cancer, Urinary bladder Cancer306ALVNVQIPLHCC, Esophageal Cancer308SQYSGQLHEVLeukemia, Gallbladder, Bile duct309GLFDGVPTTAHCC, Leukemia, BrCa, Melanoma310FLVDTPLARAUrinary bladder Cancer311RLYTGMHTVRCC, CRC, PC, Esophageal Cancer, Urinary bladder Cancer312IISDLTIALSCLC, PC313VLFDDELLMVNSCLC, RCC, Brain Cancer, HCC, Esophageal Cancer314ALIAEGIALVSCLC, Melanoma315YLQDVVEQASCLC, Endometrium316ILLERLWYVMelanoma317SLAALVVHVEsophageal Cancer, Urinary bladder Cancer318GLI NTGVLSVColon, Rectum319SLEPQIQPVNSCLC, CRC, Leukemia, Esophageal Cancer320KMFEFVEPLLColon, Rectum321GLFEDVTQPGILLLeukemia, Melanoma322TLMTSLPALSCLC,323IQIGEETVITVNSCLC, SCLC, PrC, Leukemia, Melanoma, Esophageal Cancer, Uterine Cancer, Gallbladder Cancer, Bile Duct Cancer324FLYDEIEAEVLeukemia325FIMPATVADATAVLeukemia327GLAPFTEGISFVHCC328ALNDQVFEISCLC, Brain Cancer, HCC, Esophageal Cancer, Uterine Cancer329FLVTLNNVEVMelanoma330QLALKVEGVEsophageal Cancer331KVDTVWVNVSCLC, Leukemia, BrCa, Melanoma, Urinary bladder Cancer332YLISELEAABrain Cancer, HCC, PC, PrC, Esophageal Cancer, Uterine Cancer333FLPDANSSVNSCLC, Brain Cancer, PrC, Leukemia, BrCa, Esophageal Cancer, Urinary bladder Cancer334TLTKVLVALUrinary bladder Cancer335YSLSSVVTVNSCLC, GC, PC, BrCa, Gallbladder Cancer, Bile Duct Cancer336ILLTAIVQVBrCa, Esophageal Cancer338SVLEDPVHAVNSCLC, SCLC, HCC, Melanoma339GLWEIENNPTVKAHCC, Melanoma, Endometrium340ALLSMTFPLBrain Cancer, HCC, BrCa341SQIALNEKLVNLSCLC, HCC342HIYDKVMTVColon, Rectum343SLLEVNEESTVNSCLC, Leukemia, Melanoma344YLQDQHLLLTVSCLC, Melanoma345VIWKALIHLSCLC346LLDSKVPSVSCLC, HCC, PC, Esophageal Cancer, Urinary bladder Cancer, Gallbladder Cancer, Bile Duct Cancer347SLFKHDPAAWEANSCLC, HCC, Esophageal Cancer, Urinary bladder Cancer348ILLDVKTRLNSCLC, CRC, Esophageal Cancer, Urinary bladder Cancer349SLTEYLQNVColon, Rectum, HCC351SLIPNLRNVPC354LILEGVDTVEsophageal Cancer355SIQQSIERLLVNSCLC, CRC, HCC, Leukemia, Melanoma, Esophageal Cancer356KLLGKLPELNSCLC, CRC, Esophageal Cancer357SMHDLVLQVBrain Cancer, PC, Endometrium358ALDEYTSELBrain Cancer, PC, Leukemia, BrCa, Uterine Cancer359YLLPESVDLNSCLC, CRC, HCC, Esophageal Cancer360ALDJGASLLHLRCC, HCC, Esophageal Cancer, Urinary bladder Cancer, Uterine Cancer361ALYELEGTTVEsophageal Cancer362TLYGLSVLLBrCa363KVLDVSDLESVUrinary bladder, Endometrium364LLQNEQFELRCC365YVIDQGETDVYVLeukemia, Melanoma366RLLDMGETDLMLSCLC, Leukemia, Melanoma367SLQNHNHQLHCC, Urinary bladder Cancer369GLFPEHLIDVHCC370SLLQDLVSVHCC371FLQAHLHTABrCa372TMLLNIPLVSCLC, HCC, PC, PrC, BrCa373SLLEDKGLAEVNSCLC, SCLC, Leukemia, BrCa, MCC, Melanoma374FLLQQHLISALeukemia375SLTETIEGVBrCa, Esophageal Cancer376AMFESSQNVLLColon, Rectum378ALGYFVPYVHCC379IMEGTLTRVLeukemia381FIDEAYVEVLeukemia382ALQNYIKEAEsophageal Cancer383ALLELENSVTLHCC384ILFANPNIFVCRC, Leukemia, Melanoma385SLLEQGLVEANSCLC, SCLC, Brain Cancer, HCC, Esophageal Cancer, Uterine Cancer, Gallbladder Cancer, Bile Duct Cancer386ILFRYPLTIUrinary bladder Cancer387ALFQATAEVHCC, Esophageal Cancer388SLTIDGIRYVSCLC, Melanoma389LLADVTHLLBrain Cancer, Endometrium390ALFMKQIYLUrinary bladder Cancer391YVYPQRLNFVLeukemia, Melanoma393GLLDTQTSQVLTAHCC, BrCa, Esophageal Cancer, Urinary bladder Cancer394LLAVIGGLVYLNSCLC, SCLC, RCC, HCC, PrC, Leukemia, Melanoma, Urinary bladder Cancer395ALALGGIAVVNSCLC, CRC, HCC, PrC, Leukemia, BrCa, Melanoma, Esophageal Cancer, Urinary bladder Cancer, Uterine Cancer396ALLPDLPALHCC, BrCa397YLFGERLLECColon, Rectum, Leukemia398KLLEEDGTIITLColon, Rectum, PC399YLFEPLYHVSCLC400SLLTEQDLWTVLeukemia401ILLDDTGLAYISCLC, HCC, Leukemia, BrCa, Melanoma403KLYDRILRVNSCLC, RCC404AIDIJGRDPAVSCLC, Leukemia405ALYDVFLEVPC, Esophageal Cancer406SVQGEDLYLVHCC, Endometrium407YLMDLINFLPC, Prostate408VLDDSIYLVLeukemia409LLDAMNYHLHCC, Leukemia410VLSDVIPJISCLC, RCC, Brain Cancer, GC, HCC, PC, PrC, Leukemia, Melanoma, Esophageal Cancer411LLAHLSPELHCC412YLDDLNEGVYILeukemia, Melanoma415LLDKVYSSVNSCLC, HCC, Leukemia, Esophageal Cancer418ALAELENIEVSCLC, MCC419GQYEGKVSSVHCC420FMYDTPQEVSCLC, HCC, BrCa421RLPETLPSLNSCLC, SCLC, GC, CRC, PC422FLPKLLLLABrCa423GLDGPPPTVHCC, PC, BrCa, Urinary bladder Cancer, Uterine Cancer, Gallbladder Cancer, Bile Duct Cancer424TLLDALYEIRCC, Esophageal Cancer, Endometrium425FLYEKSSQVBrain Cancer, Endometrium426RLADKSVLVColon, Rectum427ALLPLSPYLNSCLC, SCLC, HCC, PC, BrCa, Uterine Cancer428KLGHTDILVGVNSCLC, SCLC, CRC, HCC, Leukemia429GLVNDLARVNSCLC, HCC430HLYSSIEHLTTNSCLC, CRC, HCC, MCC, Esophageal Cancer431SLVNVVPKLNSCLC, SCLC, RCC, Brain Cancer, Melanoma, Esophageal Cancer432TLIEESAKVProstate433AMLNEPWAVSCLC434KVSNSGITRVNSCLC435WLMPVIPALSCLC437SMAPGLVIQAVSCLC, Prostate439YLLQEIYGISCLC, BrCa440ALADGVTMQVGallbladder, Bile duct441ALLENPKMELNSCLC, SCLC, CRC, HCC, MCC, Esophageal Cancer443GLWEIENNPTVNSCLC, SCLC, HCC, PC, PrC, Melanoma444GLLRDEALAEVNSCLC, SCLC, CRC, Melanoma, Esophageal Cancer446QLIPALAKVNSCLC, SCLC, PrC, BrCa, MCC, Uterine Cancer447QLVPALAKVNSCLC, SCLC, HCC, PrC, Esophageal Cancer, Urinary bladder Cancer448NLLETKLQLColon, Rectum, Leukemia449KLAEGLDIQLSCLC, Colon, Rectum450FMIDASVHPTLNSCLC, SCLC, RCC, Brain Cancer, CRC, HCC, Leukemia, Melanoma, Esophageal Cancer451LLLLDTVTMQVSCLC, HCC452ILLEHGADPNLHCC, Leukemia, Melanoma454KLPPPPPQANSCLC, SCLC455SLLKEPQKVQLRCC456LLIGHLERVNSCLC, Brain Cancer, CRC,457SLLPGNLVEKVNSCLC, HCC, Leukemia, Melanoma458SLIDKLYNINSCLC, Colon, Rectum,459ALITEVVRLNSCLC, CRC, PC, Leukemia, BrCa, Esophageal Cancer461VMFRTPLASVSCLC, Melanoma, Esophageal Cancer463SLVESHLSDQLTLNSCLC, SCLC, HCC, Melanoma464ALNDCIYSVBrain Cancer, HCC, PC465QLCDLNAELHCC, Esophageal Cancer466VLIANLEKLBrCa, Esophageal Cancer468YLRSVGDGETVLeukemia, Melanoma469YLASDEITTVSCLC,472KLLEVSDDPQVHCC, MCC, Melanoma, Esophageal Cancer473AMATESILHFASCLC, Brain Cancer, CRC, HCC, MCC, Gallbladder Cancer, Bile Duct Cancer474YLDPALELGPRNVNSCLC, SCLC, Brain Cancer, HCC, MCC, Melanoma475LLLNEEALAQISCLC, Leukemia476ALMERTGYSMVHCC477ALLPASGQIALNSCLC, HCC, Esophageal Cancer, Urinary bladder Cancer478YLLHEKLNLColon, Rectum,479SLFGNSGILENVNSCLC, SCLC, HCC, MCC, Urinary bladder Cancer480ALLEDSCHYLNSCLC, CRC, HCC, Leukemia, Esophageal Cancer481GLIEDYEALLSCLC483ALTDIVSQVUrinary bladder Cancer484SLIEKVTQLHCC485NVPDSFNEVStomach486AVMESIQGVNSCLC, HCC, PrC, Leukemia, Esophageal Cancer, Urinary bladder Cancer, Uterine Cancer487LLINSVFHVMelanoma488FLAEDPKVTLLeukemia489KMWEELPEVVNSCLC, HCC, Leukemia490FLLQHVQELLeukemia491GLNDRSDAVEsophageal Cancer, Endometrium492SLFDGFADGLGVNSCLC, SCLC, Brain Cancer, HCC, PrC, Esophageal Cancer493GLLGEKTQDLIGVNSCLC, SCLC494ALQPEPIKVUrinary bladder, Gallbladder, Bile duct495FIFSEKPVFVUrinary bladder Cancer496FLVEKQPPQVLeukemia, Melanoma497GLLEKLTAINSCLC, RCC, Esophageal Cancer, Uterine Cancer498KLWTGGLDNTVHCC, Esophageal Cancer499KIFDIDEAEEGVPC, Melanoma, Esophageal Cancer500SLMEDQVLQLSCLC, Colon, Rectum501LLDPNVKSIFVNSCLC, SCLC, Brain Cancer, HCC, PrC, MCC, Melanoma, Esophageal Cancer, Gallbladder Cancer, Bile Duct Cancer502RLLAQVPGLRCC, Urinary bladder Cancer503SLNHFTHSVNSCLC, Leukemia504GLSDGNPSLLeukemia, BrCa505SLAPGDVVRQVEsophageal Cancer506KLLGKVETANSCLC, Brain Cancer, Leukemia, Esophageal Cancer507KLIDDQDISISLLeukemia508ILAQEQLVVGVLeukemia, Esophageal Cancer510KLYSVVSQLColon, Rectum, Leukemia513SLWPSPEQLHCC, Esophageal Cancer514ILVDWLVQVNSCLC, SCLC, RCC, Brain Cancer, GC, CRC, HCC, Melanoma, Esophageal Cancer, Urinary bladder Cancer, Uterine Cancer517LLMPIPEGLTLNSCLC, SCLC, HCC, Melanoma518KLNAEVACVCRC, PrC, Esophageal Cancer520LAVHPSGVALLeukemia521MLLTKLPTINSCLC, SCLC, CRC, HCC, BrCa, Melanoma, Urinary bladder Cancer522TLWYRSPEVSCLC523YQIPRTFTLSCLC, Brain Cancer, HCC, Leukemia, Melanoma525VLLEAGEGLVTIMelanoma526RLAEVGQYEQVNSCLC, HCC, MCC, Gallbladder Cancer, Bile Duct Cancer527FLLEPGNLEVUrinary bladder Cancer528SVAEGRALMSVBrain Cancer, CRC, HCC, Esophageal Cancer529LLADELITVProstate, Leukemia, Urinary bladder Cancer530VMYADIGGMDISCLC, Melanoma531YTLPIASSIRLSCLC, CRC, HCC533RMVAEIQNVLeukemia, Esophageal Cancer535KLIAQNLELColon, Rectum536YLVEGRFSVLeukemia538LLLAHIIALNSCLC, Brain Cancer, HCC539ALFDAQAQVNSCLC, SCLC, Brain Cancer, HCC, PC, PrC, BrCa, Esophageal Cancer, Urinary bladder Cancer, Uterine Cancer, Gallbladder Cancer, Bile Duct Cancer540ALI PETTTLTVHCC, PC, Melanoma541SMLEPVPELNSCLC, SCLC, Brain Cancer, CRC, HCC, Esophageal Cancer542RVWDISTVSSVSCLC, Leukemia, Melanoma, Esophageal Cancer543GLLPTPITQQASLEsophageal Cancer544LLWDVPAPSLLeukemia, Melanoma545LLADLLHNVNSCLC, SCLC, Colon, Rectum546VMIAGKVAVVColon, Rectum, HCC549AMLENASDIKLMelanoma550FLYDEIEAEVNLLeukemia, Melanoma551KLYESLLPFASCLC, HCC, PrC, Melanoma552GLLDLPFRVGVSCLC, Brain Cancer, Leukemia, Melanoma554LLMPSSEDLLLNSCLC, SCLC, CRC, HCC, PrC, BrCa, Esophageal Cancer, Urinary bladder Cancer, Gallbladder Cancer, Bile Duct Cancer555YVLEGLKSVSCLC, Melanoma556FLTDLEDLTLSCLC, Leukemia557KLYDDMIRLColon, Rectum,558GLLENIPRVNSCLC, SCLC, RCC, Brain Cancer, HCC, Leukemia, Uterine Cancer, Gallbladder Cancer, Bile Duct Cancer559VTVPPGPSLLeukemia560ALWDIETGQQTTTSCLC, HCC, Melanoma, Esophageal Cancer561YLQLTQSELSCLC, Leukemia, Esophageal Cancer, Gallbladder Cancer, Bile Duct Cancer563WLLPYNGVTVSCLC, Melanoma564TVTNAVVTVRCC, GC, HCC, Melanoma565ALQETPTSVSCLC, Melanoma, Esophageal Cancer, Uterine Cancer566VIADGGIQNVLeukemia, Melanoma, Endometrium567SLLPLDDIVRVLeukemia568TLYDIAHTPGVNSCLC, SCLC, CRC, Melanoma, Esophageal Cancer571LLLTTIPQIProstate, Leukemia572ALADLIEKELSVLeukemia573ILVANAIVGVNSCLC, HCC, Leukemia, Melanoma574YLLQEPPRTVSCLC575YLISQVEGHQVCRC, HCC, MCC, Melanoma, Esophageal Cancer576ILLNNSGQIKLNSCLC, CRC, HCC, Leukemia, BrCa, Melanoma, Esophageal Cancer577VMFEDGVLMRLColon, Rectum, Leukemia578FLDPGGPMMKLNSCLC, CRC, MCC, Melanoma579NLMEMVAQLNSCLC, CRC, HCC, Leukemia580LLMENAERVCRC, Leukemia, BrCa, Melanoma581RLWNETVELSCLC, Colon, Rectum583ILANDGVLLAAHCC, Esophageal Cancer584ALAEVAAMENVMelanoma585ALWDLAADKQTLUrinary bladder Cancer586KLKPGDLVGVBrain Cancer, HCC587VMNDRLYAILeukemia588SLLPLSHLVMelanoma, Esophageal Cancer589KLYPQLPAEINSCLC, SCLC, Brain Cancer, HCC, Leukemia, MCC, Melanoma, Esophageal Cancer590SLIEKLWQTSCLC, Brain Cancer591SMAELDIKLLeukemia, Esophageal Cancer, Endometrium592RLLJAAENFLSCLC, Brain Cancer, BrCa, Esophageal Cancer593GLPRFGIEMVBrain Cancer594IMLKGDNITLEsophageal Cancer595VLLSIYPRVNSCLC, SCLC, RCC, Leukemia, BrCa596ALLDQTKTLAESALLeukemia, Melanoma597KLLEGQVIQLNSCLC, SCLC, CRC, HCC, BrCa599YLLNDASLISVNSCLC, CRC, HCC, Melanoma, Uterine Cancer600ALAAPDIVPALLeukemia601SAFPFPVTVStomach, Leukemia, Esophageal Cancer602YLLEQIKLIEVNSCLC, SCLC603FLIEPEHVNTVHCC, PC, Leukemia, Melanoma604SILDRDDIFVLeukemia606ALWETEVYISCLC, Brain Cancer, HCC, PrC607RLYSGISGLELNSCLC608SLLSVSHALRCC609ALWKQLLELPC610LLAPTPYIIGVNSCLC, SCLC, RCC, Brain Cancer, CRC, HCC, PrC, Leukemia, BrCa, MCC, Melanoma, Esophageal Cancer, Urinary bladder Cancer, Gallbladder Cancer, Bile Duct Cancer611YLLDDGTLVVHCC, Melanoma613RLLPPGAVVAVNSCLC, SCLC, HCC614LLLPDQPPYHLMelanoma616VLIDEVESLNSCLC, SCLC, RCC, GC, BrCa, Melanoma, Esophageal Cancer, Urinary bladder Cancer617ALMYESEKVGVHCC, Gallbladder, Bile duct618VLFDSESIGIYVSCLC, Melanoma619ALQDRVPLABrain Cancer, CRC, Esophageal Cancer, Uterine Cancer620KLLNKIYEABrain Cancer621VLMDRLPSLLMelanoma622NSCLC, SCLC, CRC, Melanoma624FLQEEPGQLLLeukemia, Melanoma, Esophageal Cancer625VVLEGASLETVSCLC, Melanoma626LLMATILHLSCLC, Melanoma, Urinary bladder Cancer, Gallbladder Cancer, Bile Duct Cancer627KLLETELLQEINSCLC, SCLC, CRC, HCC, MCC, Melanoma628KLWEFFQVDVSCLC, Brain Cancer, HCC629HLLNESPMLSCLC, Esophageal Cancer630LLSHVIVALPC, Leukemia631FLDVFLPRVPC, Leukemia, Melanoma, Esophageal Cancer632YLIPDIDLKLNSCLC, SCLC, CRC, HCC, PC, Leukemia, Melanoma, Urinary bladder Cancer, Uterine Cancer633ALSRVSVNVMelanoma, Esophageal Cancer634VVAEFVPLIBrain Cancer, Leukemia635SLDSTLHAVNSCLC, Brain Cancer, CRC, HCC, BrCa, Esophageal Cancer637SIYGGFLLGVNSCLC, SCLC, HCC, PrC, BrCa, Uterine Cancer638KLIQESPTVSCLC, HCC, Prostate639SLFQNCFELLeukemia640YLFSEALNAASCLC, GC, CRC, HCC, PrC, BrCa, MCC, Esophageal Cancer, Urinary bladder Cancer, Uterine Cancer, Gallbladder Cancer, Bile Duct CancerNSCLC= non-small cell lung cancer, SCLC= small cell lung cancer, RCC= kidney cancer, CRC= colorectal cancer, GC= gastric cancer, HCC= liver cancer, PC= pancreatic cancer, PrC= prostate cancer, BrCa=breast cancer, MCC= Merkel cell carcinoma Table 4B: Peptides as disclosed, SEQ ID NO: 11 is according to the present invention and their specific uses in other proliferative diseases, especially in other cancerous diseases (amendment of Table 4). The table shows, like Table 4A, for selected peptides on which additional tumor types they were found showing over-presentation (including specific presentation) on more than 5% of the measured tumor samples, or presentation on more than 5% of the measured tumor samples with a ratio of geometric means tumor vs normal tissues being larger than 3. Over-presentation is defined as higher presentation on the tumor sample as compared to the normal sample with highest presentation. Normal tissues against which over-presentation was tested were: adipose tissue, adrenal gland, artery, bone marrow, brain, central nerve, colon, duodenum, esophagus, eye, gallbladder, heart, kidney, liver, lung, lymph node, mononuclear white blood cells, pancreas, parathyroid gland, peripheral nerve, peritoneum, pituitary, pleura, rectum, salivary gland, skeletal muscle, skin, small intestine, spleen, stomach, thyroid gland, trachea, ureter, urinary bladder, vein. SEQ ID NO.SequenceAdditional organs / cancerous diseases1SLMEPPAVLLLBRCA, Urinary Bladder Cancer, Uterine Cancer, AML, HNSCC2SLLEADPFLCLL, Uterine Cancer, Gallbladder Cancer and Bile Duct Cancer3SLASKLTTLUterine Cancer5HLTEVYPELUrinary Bladder Cancer, Uterine Cancer6VLVSDGVHSVMelanoma, Urinary Bladder Cancer, Uterine Cancer, HNSCC7SLVGLLLYLGallbladder Cancer and Bile Duct Cancer, AML8FTLGNVVGMYLMelanoma, Urinary Bladder Cancer, Uterine Cancer9GAAKDLPGVEsophageal Cancer11KIFEMLEGVGallbladder Cancer and Bile Duct Cancer13YLMDESLNLNSCLC, Brain Cancer, BRCA, Melanoma14CLL, Esophageal Cancer15VLLTFKIFLUterine Cancer, NHL16VLFQGQASLMelanoma, Uterine Cancer, AML, NHL18YLVAKLVEVNSCLC, BRCA, Urinary Bladder Cancer, HNSCC21VLDELDMELMelanoma22IMEENPGIFAVCLL, Urinary Bladder Cancer, Gallbladder Cancer and Bile Duct Cancer23VLLDDIFAQLCLL, Uterine Cancer, AML24SLSDGLEEVNSCLC, BRCA, Melanoma, Uterine Cancer, HNSCC26ALLELAEELBRCA, Melanoma, Urinary Bladder Cancer, Uterine Cancer, Gallbladder Cancer and Bile Duct Cancer, AML, NHL, HNSCC27ILADIVISAMelanoma, Uterine Cancer, Gallbladder Cancer and Bile Duct Cancer28QLLDETSAITLCLL29Urinary Bladder Cancer, Gallbladder Cancer and Bile Duct Cancer30LILDWVPYIMelanoma, Uterine Cancer, HNSCC31YLAPELFVNVBRCA, Uterine Cancer32KLDDLTQDLTVSCLC, Esophageal Cancer, Urinary Bladder Cancer, Gallbladder Cancer and Bile Duct Cancer, HNSCC33VLLSLLEKVCLL, Melanoma34ILVEADSLWVVAML36YVLEDLEVTVNSCLC, CLL, BRCA, Melanoma, Urinary Bladder Cancer, Uterine Cancer, Gallbladder Cancer and Bile Duct Cancer, NHL, HNSCC38FLLEDDIHVSCLL, Urinary Bladder Cancer, NHL40TLLVKVFSVMelanoma42VLLQKIVSAEsophageal Cancer, AML43VLSSLEININHL45SLWQDIPDVBRCA, Urinary Bladder Cancer, HNSCC47ILLSVPLLVVCLL, Uterine Cancer49YLPAVFEEVCLL51LLPDLEFYVMelanoma, Urinary Bladder Cancer54NSCLC, CLL57TLAELQPPVQLCLL, Urinary Bladder Cancer, Uterine Cancer, Gallbladder Cancer and Bile Duct Cancer, NHL, HNSCC58FLDTLKDLIUrinary Bladder Cancer, Uterine Cancer, AML, NHL60SLTIDGIYYVBRCA, Uterine Cancer61FLQGYQLHLUrinary Bladder Cancer, Uterine Cancer, Gallbladder Cancer and Bile Duct Cancer, NHL, HNSCC63YLLPSGGSVTLGallbladder Cancer and Bile Duct Cancer, HNSCC64YAAPGGLIGVNSCLC, SCLC, CLL, BRCA, Urinary Bladder Cancer, Uterine Cancer, AML, NHL, HNSCC65LKVNQGLESLMelanoma, Gallbladder Cancer and Bile Duct Cancer, AML, NHL66FLDENIGGVAVMelanoma, Urinary Bladder Cancer, Uterine Cancer, Gallbladder Cancer and Bile Duct Cancer, AML, NHL, HNSCC67TLLAEALVTVSCLC69HNSCC71GILARIASVAML, NHL72SLLELDGINLBRCA, Uterine Cancer73NIFDLQIYVBRCA75GLLEVMVNLGallbladder Cancer and Bile Duct Cancer76ILIDSIYKVUterine Cancer77ILVEADGAWVVBRCA, Uterine Cancer, AML, NHL78CLL, Melanoma, Urinary Bladder Cancer, AML, HNSCC79SLFIGEKAVLLCLL, BRCA, Melanoma, Gallbladder Cancer and Bile Duct Cancer, AML, NHL, HNSCC80FLYDNLVESLCLL, NHL81FLFSQLQYLGallbladder Cancer and Bile Duct Cancer, AML82FLSSVTYNLMelanoma83ILAPTVMMIMelanoma84VTFGEKLLGVMelanoma88FLLVGDLMAVMelanoma91IMQDFPAEIFLCLL, BRCA, Melanoma, Gallbladder Cancer and Bile Duct Cancer, AML, NHL, HNSCC92YLIPFTGIVGLCLL, AML, NHL, HNSCC93LLQAIKLYLUrinary Bladder Cancer, Gallbladder Cancer and Bile Duct Cancer94YLIDIKTIAISCLC, Melanoma, Urinary Bladder Cancer97SLINGSFLVCLL, BRCA, Urinary Bladder Cancer, Uterine Cancer, Gallbladder Cancer and Bile Duct Cancer98LIIDQADIYLCLL, Urinary Bladder Cancer, Gallbladder Cancer and Bile Duct Cancer, AML, NHL100YLLSTNAQLUrinary Bladder Cancer102YLFESEGLVLCLL, Melanoma103TLAEEVVALMelanoma, HNSCC104STMEQNFLLSCLC, BRCA, Melanoma, Gallbladder Cancer and Bile Duct Cancer, HNSCC105LLLEHSFEIUrinary Bladder Cancer, Gallbladder Cancer and Bile Duct Cancer, NHL, HNSCC107FLQPVDDTQHLUterine Cancer, Gallbladder Cancer and Bile Duct Cancer108ALFPGVALLLAMelanoma111YVWGFYPAEVCLL, Uterine Cancer, NHL117ILPDGEDFLAVCLL, BRCA, Uterine Cancer, NHL119FLYIGDIVSLCLL, Melanoma120ALLGIPLTLVUterine Cancer123NLWDLTDASVVNSCLC, BRCA, Melanoma, Esophageal Cancer, Uterine Cancer, Gallbladder Cancer and Bile Duct Cancer, HNSCC124ALYETELADACLL, Uterine Cancer, AML, NHL126VLAYFLPEACLL, BRCA, Urinary Bladder Cancer, Gallbladder Cancer and Bile Duct Cancer, AML, NHL, HNSCC127KIGDEPPKVBRCA, Melanoma, Urinary Bladder Cancer, Gallbladder Cancer and Bile Duct Cancer, HNSCC128YLFDDPLSAVCLL, BRCA, Uterine Cancer, Gallbladder Cancer and Bile Duct Cancer, AML, NHL, HNSCC129GLLDGGVDILLHNSCC131FVPPVTVFPSLUterine Cancer132LLVEQPPLAGVCLL, Melanoma134YLQELIFSVCLL, HNSCC137TLVLTLPTVSCLC, CLL, Urinary Bladder Cancer, Uterine Cancer, Gallbladder Cancer and Bile Duct Cancer, AML, NHL, HNSCC138YQYPRAILSVNSCLC, AML139SCLC, CLL, Urinary Bladder Cancer, Uterine Cancer, Gallbladder Cancer and Bile Duct Cancer, NHL, HNSCC140YMDAPKAALMelanoma, AML141YLDFSNNRLCLL144YIMEPSIFNTLCLL, BRCA146SLATAGDGLIELBRCA147SLLEAVSFLGallbladder Cancer and Bile Duct Cancer, AML, HNSCC148ALNPEIVSVSCLC, CLL, Melanoma, NHL, HNSCC150RLWEEGEELELUterine Cancer, Gallbladder Cancer and Bile Duct Cancer, HNSCC151KILQQLVTLBRCA, Melanoma, Gallbladder Cancer and Bile Duct Cancer152ILFEDIFDVBRCA, Gallbladder Cancer and Bile Duct Cancer153FLIANVLYLHNSCC154ALDDGTPALUterine Cancer155RVANLHFPSVCLL, HNSCC157SLNDEVPEVBRCA, Melanoma, Urinary Bladder Cancer, Gallbladder Cancer and Bile Duct Cancer, NHL, HNSCC159GLVGNPLPSVBRCA160FLFDEEIEQIBRCA161ALLEGVNTVAML163ALDEMGDLLQLBRCA, Gallbladder Cancer and Bile Duct Cancer, HNSCC164ALLPQPKNLTVMelanoma166YLNHLEPPVBrain Cancer, CLL, BRCA, AML, NHL167KVLEVTEEFGVBRCA, Urinary Bladder Cancer170RLQETLSAAUrinary Bladder Cancer, AML171LLLPLQILLHNSCC172VLYSYTIITVSCLC, CLL, Uterine Cancer, NHL173LLDSASAGLYLSCLC, Uterine Cancer, AML, NHL174ALAQYLITASCLC, BRCA, Melanoma, Gallbladder Cancer and Bile Duct Cancer175YLFENISQLEsophageal Cancer, Urinary Bladder Cancer, HNSCC176Urinary Bladder Cancer, Gallbladder Cancer and Bile Duct Cancer177YLLPEEYTSTLNHL, HNSCC178ALTEIAFVVSCLC, CLL, BRCA, Melanoma, Uterine Cancer179KVLNELYTVCRC, BRCA, Melanoma, Uterine Cancer180SCLC182MLLEAPGIFLCLL183FGLDLVTELCLL, Urinary Bladder Cancer, Uterine Cancer, AML, NHL, HNSCC184YLMDINGKMWLCLL, Uterine Cancer, Gallbladder Cancer and Bile Duct Cancer, NHL185FLIDDKGYTLHNSCC186TLFFQQNALPC, NHL, HNSCC187RQISIRGIVGVNSCLC, Urinary Bladder Cancer, Uterine Cancer, AML, HNSCC188GLFPVTPEAVUterine Cancer190FLSSLTETIBRCA, Uterine Cancer, Gallbladder Cancer and Bile Duct Cancer191LLQEGQALEYVUterine Cancer, Gallbladder Cancer and Bile Duct Cancer192KMLDGASFTLBRCA193QLLDADGFLNVSCLC, NHL194ALPLFVITVAML, HNSCC195GLFADLLPRLPC, Uterine Cancer, AML, HNSCC197ALGPEGGRVUterine Cancer198KTINKVPTVSCLC, Brain Cancer, CRC, Urinary Bladder Cancer, Uterine Cancer, HNSCC199ALQDVPLSSVSCLC, Urinary Bladder Cancer201RLVDYLEGISCLC, Uterine Cancer, Gallbladder Cancer and Bile Duct Cancer, AML205SLYPGTETMGLAML206NSCLC, SCLC, BRCA, Uterine Cancer, HNSCC207GLTSTNAEVAML209KLIESKHEVMelanoma, Uterine Cancer210LLLNAVLTVSCLC, AML, NHL211LLWPGAALLCLL, AML, NHL214FLLDLDPLLLBrain Cancer, CRC, CLL, Urinary Bladder Cancer217ALIHPVSTVBRCA, Urinary Bladder Cancer, Uterine Cancer, Gallbladder Cancer and Bile Duct Cancer218SALEELVNVGC224TLIDAQWVLHNSCC226MLYVVPIYLSCLC, Melanoma, AML, NHL227ALMNTLLYLUterine Cancer, AML, HNSCC228AMQEYIAVVPC, Melanoma, HNSCC229RLPGPLGTVBRCA, Melanoma, Gallbladder Cancer and Bile Duct Cancer230ILVDWLVEVEsophageal Cancer, Gallbladder Cancer and Bile Duct Cancer, AML, NHL, HNSCC233VLSETLYELBRCA, HNSCC234Brain Cancer, Urinary Bladder Cancer, Gallbladder Cancer and Bile Duct Cancer, HNSCC235YLNDLHEVLLNSCLC, Urinary Bladder Cancer236GLLEAKVSLGallbladder Cancer and Bile Duct Cancer237ALLEASGTLLLBRCA, AML238YLISFQTHICLL242AIAYILQGVRCC, CRC, CLL, Melanoma, Uterine Cancer, AML, NHL, HNSCC243LLLNELPSVSCLC, BRCA, Melanoma, Urinary Bladder Cancer, Gallbladder Cancer and Bile Duct Cancer, AML, HNSCC244SLFGGTEITIUterine Cancer246LLWEVVSQLBRCA247VLLPNDLLEKVMelanoma248FLFPNQYVDVCLL, BRCA249LLDGFLVNVCLL, Melanoma, NHL250ALSEEGLLVYLBRCA, Melanoma252LLIGTDVSLCLL, NHL256FLPPEHTIVYICLL, Uterine Cancer257SI FSAFLSVMelanoma, Gallbladder Cancer and Bile Duct Cancer, AML, NHL258ELAERVPAICLL, Urinary Bladder Cancer, Gallbladder Cancer and Bile Duct Cancer, AML, NHL, HNSCC259TLMRQLQQVUterine Cancer260AML261YVLEFLEEIRCC, CLL, BRCA262LLWGDLIWLCRC, PrC, CLL, Melanoma, AML263LLVSNLDFGVCRC, CLL, Urinary Bladder Cancer, AML, NHL264SLQEQLHSVUterine Cancer266KITDTLIHLUterine Cancer267ALQDFLLSVNSCLC, SCLC, CRC, BRCA, Melanoma, Urinary Bladder Cancer, AML, NHL, HNSCC268IAGPGLPDLHCC, Uterine Cancer, NHL269RVLEVGALQAVCLL270LLLDEEGTFSLCLL, BRCA, Melanoma, NHL271LVYPLEL YPAGallbladder Cancer and Bile Duct Cancer274SLLFSLFEAUrinary Bladder Cancer, AML, NHL275YLVYILNELCLL, Melanoma, NHL276ALFTFSPLTVUterine Cancer277LLPPLESLATVCLL, BRCA, Urinary Bladder Cancer, HNSCC278QLLDVVLTIHNSCC280VLPDPEVLEAVGallbladder Cancer and Bile Duct Cancer, NHL, SCLC281ILRESTEELMelanoma282LLADVVPTTCLL, Uterine Cancer, AML, NHL, HNSCC283Esophageal Cancer, Urinary Bladder Cancer, Uterine Cancer, NHL284ILLSQTTGVCLL, Urinary Bladder Cancer, AML, HNSCC285QLLHVGVTVCLL, Melanoma, Urinary Bladder Cancer, AML, NHL286YLFPGIPELNSCLC, CLL, Melanoma, AML, NHL, HNSCC289VLLEIEDLQVCLL, NHL290GLLDLNNAILQLUterine Cancer292LLWEAGSEAMelanoma293GLGELQELYLAML, NHL294ILDPFQYQLMelanoma, Gallbladder Cancer and Bile Duct Cancer, NHL, HNSCC297VLADIELAQACLL298VMITKLVEVGallbladder Cancer and Bile Duct Cancer300ALLGQTFSLAML, HNSCC301FLVEDLVDSLCLL, BRCA, Melanoma, Uterine Cancer, AML302ALLQEGEVYSAMelanoma, Urinary Bladder Cancer303AILPQLFMVMelanoma304MTLGQIYYLNSCLC, SCLC, CRC, HCC, BRCA, Melanoma, Urinary Bladder Cancer, Uterine Cancer, Gallbladder Cancer and Bile Duct Cancer, AML, HNSCC306ALVNVQIPLMelanoma, Uterine Cancer307ALPVSLPQICLL, BRCA, Melanoma, AML, NHL, HNSCC308SQYSGQLHEVCLL309GLFDGVPTTASCLC, Urinary Bladder Cancer, Gallbladder Cancer and Bile Duct Cancer, HNSCC310FLVDTPLARAGallbladder Cancer and Bile Duct Cancer, HNSCC311RLYTGMHTVSCLC, BRCA, NHL, HNSCC312IISDLTIALNSCLC, CRC, BRCA, Melanoma, Esophageal Cancer, Uterine Cancer, Gallbladder Cancer and Bile Duct Cancer, NHL, HNSCC314ALIAEGIALVUterine Cancer317SLAALVVHVNSCLC, Gallbladder Cancer and Bile Duct Cancer, HNSCC318GLINTGVLSVSCLC, CLL, NHL, HNSCC319SLEPQIQPVHCC, CLL, BRCA, Melanoma, Gallbladder Cancer and Bile Duct Cancer, AML, HNSCC320KMFEFVEPLLSCLC, Brain Cancer, BRCA, Melanoma, Urinary Bladder Cancer, Uterine Cancer, Gallbladder Cancer and Bile Duct Cancer, AML, HNSCC321CLL322TLMTSLPALCLL, BRCA, Melanoma, Uterine Cancer, Gallbladder Cancer and Bile Duct Cancer, AML, NHL323IQIGEETVITVCRC, CLL, BRCA324FLYDEIEAEVCLL325CLL, BRCA, Melanoma, Uterine Cancer, NHL326FLPEALDFVCLL, AML, NHL327GLAPFTEGISFVNSCLC, Gallbladder Cancer and Bile Duct Cancer328ALNDQVFEIAML330QLALKVEGVCLL, Urinary Bladder Cancer, AML, NHL, HNSCC331KVDTVWVNVCLL, Gallbladder Cancer and Bile Duct Cancer, HNSCC332YLISELEAARCC, GC, BRCA, Melanoma333FLPDANSSVHCC, Melanoma334TLTKVLVALCLL335YSLSSVVTVHNSCC336ILLTAIVQVMelanoma337HLLSELEAAPYLCLL338SVLEDPVHAVBRCA, Esophageal Cancer, Uterine Cancer, Gallbladder Cancer and Bile Duct Cancer, NHL339Gallbladder Cancer and Bile Duct Cancer340ALLSMTFPLSCLC, AML341SQIALNEKLVNLUrinary Bladder Cancer342HIYDKVMTVEsophageal Cancer, Gallbladder Cancer and Bile Duct Cancer343SLLEVNEESTVCLL345VIWKALIHLNSCLC, Melanoma, NHL346LLDSKVPSVHNSCC347Uterine Cancer, HNSCC348ILLDVKTRLMelanoma, Gallbladder Cancer and Bile Duct Cancer, HNSCC350ALLDVTHSELTVBRCA, HNSCC351SLIPNLRNVCRC, Esophageal Cancer352SLLELLHIYVCLL, AML354LILEGVDTVBRCA, Urinary Bladder Cancer, Uterine Cancer, NHL356KLLGKLPELMelanoma, Urinary Bladder Cancer358ALDEYTSELUrinary Bladder Cancer359YLLPESVDLCLL, Uterine Cancer, NHL, HNSCC360ALDJGASLLHLHNSCC361ALYELEGTTVNSCLC, SCLC, CLL, BRCA, Urinary Bladder Cancer, Uterine Cancer, Gallbladder Cancer and Bile Duct Cancer, HNSCC362TLYGLSVLLAML363KVLDVSDLESVNSCLC, Esophageal Cancer, Urinary Bladder Cancer, Gallbladder Cancer and Bile Duct Cancer, HNSCC364LLQNEQFELUrinary Bladder Cancer, Uterine Cancer, Gallbladder Cancer and Bile Duct Cancer365CLL, Urinary Bladder Cancer, NHL366CLL, Urinary Bladder Cancer, AML, NHL367SLQNHNHQLNSCLC, CRC, Melanoma, Esophageal Cancer, AML, NHL, HNSCC370SLLQDLVSVBRCA, Melanoma, Gallbladder Cancer and Bile Duct Cancer, HNSCC372TMLLNIPLVCLL, Gallbladder Cancer and Bile Duct Cancer, AML, NHL374FLLQQHLISACLL375SLTETIEGVGallbladder Cancer and Bile Duct Cancer376AMFESSQNVLLCLL379IMEGTLTRVRCC, CLL, Melanoma, Urinary Bladder Cancer, NHL380TLIEDEIATISCLC, Melanoma, Uterine Cancer, Gallbladder Cancer and Bile Duct Cancer, AML, HNSCC381FIDEAYVEVGC, CLL, Melanoma, NHL382ALQNYIKEABRCA384ILFANPNIFVCLL, Urinary Bladder Cancer, Uterine Cancer, NHL385SLLEQGLVEABRCA, AML, HNSCC386ILFRYPLTIMelanoma, Uterine Cancer, AML387ALFQATAEVSCLC, Melanoma, Urinary Bladder Cancer, Uterine Cancer, Gallbladder Cancer and Bile Duct Cancer, AML, NHL, HNSCC388SLTIDGIRYVBrain Cancer389LLADVTHLLMelanoma, AML393CRC, Gallbladder Cancer and Bile Duct Cancer, HNSCC394LLAVIGGLVYLBRCA395ALALGGIAVVCLL, NHL, HNSCC396ALLPDLPALSCLC, Gallbladder Cancer and Bile Duct Cancer, AML, NHL, HNSCC397YLFGERLLECCLL, Uterine Cancer398KLLEEDGTIITLBRCA, Esophageal Cancer, Gallbladder Cancer and Bile Duct Cancer400SLLTEQDLWTVCLL401ILLDDTGLAYICLL, Urinary Bladder Cancer, Gallbladder Cancer and Bile Duct Cancer, NHL403KLYDRILRVBRCA407YLMDLINFLAML408VLDDSIYLVCLL, Uterine Cancer, NHL409LLDAMNYHLCLL, NHL411LLAHLSPELMelanoma412YLDDLNEGVYIBRCA413TLLEKVEGCMelanoma414YVDDIFLRVGC, Melanoma415LLDKVYSSVBrain Cancer, CLL, BRCA, Urinary Bladder Cancer, Uterine Cancer, Gallbladder Cancer and Bile Duct Cancer, AML, NHL, HNSCC416VLSDIIQNLSVCLL, NHL417NLQDTEYNLCLL, AML, NHL418ALAELENIEVCLL, BRCA, Urinary Bladder Cancer, Gallbladder Cancer and Bile Duct Cancer, HNSCC419GQYEGKVSSVBRCA420FMYDTPQEVGallbladder Cancer and Bile Duct Cancer422FLPKLLLLAMelanoma423GLDGPPPTVNHL424TLLDALYEIMelanoma, Gallbladder Cancer and Bile Duct Cancer, AML, HNSCC425FLYEKSSQVSCLC426RLADKSVLVBRCA, AML427ALLPLSPYLGallbladder Cancer and Bile Duct Cancer428KLGHTDILVGVCLL, Uterine Cancer, HNSCC429GLVNDLARVSCLC, BRCA, Melanoma, Gallbladder Cancer and Bile Duct Cancer, NHL430HLYSSIEHLTTSCLC, BRCA, Urinary Bladder Cancer, NHL431SLVNVVPKLCLL, BRCA, Urinary Bladder Cancer, Gallbladder Cancer and Bile Duct Cancer, AML, NHL433AMLNEPWAVBRCA, Melanoma, Urinary Bladder Cancer, HNSCC434KVSNSGITRVEsophageal Cancer, HNSCC435WLMPVIPALMelanoma, Gallbladder Cancer and Bile Duct Cancer, AML436HLAEVSAEVNSCLC, SCLC, CLL, BRCA, Melanoma, Urinary Bladder Cancer, Gallbladder Cancer and Bile Duct Cancer, AML, NHL, HNSCC438KLLPLAGLYLCLL, BRCA, Melanoma, Uterine Cancer, Gallbladder Cancer and Bile Duct Cancer, AML, HNSCC439YLLQEIYGIAML440ALADGVTMQVSCLC, BRCA, Melanoma, Uterine Cancer441ALLENPKMELUrinary Bladder Cancer443GLWEIENNPTVGallbladder Cancer and Bile Duct Cancer444GLLRDEALAEVCLL, BRCA, Urinary Bladder Cancer, Uterine Cancer, AML, NHL, HNSCC445GLYQDPVTLUterine Cancer, AML446QLIPALAKVBrain Cancer447QLVPALAKVBRCA, Melanoma, HNSCC448NLLETKLQLCLL, Melanoma, NHL, HNSCC450FMIDASVHPTLCLL, Urinary Bladder Cancer, HNSCC451LLLLDTVTMQVMelanoma, HNSCC452ILLEHGADPNLCLL, Urinary Bladder Cancer, NHL453KLLEATSAVSCLC, BRCA, Uterine Cancer, Gallbladder Cancer and Bile Duct Cancer, AML, NHL, HNSCC454KLPPPPPQABRCA, AML, HNSCC455SLLKEPQKVQLCLL, Melanoma, HNSCC456LLIGHLERVBRCA, AML, NHL, HNSCC458SLIDKLYNISCLC, Brain Cancer, Melanoma, Urinary Bladder Cancer, AML, HNSCC459ALITEVVRLSCLC, CLL, AML, NHL461VMFRTPLASVBRCA, Urinary Bladder Cancer, Uterine Cancer, NHL462KLAKQPETVNHL463CLL, BRCA, Urinary Bladder Cancer, Uterine Cancer, Gallbladder Cancer and Bile Duct Cancer, NHL, HNSCC464ALNDCIYSVHNSCC465QLCDLNAELSCLC, Melanoma, AML, HNSCC466VLIANLEKLUrinary Bladder Cancer, NHL467FLAKDFNFLNSCLC, Melanoma, Urinary Bladder Cancer, Gallbladder Cancer and Bile Duct Cancer, NHL, HNSCC468YLRSVGDGETVUterine Cancer469YLASDEITTVCLL470MLQDSIHVVBRCA472KLLEVSDDPQVHNSCC473AMATESILHFAAML474BRCA476ALMERTGYSMVUterine Cancer477ALLPASGQIALCLL, BRCA, Melanoma, Gallbladder Cancer and Bile Duct Cancer, HNSCC478YLLHEKLNLNHL479SLFGNSGILENVMelanoma, Uterine Cancer, AML, HNSCC480ALLEDSCHYLHNSCC481GLIEDYEALLMelanoma, AML482SLAPAGIADAMelanoma, Uterine Cancer, HNSCC483ALTDIVSQVNSCLC, SCLC, BRCA, Uterine Cancer, Gallbladder Cancer and Bile Duct Cancer, HNSCC484SLIEKVTQLSCLC, CRC, CLL, BRCA, Melanoma, Esophageal Cancer, Urinary Bladder Cancer, Uterine Cancer, AML, NHL486AVMESIQGVCLL487LLINSVFHVUrinary Bladder Cancer, NHL488FLAEDPKVTLCLL, BRCA, Melanoma, Urinary Bladder Cancer, NHL489KMWEELPEVVCLL, Esophageal Cancer, Urinary Bladder Cancer, AML, NHL, HNSCC490FLLQHVQELCLL, NHL491GLNDRSDAVBRCA, AML, HNSCC492BRCA493CLL, Melanoma, Urinary Bladder Cancer, Uterine Cancer, Gallbladder Cancer and Bile Duct Cancer, HNSCC495FIFSEKPVFVMelanoma, AML, NHL496FLVEKQPPQVCLL, NHL497GLLEKLTAISCLC, CLL, BRCA, Melanoma, Urinary Bladder Cancer, AML, NHL498KLWTGGLDNTVNSCLC, Brain Cancer, CLL, Urinary Bladder Cancer, Uterine Cancer, NHL500SLMEDQVLQLCLL, AML501LLDPNVKSIFVBRCA, Urinary Bladder Cancer, HNSCC502RLLAQVPGLMelanoma, Uterine Cancer, Gallbladder Cancer and Bile Duct Cancer, AML, NHL503SLNHFTHSVHCC, CLL, Urinary Bladder Cancer, AML, NHL, HNSCC504GLSDGNPSLCLL, Uterine Cancer505SLAPGDVVRQVBRCA, Urinary Bladder Cancer, HNSCC506KLLGKVETACLL, NHL507KLIDDQDISISLCLL, Urinary Bladder Cancer, NHL508ILAQEQLVVGVSCLC, Gallbladder Cancer and Bile Duct Cancer509FLFDTKPLIVCLL510KLYSVVSQLNHL511FLDPYCSASVSCLC, Uterine Cancer512SLSEIVPCLUterine Cancer, AML, HNSCC513SLWPSPEQLMelanoma, AML, NHL, HNSCC514ILVDWLVQVBRCA, Gallbladder Cancer and Bile Duct Cancer, AML, NHL, HNSCC517LLMPIPEGLTLUrinary Bladder Cancer, Uterine Cancer, HNSCC518KLNAEVACVBRCA, Melanoma, Urinary Bladder Cancer, Uterine Cancer, HNSCC519GLLHLTLLLSCLC, Gallbladder Cancer and Bile Duct Cancer, AML, HNSCC520LAVHPSGVALSCLC, CLL, BRCA, Gallbladder Cancer and Bile Duct Cancer521MLLTKLPTIBrain Cancer, CLL, Uterine Cancer, AML, NHL, HNSCC522TLWYRSPEVMelanoma523YQIPRTFTLCLL, AML524ALIENLTHQICLL, Melanoma, NHL525VLLEAGEGLVTINSCLC, SCLC, CLL, Urinary Bladder Cancer, Uterine Cancer, NHL, HNSCC526RLAEVGQYEQVUterine Cancer, NHL528SVAEGRALMSVNSCLC, CLL, BRCA, Urinary Bladder Cancer, Gallbladder Cancer and Bile Duct Cancer, HNSCC529LLADELITVSCLC, CLL, HNSCC530VMYADIGGMDICLL, Urinary Bladder Cancer, Uterine Cancer, Gallbladder Cancer and Bile Duct Cancer, HNSCC531YTLPIASSIRLBRCA532ALNNLLHSLMelanoma, Esophageal Cancer, Urinary Bladder Cancer, Uterine Cancer, Gallbladder Cancer and Bile Duct Cancer, AML, NHL533RMVAEIQNVCLL, NHL534HLANIVERLCLL535KLIAQNLELAML, NHL, HNSCC536YLVEGRFSVCLL, Urinary Bladder Cancer538LLLAHIIALBRCA, Urinary Bladder Cancer, Uterine Cancer539ALFDAQAQVMelanoma, AML540ALI PETTTLTVNHL541SMLEPVPELGallbladder Cancer and Bile Duct Cancer542RVWDISTVSSVNSCLC, CLL, BRCA543BRCA544LLWDVPAPSLCLL, Uterine Cancer, HNSCC545LLADLLHNVBRCA546VMIAGKVAVVSCLC, Urinary Bladder Cancer, HNSCC547TLDITPHTVEsophageal Cancer548ALWENPESGELBRCA549AMLENASDIKLSCLC, CLL, Urinary Bladder Cancer550FLYDEIEAEVNLCLL551KLYESLLPFACLL, BRCA, Urinary Bladder Cancer, Gallbladder Cancer and Bile Duct Cancer, AML, NHL, HNSCC552GLLDLPFRVGVCLL, AML, NHL553SLLNQDLHWSLCLL554LLMPSSEDLLLCLL, Melanoma, HNSCC555YVLEGLKSVCRC, CLL, Esophageal Cancer, Urinary Bladder Cancer, Uterine Cancer, NHL, HNSCC556FLTDLEDLTLCLL, Uterine Cancer, NHL557KLYDDMIRLBrain Cancer, NHL558GLLENIPRVCLL, BRCA, Melanoma, AML, NHL559VTVPPGPSLCLL, AML560CLL, Urinary Bladder Cancer, Uterine Cancer, Gallbladder Cancer and Bile Duct Cancer, NHL, HNSCC561YLQLTQSELCLL, NHL, HNSCC563WLLPYNGVTVCLL, Uterine Cancer, NHL565ALQETPTSVBRCA, Gallbladder Cancer and Bile Duct Cancer566VIADGGIQNVCRC, CLL, BRCA, Urinary Bladder Cancer, Gallbladder Cancer and Bile Duct Cancer, NHL567SLLPLDDIVRVCLL, BRCA568TLYDIAHTPGVCLL, Urinary Bladder Cancer, NHL, HNSCC570ALANQIPTVHCC571LLLTTIPQIMelanoma572ALADLIEKELSVCLL, NHL573ILVANAIVGVCLL, SCLC, Urinary Bladder Cancer575YLISQVEGHQVNSCLC, SCLC, BRCA, Urinary Bladder Cancer, HNSCC577VMFEDGVLMRLSCLC, CLL, Urinary Bladder Cancer, AML, NHL, HNSCC578FLDPGGPMMKLSCLC, CLL, BRCA, Urinary Bladder Cancer, HNSCC579NLMEMVAQLSCLC, CLL, Melanoma, Urinary Bladder Cancer, NHL580LLMENAERVCLL, Esophageal Cancer, Urinary Bladder Cancer, Uterine Cancer, NHL, HNSCC581RLWNETVELAML, NHL582TLCDVILMVMelanoma583ILANDGVLLAACLL, BRCA, Urinary Bladder Cancer, Uterine Cancer, Gallbladder Cancer and Bile Duct Cancer, NHL, HNSCC585Melanoma586KLKPGDLVGVUterine Cancer587VMNDRLYAICLL, NHL588SLLPLSHLVCLL, Gallbladder Cancer and Bile Duct Cancer, AML, NHL, HNSCC589KLYPQLPAEICLL, BRCA, Urinary Bladder Cancer590SLIEKLWQTUterine Cancer, AML591SMAELDIKLAML, HNSCC594IMLKGDNITLUterine Cancer595VLLSIYPRVCLL, Urinary Bladder Cancer, Gallbladder Cancer and Bile Duct Cancer596CLL, NHL597KLLEGQVIQLCLL, Melanoma, Gallbladder Cancer and Bile Duct Cancer, AML598FLFPHSVLVCRC599YLLNDASLISVSCLC600ALAAPDIVPALCLL, Uterine Cancer, AML601SAFPFPVTVCLL, Gallbladder Cancer and Bile Duct Cancer, AML603FLIEPEHVNTVCLL604SILDRDDIFVCLL, Melanoma, NHL605KLYEAVPQLGallbladder Cancer and Bile Duct Cancer, HNSCC607RLYSGISGLELCLL, Melanoma, AML, NHL609ALWKQLLELCRC, Esophageal Cancer, Uterine Cancer611YLLDDGTLVVUterine Cancer612YLYNEGLSVBRCA, Urinary Bladder Cancer, AML, NHL, HNSCC613RLLPPGAVVAVCLL, BRCA, Urinary Bladder Cancer, Gallbladder Cancer and Bile Duct Cancer, HNSCC614LLLPDQPPYHLCLL615VLPPDTDPAMelanoma, Esophageal Cancer616VLIDEVESLCRC, Uterine Cancer, Gallbladder Cancer and Bile Duct Cancer, AML, NHL, HNSCC619ALQDRVPLABRCA, Gallbladder Cancer and Bile Duct Cancer620KLLNKIYEABRCA, AML621VLMDRLPSLLCLL622Urinary Bladder Cancer, AML, NHL623YLVEDIQHINSCLC, PC624FLQEEPGQLLCLL, Urinary Bladder Cancer, Uterine Cancer, Gallbladder Cancer and Bile Duct Cancer, NHL625VVLEGASLETVCLL, Urinary Bladder Cancer626LLMATILHLCLL, AML, NHL, HNSCC627KLLETELLQEICLL, Urinary Bladder Cancer628KLWEFFQVDVMelanoma629HLLNESPMLRCC, PC, BRCA, Melanoma, Uterine Cancer, Gallbladder Cancer and Bile Duct Cancer, AML630LLSHVIVALCLL, Gallbladder Cancer and Bile Duct Cancer, NHL631FLDVFLPRVSCLC, CLL, NHL632YLIPDIDLKLCLL, AML, NHL, HNSCC633ALSRVSVNVCLL634VVAEFVPLICLL, AML, NHL635SLDSTLHAVSCLC, Melanoma, Urinary Bladder Cancer, Uterine Cancer, Gallbladder Cancer and Bile Duct Cancer636LLTEIRAVVCLL, NHL637SIYGGFLLGVUrinary Bladder Cancer, Gallbladder Cancer and Bile Duct Cancer, HNSCC638KLIQESPTVGallbladder Cancer and Bile Duct Cancer, AML639SLFQNCFELCLL, Melanoma, Uterine Cancer, NHL, HNSCC NSCLC= non-small cell lung cancer, SCLC= small cell lung cancer, RCC= kidney cancer, CRC= colon or rectum cancer, GC= stomach cancer, HCC= liver cancer, PC= pancreatic cancer, PrC= prostate cancer, BRCA=breast cancer, NHL= non-Hodgkin lymphoma, AML= acute myeloid leukemia, CLL= chronic lymphocytic leukemia, HNSCC= head and neck squamous cell carcinoma.

[0040] Thus, disclosed is the use of at least one peptide according to any one of SEQ ID No. 1, 11, 17, 27, 45, 57, 58, 61, 62, 65, 72, 74, 79, 84, 97, 98, 104, 105, 125, 126, 143, 150, 157, 161, 167, 176, 179, 183, 184, 195, 198, 201, 204, 213, 217, 222, 228, 234, 248, 263, 264, 268, 285, 287, 303, 313, 319, 323, 333, 335, 338, 343, 347, 348, 355, 356, 359, 373, 385, 394, 395, 403, 415, 421, 427, 428, 429, 430, 431, 434, 441, 443, 444, 446, 447, 450, 454, 456, 457, 458, 459, 463, 474, 477, 479, 480, 486, 489, 492, 493, 497, 501, 503, 506, 514, 517, 521, 526, 538, 539, 540, 541, 545, 554, 558, 568, 573, 576, 578, 579, 589, 595, 597, 599, 602, 607, 610, 613, 616, 627, 632, 635, and 637 for the - in one preferred embodiment combined - treatment of NSCLC.

[0041] Then, another aspect of the present invention relates to the use of the peptide according to the present invention for the - preferably combined - treatment of a proliferative disease selected from the group of ovarian cancer, non-small cell lung cancer, small cell lung cancer, kidney cancer, brain cancer, colon or rectum cancer, stomach cancer, liver cancer, pancreatic cancer, prostate cancer, leukemia, breast cancer, Merkel cell carcinoma, melanoma, esophageal cancer, urinary bladder cancer, uterine cancer, gallbladder cancer, bile duct cancer.

[0042] The present invention further relates to the peptide according to the present invention, wherein said peptide includes non-peptide bonds.

[0043] The present invention further relates to the peptide according to the present invention, wherein said peptide is fused to the N-terminal amino acids of the HLA-DR antigen-associated invariant chain (Ii).

[0044] The present invention further relates to a nucleic acid, encoding the peptide according to the present invention. The present invention further relates to the nucleic acid according to the present invention that is DNA, cDNA, PNA, RNA or combinations thereof.

[0045] The present invention further relates to an expression vector expressing a nucleic acid according to the present invention.

[0046] The present invention further relates to a peptide according to the present invention, a nucleic acid according to the present invention or an expression vector according to the present invention for use in the treatment of diseases and in medicine, in particular in the treatment of cancer.

[0047] The present invention further relates to antibodies that are specific against complexes of the peptide according to the present invention with MHC, and methods of making these.

[0048] The present invention further relates to T-cell receptors (TCRs), in particular soluble TCR (sTCRs) and cloned TCRs engineered into autologous or allogeneic T cells, and methods of making these, as well as NK cells or other cells bearing said TCR or cross-reacting with said TCRs.

[0049] The antibodies and TCRs are additional embodiments of the immunotherapeutic use of the peptide according to the invention at hand.

[0050] The present invention further relates to a host cell comprising a nucleic acid according to the present invention or an expression vector as described before. The present invention further relates to the host cell according to the present invention that is an antigen presenting cell, and preferably is a dendritic cell. The present invention further relates to a method for producing a peptide according to the present invention, said method comprising culturing the host cell according to the present invention, and isolating the peptide from said host cell or its culture medium.

[0051] The present invention further relates to said method according to the present invention, wherein the antigen is loaded onto class I MHC molecules expressed on the surface of a suitable antigen-presenting cell or artificial antigen-presenting cell by contacting a sufficient amount of the antigen with an antigen-presenting cell.

[0052] The present invention further relates to the method according to the present invention, wherein the antigen-presenting cell comprises an expression vector expressing said peptide containing SEQ ID No. 11.

[0053] The present invention further relates to activated T cells, produced by the method according to the present invention, wherein said T cell selectively recognizes a cell which expresses a polypeptide comprising an amino acid sequence according to the present invention.

[0054] The present invention discloses a method of killing target cells in a patient which target cells aberrantly express a polypeptide comprising any amino acid sequence according to the present invention, the method comprising administering to the patient an effective number of T cells as produced according to the present invention.

[0055] The present invention further relates to the use of any peptide as described, the nucleic acid according to the present invention, the expression vector according to the present invention, the cell according to the present invention, the activated T lymphocyte, the T cell receptor or the antibody according to the present invention as a medicament or in the manufacture of a medicament. Preferably, said medicament is active against cancer.

[0056] Preferably, said medicament is a cellular therapy, a vaccine or a protein based on a soluble TCR or antibody.

[0057] The present invention further relates to a use according to the present invention, wherein said cancer cells are ovarian cancer, non-small cell lung cancer, small cell lung cancer, kidney cancer, brain cancer, colon or rectum cancer, stomach cancer, liver cancer, pancreatic cancer, prostate cancer, leukemia, breast cancer, Merkel cell carcinoma, melanoma, esophageal cancer, urinary bladder cancer, uterine cancer, gallbladder cancer, bile duct cancer, and preferably ovarian cancer cells.

[0058] Optionally the antibody carries a further effector function such as an immune stimulating domain or toxin.

[0059] CT45 genes were shown to be potential prognostic biomarkers and therapeutic targets in epithelial ovarian cancer (Zhang et al., 20151). The CT45A1protein which is usually only expressed in testicular germ cells was shown to be also expressed in lung cancer, breast cancer and ovarian cancer (Chen et al., 2009d). CT45A1 was also shown to be associated with poor prognosis and poor outcomes in multiple myeloma (Andrade et al., 2009). CT45A1 was described as gene up-regulating epithelial-mesenchymal transition (EMT) and metastatic genes, promoting EMT and tumor dissemination. Furthermore, CT45A1 was described as being implicated in the initiation or maintenance of cancer stem-like cells, promoting tumorigenesis and malignant progression (Yang et al., 2015a). CT45A1 over-expression in a breast cancer model was shown to result in the up-regulation of various oncogenic and metastatic genes, constitutively activated ERK and CREB signaling pathways and increased tumorigenesis, invasion and metastasis. Silencing of CT45A1 was shown to reduce cancer cell migration and invasion. Thus, CT45A1 may function as a novel proto-oncogene and may be a target for anticancer drug discovery and therapy (Shang et al., 2014).

[0060] CT45A2 was shown to be a novel spliced MLL fusion partner in a pediatric patient with de novo bi-phenotypic acute leukemia and thus might be relevant for leukemogenesis (Cerveira et al., 2010). The cancer / testis antigen family 45 was shown to be frequently expressed in both cancer cell lines and lung cancer specimens (Chen et al., 2005). CT45 genes were shown to be potential prognostic biomarkers and therapeutic targets in epithelial ovarian cancer (Zhang et al., 2015l).

[0061] The cancer / testis antigen family 45 was shown to be frequently expressed in both cancer cell lines and lung cancer specimens (Chen et al., 2005). CT45 genes were shown to be potential prognostic biomarkers and therapeutic targets in epithelial ovarian cancer (Zhang et al., 2015l).

[0062] The cancer / testis antigen family 45 was shown to be frequently expressed in both cancer cell lines and lung cancer specimens (Chen et al., 2005). CT45 genes were shown to be potential prognostic biomarkers and therapeutic targets in epithelial ovarian cancer (Zhang et al., 2015l).DETAILED DESCRIPTION OF THE INVENTION

[0063] Stimulation of an immune response is dependent upon the presence of antigens recognized as foreign by the host immune system. The discovery of the existence of tumor associated antigens has raised the possibility of using a host's immune system to intervene in tumor growth. Various mechanisms of harnessing both the humoral and cellular arms of the immune system are currently being explored for cancer immunotherapy.

[0064] Specific elements of the cellular immune response are capable of specifically recognizing and destroying tumor cells. The isolation of T-cells from tumor-infiltrating cell populations or from peripheral blood suggests that such cells play an important role in natural immune defense against cancer. CD8-positive T-cells in particular, which recognize class I molecules of the major histocompatibility complex (MHC)-bearing peptides of usually 8 to 10 amino acid residues derived from proteins or defect ribosomal products (DRIPS) located in the cytosol, play an important role in this response. The MHC-molecules of the human are also designated as human leukocyte-antigens (HLA).

[0065] As used herein and except as noted otherwise all terms are defined as given below.

[0066] The term "T-cell response" means the specific proliferation and activation of effector functions induced by a peptide in vitro or in vivo. For MHC class I restricted cytotoxic T cells, effector functions may be lysis of peptide-pulsed, peptide-precursor pulsed or naturally peptide-presenting target cells, secretion of cytokines, preferably Interferon-gamma, TNF-alpha, or IL-2 induced by peptide, secretion of effector molecules, preferably granzymes or perforins induced by peptide, or degranulation.

[0067] The term "peptide" is used herein to designate a series of amino acid residues, connected one to the other typically by peptide bonds between the alpha-amino and carbonyl groups of the adjacent amino acids. The peptides are preferably 9 amino acids in length, but can be as short as 8 amino acids in length, and as long as 10, 11, 12, 13, or 14 or longer, and in case of MHC class II peptides (elongated variants of the peptides of the invention) they can be as long as 15, 16, 17, 18, 19 or 20 or more amino acids in length.

[0068] Furthermore, the term "peptide" shall include salts of a series of amino acid residues, connected one to the other typically by peptide bonds between the alpha-amino and carbonyl groups of the adjacent amino acids. Preferably, the salts are pharmaceutical acceptable salts of the peptides, such as, for example, the chloride or acetate (trifluoroacetate) salts. It has to be noted that the salts of the peptides according to the present invention differ substantially from the peptides in their state(s) in vivo, as the peptides are not salts in vivo.

[0069] The term "peptide" shall also include "oligopeptide". The term "oligopeptide" is used herein to designate a series of amino acid residues, connected one to the other typically by peptide bonds between the alpha-amino and carbonyl groups of the adjacent amino acids. The length of the oligopeptide is not critical to the invention, as long as the correct epitope or epitopes are maintained therein. The oligopeptides are typically less than about 30 amino acid residues in length, and greater than about 15 amino acids in length.

[0070] The term "polypeptide" designates a series of amino acid residues, connected one to the other typically by peptide bonds between the alpha-amino and carbonyl groups of the adjacent amino acids. The length of the polypeptide is not critical to the invention as long as the correct epitopes are maintained. In contrast to the terms peptide or oligopeptide, the term polypeptide is meant to refer to molecules containing more than about 30 amino acid residues.

[0071] A peptide, oligopeptide, protein or polynucleotide coding for such a molecule is "immunogenic" (and thus is an "immunogen" within the present invention), if it is capable of inducing an immune response. In the case of the present invention, immunogenicity is more specifically defined as the ability to induce a T-cell response. Thus, an "immunogen" would be a molecule that is capable of inducing an immune response, and in the case of the present invention, a molecule capable of inducing a T-cell response. In another aspect, the immunogen can be the peptide, the complex of the peptide with MHC, oligopeptide, and / or protein that is used to raise specific antibodies or TCRs against it.

[0072] A class I T cell "epitope" requires a short peptide that is bound to a class I MHC receptor, forming a ternary complex (MHC class I alpha chain, beta-2-microglobulin, and peptide) that can be recognized by a T cell bearing a matching T-cell receptor binding to the MHC / peptide complex with appropriate affinity. Peptides binding to MHC class I molecules are typically 8-14 amino acids in length, and most typically 9 amino acids in length.

[0073] In humans there are three different genetic loci that encode MHC class I molecules (the MHC-molecules of the human are also designated human leukocyte antigens (HLA)): HLA-A, HLA-B, and HLA-C. HLA-A*01, HLA-A*02, and HLA-B*07 are examples of different MHC class I alleles that can be expressed from these loci. Table 5: Expression frequencies F of HLA-A*02 and HLA-A*24 and the most frequent HLA-DR serotypes. Frequencies are deduced from haplotype frequencies Gf within the American population adapted from Mori et al. (Mori et al., 1997) employing the Hardy-Weinberg formula F = 1 - (1-Gf) 2< . Combinations of A*02 or A*24 with certain HLA-DR alleles might be enriched or less frequent than expected from their single frequencies due to linkage disequilibrium. For details refer to Chanock et al. (Chanock et al., 2004).AllelePopulationCalculated phenotype from allele frequencyA*02Caucasian (North America)49.1%A*02African American (North America)34.1%A*02Asian American (North America)43.2%A*02Latin American (North American)48.3%DR1Caucasian (North America)19.4%DR2Caucasian (North America)28.2%DR3Caucasian (North America)20.6%DR4Caucasian (North America)30.7%DR5Caucasian (North America)23.3%DR6Caucasian (North America)26.7%DR7Caucasian (North America)24.8%DR8Caucasian (North America)5.7%DR9Caucasian (North America)2.1%DR1African (North) American13.20%DR2African (North) American29.80%DR3African (North) American24.80%DR4African (North) American11.10%DR5African (North) American31.10%DR6African (North) American33.70%DR7African (North) American19.20%DR8African (North) American12.10%DR9African (North) American5.80%DR1Asian (North) American6.80%DR2Asian (North) American33.80%DR3Asian (North) American9.20%DR4Asian (North) American28.60%DR5Asian (North) American30.00%DR6Asian (North) American25.10%DR7Asian (North) American13.40%DR8Asian (North) American12.70%DR9Asian (North) American18.60%DR1Latin (North) American15.30%DR2Latin (North) American21.20%DR3Latin (North) American15.20%DR4Latin (North) American36.80%DR5Latin (North) American20.00%DR6Latin (North) American31.10%DR7Latin (North) American20.20%DR8Latin (North) American18.60%DR9Latin (North) American2.10%A*24Philippines65%A*24Russia Nenets61%A*24:02Japan59%A*24Malaysia58%A*24:02Philippines54%A*24India47%A*24South Korea40%A*24Sri Lanka37%A*24China32%A*24:02India29%A*24Australia West22%A*24USA22%A*24Russia Samara20%A*24South America20%A*24Europe18%

[0074] The peptides as disclosed, preferably when included into a vaccine of the invention as described herein bind to A*02. A vaccine may also include pan-binding MHC class II peptides. Therefore, the vaccine of the invention can be used to treat cancer in patients that are A*02 positive, whereas no selection for MHC class II allotypes is necessary due to the pan-binding nature of these peptides.

[0075] If A*02 peptides as disclosed are combined with peptides binding to another allele, for example A*24, a higher percentage of any patient population can be treated compared with addressing either MHC class I allele alone. While in most populations less than 50% of patients could be addressed by either allele alone, a vaccine comprising HLA-A*24 and HLA-A*02 epitopes can treat at least 60% of patients in any relevant population. Specifically, the following percentages of patients will be positive for at least one of these alleles in various regions: USA 61%, Western Europe 62%, China 75%, South Korea 77%, Japan 86% (calculated from www.allelefrequencies.net).

[0076] In a preferred embodiment, the term "nucleotide sequence" refers to a heteropolymer of deoxyribonucleotides.

[0077] The nucleotide sequence coding for a particular peptide, oligopeptide, or polypeptide may be naturally occurring or they may be synthetically constructed. Generally, DNA segments encoding the peptides, polypeptides, and proteins of this invention are assembled from cDNA fragments and short oligonucleotide linkers, or from a series of oligonucleotides, to provide a synthetic gene that is capable of being expressed in a recombinant transcriptional unit comprising regulatory elements derived from a microbial or viral operon.

[0078] As used herein the term "a nucleotide coding for (or encoding) a peptide" refers to a nucleotide sequence coding for the peptide including artificial (man-made) start and stop codons compatible for the biological system the sequence is to be expressed by, for example, a dendritic cell or another cell system useful for the production of TCRs.

[0079] As used herein, reference to a nucleic acid sequence includes both single stranded and double stranded nucleic acid. Thus, for example for DNA, the specific sequence, unless the context indicates otherwise, refers to the single strand DNA of such sequence, the duplex of such sequence with its complement (double stranded DNA) and the complement of such sequence.

[0080] The term "coding region" refers to that portion of a gene which either naturally or normally codes for the expression product of that gene in its natural genomic environment, i.e., the region coding in vivo for the native expression product of the gene.

[0081] The coding region can be derived from a non-mutated ("normal"), mutated or altered gene, or can even be derived from a DNA sequence, or gene, wholly synthesized in the laboratory using methods well known to those of skill in the art of DNA synthesis.

[0082] The term "expression product" means the polypeptide or protein that is the natural translation product of the gene and any nucleic acid sequence coding equivalents resulting from genetic code degeneracy and thus coding for the same amino acid(s).

[0083] The term "fragment", when referring to a coding sequence, means a portion of DNA comprising less than the complete coding region, whose expression product retains essentially the same biological function or activity as the expression product of the complete coding region.

[0084] The term "DNA segment" refers to a DNA polymer, in the form of a separate fragment or as a component of a larger DNA construct, which has been derived from DNA isolated at least once in substantially pure form, i.e., free of contaminating endogenous materials and in a quantity or concentration enabling identification, manipulation, and recovery of the segment and its component nucleotide sequences by standard biochemical methods, for example, by using a cloning vector. Such segments are provided in the form of an open reading frame uninterrupted by internal non-translated sequences, or introns, which are typically present in eukaryotic genes. Sequences of non-translated DNA may be present downstream from the open reading frame, where the same do not interfere with manipulation or expression of the coding regions.

[0085] The term "primer" means a short nucleic acid sequence that can be paired with one strand of DNA and provides a free 3'-OH end at which a DNA polymerase starts synthesis of a deoxyribonucleotide chain.

[0086] The term "promoter" means a region of DNA involved in binding of RNA polymerase to initiate transcription.

[0087] The term "isolated" means that the material is removed from its original environment (e.g., the natural environment, if it is naturally occurring). For example, a naturally-occurring polynucleotide or polypeptide present in a living animal is not isolated, but the same polynucleotide or polypeptide, separated from some or all of the coexisting materials in the natural system, is isolated. Such polynucleotides could be part of a vector and / or such polynucleotides or polypeptides could be part of a composition, and still be isolated in that such vector or composition is not part of its natural environment.

[0088] The polynucleotides, and recombinant or immunogenic polypeptides, disclosed in accordance with the present invention may also be in "purified" form. The term "purified" does not require absolute purity; rather, it is intended as a relative definition, and can include preparations that are highly purified or preparations that are only partially purified, as those terms are understood by those of skill in the relevant art. For example, individual clones isolated from a cDNA library have been conventionally purified to electrophoretic homogeneity. Purification of starting material or natural material to at least one order of magnitude, preferably two or three orders, and more preferably four or five orders of magnitude is expressly contemplated. Furthermore, a claimed polypeptide which has a purity of preferably 99.999%, or at least 99.99% or 99.9%; and even desirably 99% by weight or greater is expressly encompassed.

[0089] The nucleic acids and polypeptide expression products disclosed according to the present invention, as well as expression vectors containing such nucleic acids and / or such polypeptides, may be in "enriched form". As used herein, the term "enriched" means that the concentration of the material is at least about 2, 5, 10, 100, or 1000 times its natural concentration (for example), advantageously 0.01%, by weight, preferably at least about 0.1% by weight. Enriched preparations of about 0.5%, 1%, 5%, 10%, and 20% by weight are also contemplated. The sequences, constructs, vectors, clones, and other materials comprising the present invention can advantageously be in enriched or isolated form. The term "active fragment" means a fragment, usually of a peptide, polypeptide or nucleic acid sequence, that generates an immune response (i.e., has immunogenic activity) when administered, alone or optionally with a suitable adjuvant or in a vector, to an animal, such as a mammal, for example, a rabbit or a mouse, and also including a human, such immune response taking the form of stimulating a T-cell response within the recipient animal, such as a human. Alternatively, the "active fragment" may also be used to induce a T-cell response in vitro.

[0090] As used herein, the terms "portion", "segment" and "fragment", when used in relation to polypeptides, refer to a continuous sequence of residues, such as amino acid residues, which sequence forms a subset of a larger sequence. For example, if a polypeptide were subjected to treatment with any of the common endopeptidases, such as trypsin or chymotrypsin, the oligopeptides resulting from such treatment would represent portions, segments or fragments of the starting polypeptide. When used in relation to polynucleotides, these terms refer to the products produced by treatment of said polynucleotides with any of the endonucleases.

[0091] In accordance with the present invention, the term "percent identity" or "percent identical", when referring to a sequence, means that a sequence is compared to a claimed or described sequence after alignment of the sequence to be compared (the "Compared Sequence") with the described or claimed sequence (the "Reference Sequence"). The percent identity is then determined according to the following formula: percent identity = 100 1 − C / R wherein C is the number of differences between the Reference Sequence and the Compared Sequence over the length of alignment between the Reference Sequence and the Compared Sequence, wherein (i) each base or amino acid in the Reference Sequence that does not have a corresponding aligned base or amino acid in the Compared Sequence and (ii) each gap in the Reference Sequence and (iii) each aligned base or amino acid in the Reference Sequence that is different from an aligned base or amino acid in the Compared Sequence, constitutes a difference and (iiii) the alignment has to start at position 1 of the aligned sequences; and R is the number of bases or amino acids in the Reference Sequence over the length of the alignment with the Compared Sequence with any gap created in the Reference Sequence also being counted as a base or amino acid.

[0092] If an alignment exists between the Compared Sequence and the Reference Sequence for which the percent identity as calculated above is about equal to or greater than a specified minimum Percent Identity, then the Compared Sequence has the specified minimum percent identity to the Reference Sequence even though alignments may exist in which the herein above calculated percent identity is less than the specified percent identity.

[0093] As mentioned above, the present invention thus provides a peptide consisting of SEQ ID NO: 11. The peptide of the invention has the ability to bind to a molecule of the human major histocompatibility complex (MHC) class-I.

[0094] In the present invention, the term "homologous" refers to the degree of identity (see percent identity above) between sequences of two amino acid sequences, i.e. peptide or polypeptide sequences. The aforementioned "homology" is determined by comparing two sequences aligned under optimal conditions over the sequences to be compared. Such a sequence homology can be calculated by creating an alignment using, for example, the ClustalW algorithm. Commonly available sequence analysis software, more specifically, Vector NTI, GENETYX or other tools are provided by public databases.

[0095] A person skilled in the art will be able to assess, whether T cells induced by a variant of a specific peptide will be able to cross-react with the peptide itself (Appay et al., 2006; Colombetti et al., 2006; Fong et al., 2001; Zaremba et al., 1997).

[0096] T cells can subsequently cross-react with cells and kill cells that express a polypeptide that contains the natural amino acid sequence of the cognate peptide as defined in the aspects of the invention. As can be derived from the scientific literature and databases (Rammensee et al., 1999; Godkin et al., 1997), certain positions of HLA binding peptides are typically anchor residues forming a core sequence fitting to the binding motif of the HLA receptor, which is defined by polar, electrophysical, hydrophobic and spatial properties of the polypeptide chains constituting the binding groove.

[0097] Of course, the peptide according to the present invention will have the ability to bind to a molecule of the human major histocompatibility complex (MHC) class I. Binding of a peptide or a variant to a MHC complex may be tested by methods known in the art.

[0098] Preferably, when the T cells specific for a peptide according to the present invention are tested against the substituted peptides, the peptide concentration at which the substituted peptides achieve half the maximal increase in lysis relative to background is no more than about 1 mM, preferably no more than about 1 µM, more preferably no more than about 1 nM, and still more preferably no more than about 100 pM, and most preferably no more than about 10 pM. It is also preferred that the substituted peptide be recognized by T cells from more than one individual, at least two, and more preferably three individuals.

[0099] In a particularly preferred embodiment of the invention the peptide consists of an amino acid sequence according to SEQ ID NO: 11.

[0100] present invention, the peptide is fused to the 80 N-terminal amino acids of the HLA-DR antigen-associated invariant chain (p33, in the following "Ii") as derived from the NCBI, GenBank Accession number X00497.

[0101] In addition, the peptide may be modified further to improve stability and / or binding to MHC molecules in order to elicit a stronger immune response.

[0102] A non-peptide bond is, for example, -CH 2 -NH, -CH 2 S-, -CH 2 CH 2 -, -CH=CH-, - COCH 2 -, -CH(OH)CH 2 -, and -CH 2 SO-. US 4,897,445 provides a method for the solid phase synthesis of non-peptide bonds (-CH 2 -NH) in polypeptide chains which involves polypeptides synthesized by standard procedures and the non-peptide bond synthesized by reacting an amino aldehyde and an amino acid in the presence of NaCNBH 3 .

[0103] Peptides comprising the sequences described above may be synthesized with additional chemical groups present at their amino and / or carboxy termini, to enhance the stability, bioavailability, and / or affinity of the peptides. For example, hydrophobic groups such as carbobenzoxyl, dansyl, or t-butyloxycarbonyl groups may be added to the peptides' amino termini. Likewise, an acetyl group or a 9-fluorenylmethoxy-carbonyl group may be placed at the peptides' amino termini. Additionally, the hydrophobic group, t-butyloxycarbonyl, or an amido group may be added to the peptides' carboxy termini.

[0104] A peptide or variant, wherein the peptide includes non-peptide bonds is a preferred embodiment of the invention. Generally, peptides (at least those containing peptide linkages between amino acid residues) may be synthesized by the Fmoc-polyamide mode of solid-phase peptide synthesis as disclosed by Lukas et al. (Lukas et al., 1981) and by references as cited therein. Temporary N-amino group protection is afforded by the 9-fluorenylmethyloxycarbonyl (Fmoc) group. Repetitive cleavage of this highly base-labile protecting group is done using 20% piperidine in N, N-dimethylformamide. Side-chain functionalities may be protected as their butyl ethers (in the case of serine, threonine, and tyrosine), butyl esters (in the case of glutamic acid and aspartic acid), butyloxycarbonyl derivative (in the case of lysine and histidine), trityl derivative (in the case of cysteine) and 4-methoxy-2,3,6-trimethylbenzenesulphonyl derivative (in the case of arginine). Where glutamine or asparagine are C-terminal residues, use is made of the 4,4'-dimethoxybenzhydryl group for protection of the side chain amido functionalities. The solid-phase support is based on a polydimethyl-acrylamide polymer constituted from the three monomers dimethylacrylamide (backbone-monomer), bisacryloylethylene diamine (cross linker) and acryloylsarcosine methyl ester (functionalizing agent). The peptide-to-resin cleavable linked agent used is the acid-labile 4-hydroxymethyl-phenoxyacetic acid derivative. All amino acid derivatives are added as their preformed symmetrical anhydride derivatives with the exception of asparagine and glutamine, which are added using a reversed N,N-dicyclohexyl-carbodiimide / 1hydroxybenzotriazole mediated coupling procedure. All coupling and deprotection reactions are monitored using ninhydrin, trinitrobenzene sulphonic acid or isotin test procedures. Upon completion of synthesis, peptides are cleaved from the resin support with concomitant removal of side-chain protecting groups by treatment with 95% trifluoroacetic acid containing a 50 % scavenger mix. Scavengers commonly used include ethanedithiol, phenol, anisole and water, the exact choice depending on the constituent amino acids of the peptide being synthesized. Also a combination of solid phase and solution phase methodologies for the synthesis of peptides is possible (see, for example, (Bruckdorfer et al., 2004), and the references as cited therein).

[0105] Trifluoroacetic acid is removed by evaporation in vacuo, with subsequent trituration with diethyl ether affording the crude peptide. Any scavengers present are removed by a simple extraction procedure which on lyophilization of the aqueous phase affords the crude peptide free of scavengers. Reagents for peptide synthesis are generally available from e.g. Calbiochem-Novabiochem (Nottingham, UK).

[0106] Purification may be performed by any one, or a combination of, techniques such as recrystallization, size exclusion chromatography, ion-exchange chromatography, hydrophobic interaction chromatography and (usually) reverse-phase high performance liquid chromatography using e.g. acetonitrile / water gradient separation.

[0107] Analysis of peptides may be carried out using thin layer chromatography, electrophoresis, in particular capillary electrophoresis, solid phase extraction (CSPE), reverse-phase high performance liquid chromatography, amino-acid analysis after acid hydrolysis and by fast atom bombardment (FAB) mass spectrometric analysis, as well as MALDI and ESI-Q-TOF mass spectrometric analysis.

[0108] In order to select over-presented peptides, a presentation profile is calculated showing the median sample presentation as well as replicate variation. The profile juxtaposes samples of the tumor entity of interest to a baseline of normal tissue samples. Each of these profiles can then be consolidated into an over-presentation score by calculating the p-value of a Linear Mixed-Effects Model (Pinheiro et al., 2015) adjusting for multiple testing by False Discovery Rate (Benjamini and Hochberg, 1995).

[0109] For the identification and relative quantitation of HLA ligands by mass spectrometry, HLA molecules from shock-frozen tissue samples were purified and HLA-associated peptides were isolated. The isolated peptides were separated and sequences were identified by online nano-electrospray-ionization (nanoESI) liquid chromatography-mass spectrometry (LC-MS) experiments. The resulting peptide sequences were verified by comparison of the fragmentation pattern of natural tumor-associated peptides (TUMAPs) recorded from ovarian cancer samples (N = 20 A*02-positive samples) with the fragmentation patterns of corresponding synthetic reference peptides of identical sequences. Since the peptides were directly identified as ligands of HLA molecules of primary tumors, these results provide direct evidence for the natural processing and presentation of the identified peptides on primary cancer tissue obtained from 20 ovarian cancer patients.

[0110] The discovery pipeline XPRESIDENT® v2.1 (see, for example, US 2013-0096016) allows the identification and selection of relevant over-presented peptide vaccine candidates based on direct relative quantitation of HLA-restricted peptide levels on cancer tissues in comparison to several different non-cancerous tissues and organs. This was achieved by the development of label-free differential quantitation using the acquired LC-MS data processed by a proprietary data analysis pipeline, combining algorithms for sequence identification, spectral clustering, ion counting, retention time alignment, charge state deconvolution and normalization.

[0111] Presentation levels including error estimates for each peptide and sample were established. Peptides exclusively presented on tumor tissue and peptides over-presented in tumor versus non-cancerous tissues and organs have been identified.

[0112] HLA-peptide complexes from ovarian cancer tissue samples were purified and HLA-associated peptides were isolated and analyzed by LC-MS (see examples). All TUMAPs contained in the present application were identified with this approach on primary ovarian cancer samples confirming their presentation on primary ovarian cancer.

[0113] TUMAPs identified on multiple ovarian cancer and normal tissues were quantified using ion-counting of label-free LC-MS data. The method assumes that LC-MS signal areas of a peptide correlate with its abundance in the sample. All quantitative signals of a peptide in various LC-MS experiments were normalized based on central tendency, averaged per sample and merged into a bar plot, called presentation profile. The presentation profile consolidates different analysis methods like protein database search, spectral clustering, charge state deconvolution (decharging) and retention time alignment and normalization.

[0114] Furthermore, the discovery pipeline XPRESIDENT® v2.x allows the direct absolute quantitation of MHC-, preferably HLA-restricted, peptide levels on cancer or other infected tissues. Briefly, the total cell count was calculated from the total DNA content of the analyzed tissue sample. The total peptide amount for a TUMAP in a tissue sample was measured by nanoLC-MS / MS as the ratio of the natural TUMAP and a known amount of an isotope-labelled version of the TUMAP, the so-called internal standard. The efficiency of TUMAP isolation was determined by spiking peptide:MHC complexes of all selected TUMAPs into the tissue lysate at the earliest possible point of the TUMAP isolation procedure and their detection by nanoLC-MS / MS following completion of the peptide isolation procedure. The total cell count and the amount of total peptide were calculated from triplicate measurements per tissue sample. The peptide-specific isolation efficiencies were calculated as an average from 10 spike experiments each measured as a triplicate (see Example 6 and Table 11).

[0115] In addition to an over-presentation of the peptide, the mRNA expression of the underlying gene was analyzed as well. mRNA data were obtained via RNASeq analyses of normal tissues and cancer tissues (see Example 2). An additional source of normal tissue data was a database of publicly available RNA expression data from around 3000 normal tissue samples (Lonsdale, 2013). Peptides which are derived from proteins that show a highly expressed coding mRNA in cancer tissue, but a very low or absent one in vital healthy (normal) tissues, were included as preferred into the present invention.

[0116] The present invention provides a peptide that is useful in treating cancers / tumors, preferably ovarian cancer that over- or exclusively present the peptide of the invention. The peptide was shown by mass spectrometry to be naturally presented by HLA molecules on primary human ovarian cancer samples.

[0117] Many of the source gene / proteins (also designated "full-length proteins" or "underlying proteins") from which the peptides are derived were shown to be highly over-expressed in cancer compared with normal tissues - "normal tissues" in relation to this invention shall mean either healthy ovaries or other normal tissues, demonstrating a high degree of tumor association of the source genes (see Example 2). Moreover, the peptides themselves are strongly over-presented on tumor tissue - "tumor tissue" in relation to this invention shall mean a sample from a patient suffering from ovarian cancer, but not on normal tissues (see Example 1).

[0118] HLA-bound peptides can be recognized by the immune system, specifically T lymphocytes. T cells can destroy the cells presenting the recognized HLA / peptide complex, e.g. ovarian cancer cells presenting the derived peptides.

[0119] The peptide of the present invention has been shown to be capable of stimulating T cell responses and / or is over-presented and thus can be used for the production of antibodies and / or TCRs, such as soluble TCRs, according to the present invention (see Example 3, Example 4). Furthermore, the peptide when complexed with the respective MHC can be used for the production of antibodies and / or TCRs, in particular sTCRs, according to the present invention, as well. Respective methods are well known to the person of skill, and can be found in the respective literature as well. Thus, the peptide of the present invention is useful for generating an immune response in a patient by which tumor cells can be destroyed. An immune response in a patient can be induced by direct administration of the described peptides or suitable precursor substances (e.g. elongated peptides, proteins, or nucleic acids encoding these peptides) to the patient, ideally in combination with an agent enhancing the immunogenicity (i.e. an adjuvant). The immune response originating from such a therapeutic vaccination can be expected to be highly specific against tumor cells because the target peptide of the present invention is not presented on normal tissues in comparable copy numbers, preventing the risk of undesired autoimmune reactions against normal cells in the patient.

[0120] The present description further relates to T-cell receptors (TCRs) comprising an alpha chain and a beta chain ("alpha / beta TCRs"). The present description also relates to nucleic acids, vectors and host cells for expressing TCRs and the peptide of the present description; and methods of using the same.

[0121] The term "T-cell receptor" (abbreviated TCR) refers to a heterodimeric molecule comprising an alpha polypeptide chain (alpha chain) and a beta polypeptide chain (beta chain), wherein the heterodimeric receptor is capable of binding to a peptide antigen presented by an HLA molecule. The term also includes so-called gamma / delta TCRs.

[0122] In one embodiment the description provides a method of producing a TCR as described herein, the method comprising culturing a host cell capable of expressing the TCR under conditions suitable to promote expression of the TCR.

[0123] The description in another aspect relates to methods according to the description, wherein the antigen is loaded onto class I MHC molecules expressed on the surface of a suitable antigen-presenting cell or artificial antigen-presenting cell by contacting a sufficient amount of the antigen with an antigen-presenting cell or the antigen is loaded onto class I MHC tetramers by tetramerizing the antigen / class I MHC complex monomers.

[0124] The alpha and beta chains of alpha / beta TCR's, and the gamma and delta chains of gamma / delta TCRs, are generally regarded as each having two "domains", namely variable and constant domains. The variable domain consists of a concatenation of variable region (V), and joining region (J). The variable domain may also include a leader region (L). Beta and delta chains may also include a diversity region (D). The alpha and beta constant domains may also include C-terminal transmembrane (TM) domains that anchor the alpha and beta chains to the cell membrane.

[0125] With respect to gamma / delta TCRs, the term "TCR gamma variable domain" as used herein refers to the concatenation of the TCR gamma V (TRGV) region without leader region (L), and the TCR gamma J (TRGJ) region, and the term TCR gamma constant domain refers to the extracellular TRGC region, or to a C-terminal truncated TRGC sequence. Likewise the term "TCR delta variable domain" refers to the concatenation of the TCR delta V (TRDV) region without leader region (L) and the TCR delta D / J (TRDD / TRDJ) region, and the term "TCR delta constant domain" refers to the extracellular TRDC region, or to a C-terminal truncated TRDC sequence.

[0126] TCRs of the present description preferably bind to a peptide-HLA molecule complex with a binding affinity (KD) of about 100 µM or less, about 50 µM or less, about 25 µM or less, or about 10 µM or less. More preferred are high-affinity TCRs having binding affinities of about 1 µM or less, about 100 nM or less, about 50 nM or less, about 25 nM or less. Non-limiting examples of preferred binding affinity ranges for TCRs of the present invention include about 1 nM to about 10 nM; about 10 nM to about 20 nM; about 20 nM to about 30 nM; about 30 nM to about 40 nM; about 40 nM to about 50 nM; about 50 nM to about 60 nM; about 60 nM to about 70 nM; about 70 nM to about 80 nM; about 80 nM to about 90 nM; and about 90 nM to about 100 nM.

[0127] As used herein in connect with TCRs of the present description, "specific binding" and grammatical variants thereof are used to mean a TCR having a binding affinity (KD) for a peptide-HLA molecule complex of 100 µM or less.

[0128] Alpha / beta heterodimeric TCRs of the present description may have an introduced disulfide bond between their constant domains. Preferred TCRs of this type include those which have a TRAC constant domain sequence and a TRBC1 or TRBC2 constant domain sequence except that Thr 48 of TRAC and Ser 57 of TRBC1 or TRBC2 are replaced by cysteine residues, the said cysteines forming a disulfide bond between the TRAC constant domain sequence and the TRBC1 or TRBC2 constant domain sequence of the TCR.

[0129] With or without the introduced inter-chain bond mentioned above, alpha / beta hetero-dimeric TCRs of the present description may have a TRAC constant domain sequence and a TRBC1 or TRBC2 constant domain sequence, and the TRAC constant domain sequence and the TRBC1 or TRBC2 constant domain sequence of the TCR may be linked by the native disulfide bond between Cys4 of exon 2 of TRAC and Cys2 of exon 2 of TRBC1 or TRBC2.

[0130] TCRs of the present description may comprise a detectable label selected from the group consisting of a radionuclide, a fluorophore and biotin. TCRs of the present description may be conjugated to a therapeutically active agent, such as a radionuclide, a chemotherapeutic agent, or a toxin.

[0131] In an embodiment, a TCR of the present description having at least one mutation in the alpha chain and / or having at least one mutation in the beta chain has modified glycosylation compared to the unmutated TCR.

[0132] In an embodiment, a TCR comprising at least one mutation in the TCR alpha chain and / or TCR beta chain has a binding affinity for, and / or a binding half-life for, a peptide-HLA molecule complex, which is at least double that of a TCR comprising the unmutated TCR alpha chain and / or unmutated TCR beta chain. Affinity-enhancement of tumor-specific TCRs, and its exploitation, relies on the existence of a window for optimal TCR affinities. The existence of such a window is based on observations that TCRs specific for HLA-A2-restricted pathogens have KD values that are generally about 10-fold lower when compared to TCRs specific for HLA-A2-restricted tumor-associated self-antigens. It is now known, although tumor antigens have the potential to be immunogenic, because tumors arise from the individual's own cells only mutated proteins or proteins with altered translational processing will be seen as foreign by the immune system. Antigens that are upregulated or overexpressed (so called self-antigens) will not necessarily induce a functional immune response against the tumor: T-cells expressing TCRs that are highly reactive to these antigens will have been negatively selected within the thymus in a process known as central tolerance, meaning that only T-cells with low-affinity TCRs for self-antigens remain. Therefore, affinity of TCRs or variants of the present description to HAVCR1-001 can be enhanced by methods well known in the art.

[0133] The present description further relates to a method of identifying and isolating a TCR according to the present description, said method comprising incubating PBMCs from HLA-A*02-negative healthy donors with A2 / peptide monomers, incubating the PBMCs with tetramer-phycoerythrin (PE) and isolating the high avidity T-cells by fluo-rescence activated cell sorting (FACS)-Calibur analysis.

[0134] The present description further relates to a method of identifying and isolating a TCR according to the present description, said method comprising obtaining a transgenic mouse with the entire human TCRαβ gene loci (1.1 and 0.7 Mb), whose T-cells express a diverse human TCR repertoire that compensates for mouse TCR deficiency, immunizing the mouse with peptide, incubating PBMCs obtained from the transgenic mice with tetramer-phycoerythrin (PE), and isolating the high avidity T-cells by fluorescence activated cell sorting (FACS)-Calibur analysis.

[0135] In one aspect, to obtain T-cells expressing TCRs of the present description, nucleic acids encoding TCR-alpha and / or TCR-beta chains of the present description are cloned into expression vectors, such as gamma retrovirus or lentivirus. The recombinant viruses are generated and then tested for functionality, such as antigen specificity and functional avidity. An aliquot of the final product is then used to transduce the target T-cell population (generally purified from patient PBMCs), which is expanded before infusion into the patient.

[0136] In another aspect, to obtain T-cells expressing TCRs of the present description, TCR RNAs are synthesized by techniques known in the art, e.g., in vitro transcription systems. The in vitro-synthesized TCR RNAs are then introduced into primary CD8+ T-cells obtained from healthy donors by electroporation to re-express tumor specific TCR-alpha and / or TCR-beta chains.

[0137] To increase the expression, nucleic acids encoding TCRs of the present description may be operably linked to strong promoters, such as retroviral long terminal repeats (LTRs), cytomegalovirus (CMV), murine stem cell virus (MSCV) U3, phosphoglycerate kinase (PGK), β-actin, ubiquitin, and a simian virus 40 (SV40) / CD43 composite promoter, elongation factor (EF)-1a and the spleen focus-forming virus (SFFV) promoter. In a preferred embodiment, the promoter is heterologous to the nucleic acid being expressed.

[0138] In addition to strong promoters, TCR expression cassettes of the present description may contain additional elements that can enhance transgene expression, including a central polypurine tract (cPPT), which promotes the nuclear translocation of lentiviral constructs (Follenzi et al., 2000), and the woodchuck hepatitis virus posttranscriptional regulatory element (wPRE), which increases the level of transgene expression by increasing RNA stability (Zufferey et al., 1999).

[0139] The alpha and beta chains of a TCR of the present invention may be encoded by nucleic acids located in separate vectors, or may be encoded by polynucleotides located in the same vector.

[0140] Achieving high-level TCR surface expression requires that both the TCR-alpha and TCR-beta chains of the introduced TCR be transcribed at high levels. To do so, the TCR-alpha and TCR-beta chains of the present description may be cloned into bicistronic constructs in a single vector, which has been shown to be capable of overcoming this obstacle. The use of a viral intraribosomal entry site (IRES) between the TCR-alpha and TCR-beta chains results in the coordinated expression of both chains, because the TCR-alpha and TCR-beta chains are generated from a single transcript that is broken into two proteins during translation, ensuring that an equal molar ratio of TCR-alpha and TCR-beta chains are produced. (Schmitt et al. 2009).

[0141] Nucleic acids encoding TCRs of the present description may be codon optimized to increase expression from a host cell. Redundancy in the genetic code allows some amino acids to be encoded by more than one codon, but certain codons are less "optimal" than others because of the relative availability of matching tRNAs as well as other factors (Gustafsson et al., 2004). Modifying the TCR-alpha and TCR-beta gene sequences such that each amino acid is encoded by the optimal codon for mammalian gene expression, as well as eliminating mRNA instability motifs or cryptic splice sites, has been shown to significantly enhance TCR-alpha and TCR-beta gene expression (Scholten et al., 2006).

[0142] Furthermore, mispairing between the introduced and endogenous TCR chains may result in the acquisition of specificities that pose a significant risk for autoimmunity. For example, the formation of mixed TCR dimers may reduce the number of CD3 molecules available to form properly paired TCR complexes, and therefore can significantly decrease the functional avidity of the cells expressing the introduced TCR (Kuball et al., 2007).

[0143] To reduce mispairing, the C-terminus domain of the introduced TCR chains of the present description may be modified in order to promote interchain affinity, while decreasing the ability of the introduced chains to pair with the endogenous TCR. These strategies may include replacing the human TCR-alpha and TCR-beta C-terminus domains with their murine counterparts (murinized C-terminus domain); generating a second interchain disulfide bond in the C-terminus domain by introducing a second cysteine residue into both the TCR-alpha and TCR-beta chains of the introduced TCR (cysteine modification); swapping interacting residues in the TCR-alpha and TCR-beta chain C-terminus domains ("knob-in-hole"); and fusing the variable domains of the TCR-alpha and TCR-beta chains directly to CD3ζ (CD3ζ fusion). (Schmitt et al. 2009).

[0144] In an embodiment, a host cell is engineered to express a TCR of the present description. In preferred embodiments, the host cell is a human T-cell or T-cell progenitor. In some embodiments the T-cell or T-cell progenitor is obtained from a cancer patient. In other embodiments the T-cell or T-cell progenitor is obtained from a healthy donor. Host cells of the present description can be allogeneic or autologous with respect to a patient to be treated. In one embodiment, the host is a gamma / delta T-cell transformed to express an alpha / beta TCR.

[0145] A "pharmaceutical composition" is a composition suitable for administration to a human being in a medical setting. Preferably, a pharmaceutical composition is sterile and produced according to GMP guidelines.

[0146] The pharmaceutical compositions comprise the peptides either in the free form or in the form of a pharmaceutically acceptable salt (see also above). As used herein, "a pharmaceutically acceptable salt" refers to a derivative of the disclosed peptides wherein the peptide is modified by making acid or base salts of the agent. For example, acid salts are prepared from the free base (typically wherein the neutral form of the drug has a neutral -NH2 group) involving reaction with a suitable acid. Suitable acids for preparing acid salts include both organic acids, e.g., acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methane sulfonic acid, ethane sulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like, as well as inorganic acids, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid phosphoric acid and the like. Conversely, preparation of basic salts of acid moieties which may be present on a peptide are prepared using a pharmaceutically acceptable base such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide, trimethylamine or the like.

[0147] In an especially preferred embodiment, the pharmaceutical compositions comprise the peptides as salts of acetic acid (acetates), trifluoro acetates or hydrochloric acid (chlorides).

[0148] Preferably, the medicament of the present invention is an immunotherapeutics such as a vaccine. It may be administered directly into the patient, into the affected organ or systemically i.d., i.m., s.c., i.p. and i.v., or applied ex vivo to cells derived from the patient or a human cell line which are subsequently administered to the patient, or used in vitro to select a subpopulation of immune cells derived from the patient, which are then re-administered to the patient. If the nucleic acid is administered to cells in vitro, it may be useful for the cells to be transfected so as to co-express immune-stimulating cytokines, such as interleukin-2. The peptide may be substantially pure, or combined with an immune-stimulating adjuvant (see below) or used in combination with immune-stimulatory cytokines, or be administered with a suitable delivery system, for example liposomes. The peptide may also be conjugated to a suitable carrier such as keyhole limpet haemocyanin (KLH) or mannan (see WO 95 / 18145 and (Longenecker et al., 1993)). The peptide may also be tagged, may be a fusion protein, or may be a hybrid molecule. The peptides whose sequence is given in the present invention are expected to stimulate CD4 or CD8 T cells. However, stimulation of CD8 T cells is more efficient in the presence of help provided by CD4 T-helper cells. Thus, for MHC Class I epitopes that stimulate CD8 T cells the fusion partner or sections of a hybrid molecule suitably provide epitopes which stimulate CD4-positive T cells. CD4- and CD8-stimulating epitopes are well known in the art and include those identified in the present invention. In one aspect, the vaccine comprises at least one peptide having the amino acid sequence set forth in SEQ ID No. 11, and at least one additional peptide as disclosed, preferably two to 50, more preferably two to 25, even more preferably two to 20 and most preferably two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen or eighteen peptides. The peptide(s) may be derived from one or more specific TAAs and may bind to MHC class I molecules.

[0149] A further aspect of the invention provides a nucleic acid (for example a polynucleotide) encoding a peptide of the invention. The polynucleotide may be, for example, DNA, cDNA, PNA, RNA or combinations thereof, either single-and / or double-stranded, or native or stabilized forms of polynucleotides, such as, for example, polynucleotides with a phosphorothioate backbone and it may or may not contain introns so long as it codes for the peptide. Of course, only peptides that contain naturally occurring amino acid residues joined by naturally occurring peptide bonds are encodable by a polynucleotide. A still further aspect of the invention provides an expression vector expressing a polypeptide according to the invention.

[0150] A variety of methods have been developed to link polynucleotides, especially DNA, to vectors for example via complementary cohesive termini. For instance, complementary homopolymer tracts can be added to the DNA segment to be inserted to the vector DNA. The vector and DNA segment are then joined by hydrogen bonding between the complementary homopolymeric tails to form recombinant DNA molecules.

[0151] Synthetic linkers containing one or more restriction sites provide an alternative method of joining the DNA segment to vectors. Synthetic linkers containing a variety of restriction endonuclease sites are commercially available from a number of sources including International Biotechnologies Inc. New Haven, CN, USA.

[0152] A desirable method of modifying the DNA encoding the polypeptide of the invention employs the polymerase chain reaction as disclosed by Saiki RK, et al. (Saiki et al. 1988).This method may be used for introducing the DNA into a suitable vector, for example by engineering in suitable restriction sites, or it may be used to modify the DNA in other useful ways as is known in the art. If viral vectors are used, pox- or adenovirus vectors are preferred.

[0153] The DNA (or in the case of retroviral vectors, RNA) may then be expressed in a suitable host to produce a polypeptide comprising the peptide or variant of the invention. Thus, the DNA encoding the peptide or variant of the invention may be used in accordance with known techniques, appropriately modified in view of the teachings contained herein, to construct an expression vector, which is then used to transform an appropriate host cell for the expression and production of the polypeptide of the invention. Such techniques include those disclosed, for example, in US 4,440,859, 4,530,901, 4,582,800, 4,677,063, 4,678,751, 4,704,362, 4,710,463, 4,757,006, 4,766,075, and 4,810,648.

[0154] The DNA (or in the case of retroviral vectors, RNA) encoding the polypeptide constituting the compound of the invention may be joined to a wide variety of other DNA sequences for introduction into an appropriate host. The companion DNA will depend upon the nature of the host, the manner of the introduction of the DNA into the host, and whether episomal maintenance or integration is desired.

[0155] Generally, the DNA is inserted into an expression vector, such as a plasmid, in proper orientation and correct reading frame for expression. If necessary, the DNA may be linked to the appropriate transcriptional and translational regulatory control nucleotide sequences recognized by the desired host, although such controls are generally available in the expression vector. The vector is then introduced into the host through standard techniques. Generally, not all of the hosts will be transformed by the vector. Therefore, it will be necessary to select for transformed host cells. One selection technique involves incorporating into the expression vector a DNA sequence, with any necessary control elements, that codes for a selectable trait in the transformed cell, such as antibiotic resistance.

[0156] Alternatively, the gene for such selectable trait can be on another vector, which is used to co-transform the desired host cell.

[0157] Host cells that have been transformed by the recombinant DNA of the invention are then cultured for a sufficient time and under appropriate conditions known to those skilled in the art in view of the teachings disclosed herein to permit the expression of the polypeptide, which can then be recovered.

[0158] Many expression systems are known, including bacteria (for example E. coli and Bacillus subtilis), yeasts (for example Saccharomyces cerevisiae), filamentous fungi (for example Aspergillus spec.), plant cells, animal cells and insect cells. Preferably, the system can be mammalian cells such as CHO cells available from the ATCC Cell Biology Collection.

[0159] A typical mammalian cell vector plasmid for constitutive expression comprises the CMV or SV40 promoter with a suitable poly A tail and a resistance marker, such as neomycin. One example is pSVL available from Pharmacia, Piscataway, NJ, USA. An example of an inducible mammalian expression vector is pMSG, also available from Pharmacia. Useful yeast plasmid vectors are pRS403-406 and pRS413-416 and are generally available from Stratagene Cloning Systems, La Jolla, CA 92037, USA. Plasmids pRS403, pRS404, pRS405 and pRS406 are Yeast Integrating plasmids (Yips) and incorporate the yeast selectable markers HIS3, TRP1, LEU2 and URA3. Plasmids pRS413-416 are Yeast Centromere plasmids (Ycps). CMV promoter-based vectors (for example from Sigma-Aldrich) provide transient or stable expression, cytoplasmic expression or secretion, and N-terminal or C-terminal tagging in various combinations of FLAG, 3xFLAG, c-myc or MAT. These fusion proteins allow for detection, purification and analysis of recombinant protein. Dual-tagged fusions provide flexibility in detection.

[0160] The strong human cytomegalovirus (CMV) promoter regulatory region drives constitutive protein expression levels as high as 1 mg / L in COS cells. For less potent cell lines, protein levels are typically ∼0.1 mg / L. The presence of the SV40 replication origin will result in high levels of DNA replication in SV40 replication permissive COS cells. CMV vectors, for example, can contain the pMB1 (derivative of pBR322) origin for replication in bacterial cells, the b-lactamase gene for ampicillin resistance selection in bacteria, hGH polyA, and the f1 origin. Vectors containing the pre-pro-trypsin leader (PPT) sequence can direct the secretion of FLAG fusion proteins into the culture medium for purification using ANTI-FLAG antibodies, resins, and plates. Other vectors and expression systems are well known in the art for use with a variety of host cells.

[0161] In another embodiment two or more peptides as disclosed are encoded and thus expressed in a successive order (similar to "beads on a string" constructs). In doing so, the peptides may be linked or fused together by stretches of linker amino acids, such as for example LLLLLL, or may be linked without any additional peptide(s) between them. These constructs can also be used for cancer therapy, and may induce immune responses both involving MHC I and MHC II.

[0162] The present invention also relates to a host cell transformed with a polynucleotide vector construct of the present invention. The host cell can be either prokaryotic or eukaryotic. Bacterial cells may be preferred prokaryotic host cells in some circumstances and typically are a strain of E. coli such as, for example, the E. coli strains DH5 available from Bethesda Research Laboratories Inc., Bethesda, MD, USA, and RR1 available from the American Type Culture Collection (ATCC) of Rockville, MD, USA (No ATCC 31343). Preferred eukaryotic host cells include yeast, insect and mammalian cells, preferably vertebrate cells such as those from a mouse, rat, monkey or human fibroblastic and colon cell lines. Yeast host cells include YPH499, YPH500 and YPH501, which are generally available from Stratagene Cloning Systems, La Jolla, CA 92037, USA. Preferred mammalian host cells include Chinese hamster ovary (CHO) cells available from the ATCC as CCL61, NIH Swiss mouse embryo cells NIH / 3T3 available from the ATCC as CRL 1658, monkey kidney-derived COS-1 cells available from the ATCC as CRL 1650 and 293 cells which are human embryonic kidney cells.

[0163] Preferred insect cells are Sf9 cells which can be transfected with baculovirus expression vectors. An overview regarding the choice of suitable host cells for expression can be found in, for example, the textbook of Paulina Balbás and Argelia Lorence "Methods in Molecular Biology Recombinant Gene Expression, Reviews and Protocols," Part One, Second Edition, ISBN 978-1-58829-262-9, and other literature known to the person of skill.

[0164] Transformation of appropriate cell hosts with a DNA construct of the present invention is accomplished by well-known methods that typically depend on the type of vector used. With regard to transformation of prokaryotic host cells, see, for example, Cohen et al. (Cohen et al., 1972) and (Green and Sambrook, 2012). Transformation of yeast cells is described in Sherman et al. (Sherman et al., 1986). The method of Beggs (Beggs, 1978) is also useful. With regard to vertebrate cells, reagents useful in transfecting such cells, for example calcium phosphate and DEAE-dextran or liposome formulations, are available from Stratagene Cloning Systems, or Life Technologies Inc., Gaithersburg, MD 20877, USA. Electroporation is also useful for transforming and / or transfecting cells and is well known in the art for transforming yeast cell, bacterial cells, insect cells and vertebrate cells.

[0165] Successfully transformed cells, i.e. cells that contain a DNA construct of the present invention, can be identified by well-known techniques such as PCR. Alternatively, the presence of the protein in the supernatant can be detected using antibodies.

[0166] It will be appreciated that certain host cells of the invention are useful in the preparation of the peptide of the invention, for example bacterial, yeast and insect cells. However, other host cells may be useful in certain therapeutic methods. For example, antigen-presenting cells, such as dendritic cells, may usefully be used to express the peptide of the invention such that they may be loaded into appropriate MHC molecules. Thus, the current invention provides a host cell comprising a nucleic acid or an expression vector according to the invention.

[0167] In a preferred embodiment the host cell is an antigen presenting cell, in particular a dendritic cell or antigen presenting cell. APCs loaded with a recombinant fusion protein containing prostatic acid phosphatase (PAP) were approved by the U.S. Food and Drug Administration (FDA) on April 29, 2010, to treat asymptomatic or minimally symptomatic metastatic HRPC (Sipuleucel-T) (Rini et al., 2006; Small et al., 2006).

[0168] A further aspect of the invention provides a method of producing a peptide the method comprising culturing a host cell and isolating the peptide from the host cell or its culture medium.

[0169] In another embodiment the peptide, the nucleic acid or the expression vector of the invention are used in medicine. For example, the peptide may be prepared for intravenous (i.v.) injection, sub-cutaneous (s.c.) injection, intradermal (i.d.) injection, intraperitoneal (i.p.) injection, intramuscular (i.m.) injection. Preferred methods of peptide injection include s.c., i.d., i.p., i.m., and i.v. Preferred methods of DNA injection include i.d., i.m., s.c., i.p. and i.v. Doses of e.g. between 50 µg and 1.5 mg, preferably 125 µg to 500 µg, of peptide or DNA may be given and will depend on the respective peptide or DNA. Dosages of this range were successfully used in previous trials (Walter et al., 2012).

[0170] The polynucleotide used for active vaccination may be substantially pure, or contained in a suitable vector or delivery system. The nucleic acid may be DNA, cDNA, PNA, RNA or a combination thereof. Methods for designing and introducing such a nucleic acid are well known in the art. An overview is provided by e.g. Teufel et al. (Teufel et al., 2005). Polynucleotide vaccines are easy to prepare, but the mode of action of these vectors in inducing an immune response is not fully understood. Suitable vectors and delivery systems include viral DNA and / or RNA, such as systems based on adenovirus, vaccinia virus, retroviruses, herpes virus, adeno-associated virus or hybrids containing elements of more than one virus. Non-viral delivery systems include cationic lipids and cationic polymers and are well known in the art of DNA delivery. Physical delivery, such as via a "gene-gun" may also be used. The peptide or peptides encoded by the nucleic acid may be a fusion protein, for example with an epitope that stimulates T cells for the respective opposite CDR as noted above.

[0171] The medicament of the invention may also include one or more adjuvants. Adjuvants are substances that non-specifically enhance or potentiate the immune response (e.g., immune responses mediated by CD8-positive T cells and helper-T (TH) cells to an antigen, and would thus be considered useful in the medicament of the present invention. Suitable adjuvants include, but are not limited to, 1018 ISS, aluminum salts, AMPLIVAX®, AS15, BCG, CP-870,893, CpG7909, CyaA, dSLIM, flagellin or TLR5 ligands derived from flagellin, FLT3 ligand, GM-CSF, IC30, IC31, Imiquimod (ALDARA®), resiquimod, ImuFact IMP321, Interleukins as IL-2, IL-13, IL-21, Interferon-alpha or -beta, or pegylated derivatives thereof, IS Patch, ISS, ISCOMATRIX, ISCOMs, JuvImmune®, LipoVac, MALP2, MF59, monophosphoryl lipid A, Montanide IMS 1312, Montanide ISA 206, Montanide ISA 50V, Montanide ISA-51, water-in-oil and oil-in-water emulsions, OK-432, OM-174, OM-197-MP-EC, ONTAK, OspA, PepTel® vector system, poly(lactid co-glycolid) [PLG]-based and dextran microparticles, talactoferrin SRL172, Virosomes and other Virus-like particles, YF-17D, VEGF trap, R848, beta-glucan, Pam3Cys, Aquila's QS21 stimulon, which is derived from saponin, mycobacterial extracts and synthetic bacterial cell wall mimics, and other proprietary adjuvants such as Ribi's Detox, Quil, or Superfos. Adjuvants such as Freund's or GM-CSF are preferred. Several immunological adjuvants (e.g., MF59) specific for dendritic cells and their preparation have been described previously (Allison and Krummel, 1995). Also cytokines may be used. Several cytokines have been directly linked to influencing dendritic cell migration to lymphoid tissues (e.g., TNF-), accelerating the maturation of dendritic cells into efficient antigen-presenting cells for T-lymphocytes (e.g., GM-CSF, IL-1 and IL-4) (U.S. Pat. No. 5,849,589) and acting as immunoadjuvants (e.g., IL-12, IL-15, IL-23, IL-7, IFN-alpha. IFN-beta) (Gabrilovich et al., 1996).

[0172] CpG immunostimulatory oligonucleotides have also been reported to enhance the effects of adjuvants in a vaccine setting. Without being bound by theory, CpG oligonucleotides act by activating the innate (non-adaptive) immune system via Toll-like receptors (TLR), mainly TLR9. CpG triggered TLR9 activation enhances antigen-specific humoral and cellular responses to a wide variety of antigens, including peptide or protein antigens, live or killed viruses, dendritic cell vaccines, autologous cellular vaccines and polysaccharide conjugates in both prophylactic and therapeutic vaccines. More importantly it enhances dendritic cell maturation and differentiation, resulting in enhanced activation of TH1 cells and strong cytotoxic T-lymphocyte (CTL) generation, even in the absence of CD4 T cell help. The TH1 bias induced by TLR9 stimulation is maintained even in the presence of vaccine adjuvants such as alum or incomplete Freund's adjuvant (IFA) that normally promote a TH2 bias. CpG oligonucleotides show even greater adjuvant activity when formulated or co-administered with other adjuvants or in formulations such as microparticles, nanoparticles, lipid emulsions or similar formulations, which are especially necessary for inducing a strong response when the antigen is relatively weak. They also accelerate the immune response and enable the antigen doses to be reduced by approximately two orders of magnitude, with comparable antibody responses to the full-dose vaccine without CpG in some experiments (Krieg, 2006). US 6,406,705 B1 describes the combined use of CpG oligonucleotides, non-nucleic acid adjuvants and an antigen to induce an antigen-specific immune response. A CpG TLR9 antagonist is dSLIM (double Stem Loop Immunomodulator) by Mologen (Berlin, Germany) which is a preferred component of the pharmaceutical composition of the present invention. Other TLR binding molecules such as RNA binding TLR 7, TLR 8 and / or TLR 9 may also be used.

[0173] Other examples for useful adjuvants include, but are not limited to chemically modified CpGs (e.g. CpR, Idera), dsRNA analogues such as Poly(I:C) and derivates thereof (e.g. AmpliGen®, Hiltonol®, poly-(ICLC), poly(IC-R), poly(I:C12U), non-CpG bacterial DNA or RNA as well as immunoactive small molecules and antibodies such as cyclophosphamide, sunitinib, Bevacizumab®, celebrex, NCX-4016, sildenafil, tadalafil, vardenafil, sorafenib, temozolomide, temsirolimus, XL-999, CP-547632, pazopanib, VEGF Trap, ZD2171, AZD2171, anti-CTLA4, other antibodies targeting key structures of the immune system (e.g. anti-CD40, anti-TGFbeta, anti-TNFalpha receptor) and SC58175, which may act therapeutically and / or as an adjuvant. The amounts and concentrations of adjuvants and additives useful in the context of the present invention can readily be determined by the skilled artisan without undue experimentation.

[0174] Preferred adjuvants are anti-CD40, imiquimod, resiquimod, GM-CSF, cyclophosphamide, sunitinib, bevacizumab, interferon-alpha, CpG oligonucleotides and derivates, poly-(I:C) and derivates, RNA, sildenafil, and particulate formulations with PLG or virosomes.

[0175] In a preferred embodiment, the pharmaceutical composition according to the invention the adjuvant is selected from the group consisting of colony-stimulating factors, such as Granulocyte Macrophage Colony Stimulating Factor (GM-CSF, sargramostim), cyclophosphamide, imiquimod, resiquimod, and interferon-alpha.

[0176] In a preferred embodiment, the pharmaceutical composition according to the invention the adjuvant is selected from the group consisting of colony-stimulating factors, such as Granulocyte Macrophage Colony Stimulating Factor (GM-CSF, sargramostim), cyclophosphamide, imiquimod and resiquimod. In a preferred embodiment of the pharmaceutical composition according to the invention, the adjuvant is cyclophosphamide, imiquimod or resiquimod. Even more preferred adjuvants are Montanide IMS 1312, Montanide ISA 206, Montanide ISA 50V, Montanide ISA-51, poly-ICLC (Hiltonol®) and anti-CD40 mAB, or combinations thereof.

[0177] This composition is used for parenteral administration, such as subcutaneous, intradermal, intramuscular or oral administration. For this, the peptides and optionally other molecules are dissolved or suspended in a pharmaceutically acceptable, preferably aqueous carrier. In addition, the composition can contain excipients, such as buffers, binding agents, blasting agents, diluents, flavors, lubricants, etc. The peptides can also be administered together with immune stimulating substances, such as cytokines. An extensive listing of excipients that can be used in such a composition, can be, for example, taken from A. Kibbe, Handbook of Pharmaceutical Excipients (Kibbe, 2000). The composition can be used for a prevention, prophylaxis and / or therapy of adenomatous or cancerous diseases. Exemplary formulations can be found in, for example, EP2112253.

[0178] It is important to realize that the immune response triggered by the vaccine according to the invention attacks the cancer in different cell-stages and different stages of development. Furthermore, different cancer associated signaling pathways are attacked. This is an advantage over vaccines that address only one or few targets, which may cause the tumor to easily adapt to the attack (tumor escape). Furthermore, not all individual tumors express the same pattern of antigens. Therefore, a combination of several tumor-associated peptides ensures that every single tumor bears at least some of the targets. The composition is designed in such a way that each tumor is expected to express several of the antigens and cover several independent pathways necessary for tumor growth and maintenance. Thus, the vaccine can easily be used "off-the-shelf" for a larger patient population. This means that a pre-selection of patients to be treated with the vaccine can be restricted to HLA typing, does not require any additional biomarker assessments for antigen expression, but it is still ensured that several targets are simultaneously attacked by the induced immune response, which is important for efficacy (Banchereau et al., 2001; Walter et al., 2012).

[0179] The peptide of the present invention can be used to generate and develop specific antibodies against MHC / peptide complexes. These can be used for therapy, targeting toxins or radioactive substances to the diseased tissue. Another use of these antibodies can be targeting radionuclides to the diseased tissue for imaging purposes such as PET. This use can help to detect small metastases or to determine the size and precise localization of diseased tissues.

[0180] Therefore, it is a further aspect of the invention to provide a method for producing a recombinant antibody specifically binding to a human major histocompatibility complex (MHC) class I being complexed with a HLA-restricted antigen, the method comprising: immunizing a genetically engineered non-human mammal comprising cells expressing said human major histocompatibility complex (MHC) class I with a soluble form of a MHC class I molecule being complexed with said HLA-restricted antigen; isolating mRNA molecules from antibody producing cells of said non-human mammal; producing a phage display library displaying protein molecules encoded by said mRNA molecules; and isolating at least one phage from said phage display library, said at least one phage displaying said antibody specifically binding to said human major histocompatibility complex (MHC) class I being complexed with said HLA-restricted antigen.

[0181] It is a further aspect of the invention to provide an antibody that specifically binds to a human major histocompatibility complex (MHC) class I being complexed with a HLA-restricted antigen, wherein the antibody preferably is a polyclonal antibody, monoclonal antibody, bi-specific antibody and / or a chimeric antibody.

[0182] Respective methods for producing such antibodies and single chain class I major histocompatibility complexes, as well as other tools for the production of these antibodies are disclosed in WO 03 / 068201, WO 2004 / 084798, WO 01 / 72768, WO 03 / 070752, and in publications (Cohen et al., 2003a; Cohen et al., 2003b; Denkberg et al., 2003).

[0183] Preferably, the antibody is binding with a binding affinity of below 20 nanomolar, preferably of below 10 nanomolar, to the complex, which is also regarded as "specific" in the context of the present invention.

[0184] The present invention relates to a peptide consisting of SEQ ID NO: 11.

[0185] The present invention further relates to the peptide according to the invention that have the ability to bind to a molecule of the human major histocompatibility complex (MHC) class-I.

[0186] The present invention further relates to the peptide according to the invention, wherein the peptide includes non-peptide bonds.

[0187] The present invention further relates to the peptides according to the invention, wherein the peptide is part of a fusion protein with N-terminal amino acids of the HLA-DR antigen-associated invariant chain (Ii).

[0188] The present invention further relates to a nucleic acid, encoding the peptide according to the invention.

[0189] The present invention further relates to the nucleic acid according to the invention that is DNA, cDNA, PNA, RNA or combinations thereof.

[0190] The present invention further relates to an expression vector expressing a nucleic acid according to the present invention.

[0191] The present invention further relates to a peptide according to the present invention, a nucleic acid according to the present invention or an expression vector according to the present invention for use in medicine, in particular in the treatment of ovarian cancer.

[0192] The present invention further relates to a host cell comprising a nucleic acid according to the invention or an expression vector according to the invention.

[0193] The present invention further relates to the host cell according to the present invention that is an antigen presenting cell, and preferably a dendritic cell.

[0194] The present invention further relates to a method of producing a peptide according to the present invention, said method comprising culturing the host cell according to the present invention, and isolating the peptide from said host cell or its culture medium.

[0195] The present invention further relates to the method according to the present invention, where-in the antigen is loaded onto class I MHC molecules expressed on the surface of a suitable antigen-presenting cell by contacting a sufficient amount of the antigen with an antigen-presenting cell.

[0196] The present invention further relates to the method according to the invention, wherein the antigen-presenting cell comprises an expression vector expressing said peptide containing SEQ ID NO: 11.

[0197] The present invention further relates to activated T cells, produced by the method according to the present invention, wherein said T cells selectively recognizes a cell which aberrantly expresses a polypeptide comprising an amino acid sequence according to the present invention.

[0198] Disclosed is a method of killing target cells in a patient which target cells aberrantly express a polypeptide comprising any amino acid sequence according to the present invention, the method comprising administering to the patient an effective number of T cells as according to the present invention.

[0199] The present invention further relates to the use of the peptide according to the present invention, a nucleic acid according to the present invention, an expression vector according to the present invention, a cell according to the present invention, or an activated cytotoxic T lymphocyte according to the present invention as a medicament or in the manufacture of a medicament. The present invention further relates to a use according to the present invention, wherein the medicament is active against cancer.

[0200] The present invention further relates to a use according to the invention, wherein the medicament is a vaccine. The present invention further relates to a use according to the invention, wherein the medicament is active against cancer.

[0201] The present invention further relates to a use according to the invention, wherein said cancer cells are ovarian cancer cells or other solid or hematological tumor cells such as non-small cell lung cancer, small cell lung cancer, kidney cancer, brain cancer, colon or rectum cancer, stomach cancer, liver cancer, pancreatic cancer, prostate cancer, leukemia, breast cancer, Merkel cell carcinoma, melanoma, esophageal cancer, urinary bladder cancer, uterine cancer, gallbladder cancer, bile duct cancer.

[0202] The term "antibody" or "antibodies" is used herein in a broad sense and includes both polyclonal and monoclonal antibodies. In addition to intact or "full" immunoglobulin molecules, also included in the term "antibodies" are fragments (e.g. CDRs, Fv, Fab and Fc fragments) or polymers of those immunoglobulin molecules and humanized versions of immunoglobulin molecules, as long as they exhibit any of the desired properties (e.g., specific binding of a ovarian cancer marker (poly)peptide, delivery of a toxin to a ovarian cancer cell expressing a cancer marker gene at an increased level, and / or inhibiting the activity of a ovarian cancer marker polypeptide) according to the invention.

[0203] Whenever possible, the antibodies of the invention may be purchased from commercial sources. The antibodies of the invention may also be generated using well-known methods. The skilled artisan will understand that either full length ovarian cancer marker polypeptides or fragments thereof may be used to generate the antibodies of the invention. A polypeptide to be used for generating an antibody of the invention may be partially or fully purified from a natural source, or may be produced using recombinant DNA techniques.

[0204] For example, a cDNA encoding a peptide according to the present invention, such as a peptide according to SEQ ID NO: 11, can be expressed in prokaryotic cells (e.g., bacteria) or eukaryotic cells (e.g., yeast, insect, or mammalian cells), after which the recombinant protein can be purified and used to generate a monoclonal or polyclonal antibody preparation that specifically bind the ovarian cancer marker polypeptide used to generate the antibody according to the invention.

[0205] One of skill in the art will realize that the generation of two or more different sets of monoclonal or polyclonal antibodies maximizes the likelihood of obtaining an antibody with the specificity and affinity required for its intended use (e.g., ELISA, immunohistochemistry, in vivo imaging, immunotoxin therapy). The antibodies are tested for their desired activity by known methods, in accordance with the purpose for which the antibodies are to be used (e.g., ELISA, immunohistochemistry, immunotherapy, etc.; for further guidance on the generation and testing of antibodies, see, e.g., Greenfield, 2014 (Greenfield, 2014)). For example, the antibodies may be tested in ELISA assays or, Western blots, immunohistochemical staining of formalin-fixed cancers or frozen tissue sections. After their initial in vitro characterization, antibodies intended for therapeutic or in vivo diagnostic use are tested according to known clinical testing methods.

[0206] The term "monoclonal antibody" as used herein refers to an antibody obtained from a substantially homogeneous population of antibodies, i.e.; the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in minor amounts. The monoclonal antibodies herein specifically include "chimeric" antibodies in which a portion of the heavy and / or light chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired antagonistic activity (US 4,816,567).

[0207] Monoclonal antibodies of the invention may be prepared using hybridoma methods. In a hybridoma method, a mouse or other appropriate host animal is typically immunized with an immunizing agent to elicit lymphocytes that produce or are capable of producing antibodies that will specifically bind to the immunizing agent. Alternatively, the lymphocytes may be immunized in vitro.

[0208] The monoclonal antibodies may also be made by recombinant DNA methods, such as those described in US 4,816,567. DNA encoding the monoclonal antibodies of the invention can be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of binding specifically to genes encoding the heavy and light chains of murine antibodies).

[0209] In vitro methods are also suitable for preparing monovalent antibodies. Digestion of antibodies to produce fragments thereof, particularly Fab fragments, can be accomplished using routine techniques known in the art. For instance, digestion can be performed using papain. Examples of papain digestion are described in WO 94 / 29348 and US 4,342,566. Papain digestion of antibodies typically produces two identical antigen binding fragments, called Fab fragments, each with a single antigen binding site, and a residual Fc fragment. Pepsin treatment yields a F(ab')2 fragment and a pFc' fragment.

[0210] The antibody fragments, whether attached to other sequences or not, can also include insertions, deletions, substitutions, or other selected modifications of particular regions or specific amino acids residues, provided the activity of the fragment is not significantly altered or impaired compared to the non-modified antibody or antibody fragment. These modifications can provide for some additional property, such as to remove / add amino acids capable of disulfide bonding, to increase its bio-longevity, to alter its secretory characteristics, etc. In any case, the antibody fragment must possess a bioactive property, such as binding activity, regulation of binding at the binding domain, etc. Functional or active regions of the antibody may be identified by mutagenesis of a specific region of the protein, followed by expression and testing of the expressed polypeptide. Such methods are readily apparent to a skilled practitioner in the art and can include site-specific mutagenesis of the nucleic acid encoding the antibody fragment.

[0211] The antibodies of the invention may further comprise humanized antibodies or human antibodies. Humanized forms of non-human (e.g., murine) antibodies are chimeric immunoglobulins, immunoglobulin chains or fragments thereof (such as Fv, Fab, Fab' or other antigen-binding subsequences of antibodies) which contain minimal sequence derived from non-human immunoglobulin. Humanized antibodies include human immunoglobulins (recipient antibody) in which residues from a complementary determining region (CDR) of the recipient are replaced by residues from a CDR of a non-human species (donor antibody) such as mouse, rat or rabbit having the desired specificity, affinity and capacity. In some instances, Fv framework (FR) residues of the human immunoglobulin are replaced by corresponding non-human residues. Humanized antibodies may also comprise residues which are found neither in the recipient antibody nor in the imported CDR or framework sequences. In general, the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin and all or substantially all of the FR regions are those of a human immunoglobulin consensus sequence. The humanized antibody optimally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin.

[0212] Methods for humanizing non-human antibodies are well known in the art. Generally, a humanized antibody has one or more amino acid residues introduced into it from a source which is non-human. These non-human amino acid residues are often referred to as "import" residues, which are typically taken from an "import" variable domain. Humanization can be essentially performed by substituting rodent CDRs or CDR sequences for the corresponding sequences of a human antibody. Accordingly, such "humanized" antibodies are chimeric antibodies (US 4,816,567), wherein substantially less than an intact human variable domain has been substituted by the corresponding sequence from a non-human species. In practice, humanized antibodies are typically human antibodies in which some CDR residues and possibly some FR residues are substituted by residues from analogous sites in rodent antibodies.

[0213] Transgenic animals (e.g., mice) that are capable, upon immunization, of producing a full repertoire of human antibodies in the absence of endogenous immunoglobulin production can be employed. For example, it has been described that the homozygous deletion of the antibody heavy chain joining region gene in chimeric and germ-line mutant mice results in complete inhibition of endogenous antibody production. Transfer of the human germ-line immunoglobulin gene array in such germ-line mutant mice will result in the production of human antibodies upon antigen challenge. Human antibodies can also be produced in phage display libraries.

[0214] Antibodies of the invention are preferably administered to a subject in a pharmaceutically acceptable carrier. Typically, an appropriate amount of a pharmaceutically-acceptable salt is used in the formulation to render the formulation isotonic. Examples of the pharmaceutically-acceptable carrier include saline, Ringer's solution and dextrose solution. The pH of the solution is preferably from about 5 to about 8, and more preferably from about 7 to about 7.5. Further carriers include sustained release preparations such as semipermeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, e.g., films, liposomes or microparticles. It will be apparent to those persons skilled in the art that certain carriers may be more preferable depending upon, for instance, the route of administration and concentration of antibody being administered.

[0215] The antibodies can be administered to the subject, patient, or cell by injection (e.g., intravenous, intraperitoneal, subcutaneous, intramuscular), or by other methods such as infusion that ensure its delivery to the bloodstream in an effective form. The antibodies may also be administered by intratumoral or peritumoral routes, to exert local as well as systemic therapeutic effects. Local or intravenous injection is preferred.

[0216] Effective dosages and schedules for administering the antibodies may be determined empirically, and making such determinations is within the skill in the art. Those skilled in the art will understand that the dosage of antibodies that must be administered will vary depending on, for example, the subject that will receive the antibody, the route of administration, the particular type of antibody used and other drugs being administered. A typical daily dosage of the antibody used alone might range from about 1 (µg / kg to up to 100 mg / kg of body weight or more per day, depending on the factors mentioned above. Following administration of an antibody, preferably for treating ovarian cancer, the efficacy of the therapeutic antibody can be assessed in various ways well known to the skilled practitioner. For instance, the size, number, and / or distribution of cancer in a subject receiving treatment may be monitored using standard tumor imaging techniques. A therapeutically-administered antibody that arrests tumor growth, results in tumor shrinkage, and / or prevents the development of new tumors, compared to the disease course that would occur in the absence of antibody administration, is an efficacious antibody for treatment of cancer.

[0217] It is a further aspect of the invention to provide a method for producing a soluble T-cell receptor (sTCR) recognizing a specific peptide-MHC complex. Such soluble T-cell receptors can be generated from specific T-cell clones, and their affinity can be increased by mutagenesis targeting the complementarity-determining regions. For the purpose of T-cell receptor selection, phage display can be used (US 2010 / 0113300, (Liddy et al., 2012)). For the purpose of stabilization of T-cell receptors during phage display and in case of practical use as drug, alpha and beta chain can be linked e.g. by non-native disulfide bonds, other covalent bonds (single-chain T-cell receptor), or by dimerization domains (Boulter et al., 2003; Card et al., 2004; Willcox et al., 1999). The T-cell receptor can be linked to toxins, drugs, cytokines (see, for example, US 2013 / 0115191), domains recruiting effector cells such as an anti-CD3 domain, etc., in order to execute particular functions on target cells. Moreover, it could be expressed in T cells used for adoptive transfer. Further information can be found in WO 2004 / 033685A1 and WO 2004 / 074322A1. A combination of sTCRs is described in WO 2012 / 056407A1. Further methods for the production are disclosed in WO 2013 / 057586A1.

[0218] Another aspect of the present invention includes an in vitro method for producing activated T cells, the method comprising contacting in vitro T cells with antigen loaded human MHC molecules expressed on the surface of a suitable antigen-presenting cell for a period of time sufficient to activate the T cell in an antigen specific manner, wherein the antigen is a peptide according to the invention. Preferably a sufficient amount of the antigen is used with an antigen-presenting cell.

[0219] Preferably the mammalian cell lacks or has a reduced level or function of the TAP peptide transporter. Suitable cells that lack the TAP peptide transporter include T2, RMA-S and Drosophila cells. TAP is the transporter associated with antigen processing.

[0220] The human peptide loading deficient cell line T2 is available from the American Type Culture Collection, 12301 Parklawn Drive, Rockville, Maryland 20852, USA under Catalogue No CRL 1992; the Drosophila cell line Schneider line 2 is available from the ATCC under Catalogue No CRL 19863; the mouse RMA-S cell line is described in Ljunggren et al. (Ljunggren and Karre, 1985).

[0221] Preferably, before transfection the host cell expresses substantially no MHC class I molecules. It is also preferred that the stimulator cell expresses a molecule important for providing a co-stimulatory signal for T-cells such as any of B7.1, B7.2, ICAM-1 and LFA 3. The nucleic acid sequences of numerous MHC class I molecules and of the co-stimulator molecules are publicly available from the GenBank and EMBL databases.

[0222] In case of a MHC class I epitope being used as an antigen, the T cells are CD8-positive T cells.

[0223] If an antigen-presenting cell is transfected to express such an epitope, preferably the cell comprises an expression vector expressing a peptide containing SEQ ID NO: 11.

[0224] A number of other methods may be used for generating T cells in vitro. For example, autologous tumor-infiltrating lymphocytes can be used in the generation of CTL. Plebanski et al. (Plebanski et al., 1995) made use of autologous peripheral blood lymphocytes (PLBs) in the preparation of T cells. Furthermore, the production of autologous T cells by pulsing dendritic cells with peptide or polypeptide, or via infection with recombinant virus is possible. Also, B cells can be used in the production of autologous T cells. In addition, macrophages pulsed with peptide or polypeptide, or infected with recombinant virus, may be used in the preparation of autologous T cells. S. Walter et al. (Walter et al., 2003) describe the in vitro priming of T cells by using artificial antigen presenting cells (aAPCs), which is also a suitable way for generating T cells against the peptide of choice. In the present invention, aAPCs were generated by the coupling of preformed MHC:peptide complexes to the surface of polystyrene particles (microbeads) by biotin:streptavidin biochemistry. This system permits the exact control of the MHC density on aAPCs, which allows to selectively elicit high- or low-avidity antigen-specific T cell responses with high efficiency from blood samples. Apart from MHC:peptide complexes, aAPCs should carry other proteins with co-stimulatory activity like anti-CD28 antibodies coupled to their surface. Furthermore, such aAPC-based systems often require the addition of appropriate soluble factors, e. g. cytokines, like interleukin-12.

[0225] Allogeneic cells may also be used in the preparation of T cells and a method is described in detail in WO 97 / 26328. For example, in addition to Drosophila cells and T2 cells, other cells may be used to present antigens such as CHO cells, baculovirus-infected insect cells, bacteria, yeast, vaccinia-infected target cells. In addition, plant viruses may be used (see, for example, Porta et al. (Porta et al., 1994) which describes the development of cowpea mosaic virus as a high-yielding system for the presentation of foreign peptides.

[0226] The activated T cells that are directed against the peptide of the invention are useful in therapy. Thus, a further aspect of the invention provides activated T cells obtainable by the foregoing methods of the invention.

[0227] Activated T cells, which are produced by the above method, will selectively recognize a cell that aberrantly expresses a polypeptide that comprises an amino acid sequence of SEQ ID NO: 11.

[0228] Preferably, the T cell recognizes the cell by interacting through its TCR with the HLA / peptide-complex (for example, binding). The T cells are useful in a method of killing target cells in a patient whose target cells aberrantly express a polypeptide comprising an amino acid sequence of the invention wherein the patient is administered an effective number of the activated T cells. The T cells that are administered to the patient may be derived from the patient and activated as described above (i.e. they are autologous T cells). Alternatively, the T cells are not from the patient but are from another individual. Of course, it is preferred if the individual is a healthy individual. By "healthy individual" the inventors mean that the individual is generally in good health, preferably has a competent immune system and, more preferably, is not suffering from any disease that can be readily tested for, and detected.

[0229] In vivo, the target cells for the CD8-positive T cells according to the present invention can be cells of the tumor (which sometimes express MHC class II) and / or stromal cells surrounding the tumor (tumor cells) (which sometimes also express MHC class II; (Dengjel et al., 2006)).

[0230] The T cells of the present invention may be used as active ingredients of a therapeutic composition. Thus, the invention also provides a method of killing target cells in a patient whose target cells aberrantly express a polypeptide comprising an amino acid sequence of the invention, the method comprising administering to the patient an effective number of T cells as defined above.

[0231] By "aberrantly expressed" the inventors also mean that the polypeptide is over-expressed compared to normal levels of expression or that the gene is silent in normal (healthy) tissues. By "over-expressed" the inventors mean that the polypeptide is present at a level at least 1.2-fold of that present in normal tissue; preferably at least 2-fold, and more preferably at least 5-fold or 10-fold the level present in normal tissue.

[0232] T cells may be obtained by methods known in the art, e.g. those described above.

[0233] Protocols for this so-called adoptive transfer of T cells are well known in the art. Reviews can be found in: Gattioni et al. and Morgan et al. (Gattinoni et al., 2006; Morgan et al., 2006).

[0234] Another aspect of the present invention includes the use of the peptides complexed with MHC to generate a T-cell receptor whose nucleic acid is cloned and is introduced into a host cell, preferably a T cell. This engineered T cell can then be transferred to a patient for therapy of cancer.

[0235] Any molecule of the invention, i.e. the peptide, nucleic acid, antibody, expression vector, cell, activated T cell, T-cell receptor or the nucleic acid encoding it, is useful for the treatment of disorders, characterized by cells escaping an immune response. Therefore, any molecule of the present invention may be used as medicament or in the manufacture of a medicament. The molecule may be used by itself or combined with other molecule(s) of the invention or (a) known molecule(s).

[0236] The present invention further provides a medicament that is useful in treating cancer, in particular ovarian cancer and other malignancies.

[0237] The present invention is further directed at a kit comprising: (a) a container containing a pharmaceutical composition as described above, in solution or in lyophilized form; (b) optionally a second container containing a diluent or reconstituting solution for the lyophilized formulation; c) optionally, at least one more peptide selected from the group consisting of SEQ ID No.1 to 10, and 12 to 640, and (d) optionally, instructions for (i) use of the solution or (ii) reconstitution and / or use of the lyophilized formulation.

[0238] The kit may further comprise one or more of (iii) a buffer, (iv) a diluent, (v) a filter, (vi) a needle, or (v) a syringe. The container is preferably a bottle, a vial, a syringe or test tube; and it may be a multi-use container. The pharmaceutical composition is preferably lyophilized.

[0239] Kits of the present invention preferably comprise a lyophilized formulation of the present invention in a suitable container and instructions for its reconstitution and / or use. Suitable containers include, for example, bottles, vials (e.g. dual chamber vials), syringes (such as dual chamber syringes) and test tubes. The container may be formed from a variety of materials such as glass or plastic. Preferably the kit and / or container contain / s instructions on or associated with the container that indicates directions for reconstitution and / or use. For example, the label may indicate that the lyophilized formulation is to be reconstituted to peptide concentrations as described above. The label may further indicate that the formulation is useful or intended for subcutaneous administration.

[0240] The container holding the formulation may be a multi-use vial, which allows for repeat administrations (e.g., from 2-6 administrations) of the reconstituted formulation. The kit may further comprise a second container comprising a suitable diluent (e.g., sodium bicarbonate solution).

[0241] Upon mixing of the diluent and the lyophilized formulation, the final peptide concentration in the reconstituted formulation is preferably at least 0.15 mg / mL / peptide (=75 µg) and preferably not more than 3 mg / mL / peptide (=1500 µg). The kit may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, syringes, and package inserts with instructions for use.

[0242] Kits of the present invention may have a single container that contains the formulation of the pharmaceutical compositions according to the present invention with or without other components (e.g., other compounds or pharmaceutical compositions of these other compounds) or may have distinct container for each component.

[0243] Preferably, kits of the invention include a formulation of the invention packaged for use in combination with the co-administration of a second compound (such as adjuvants (e.g. GM-CSF), a chemotherapeutic agent, a natural product, a hormone or antagonist, an anti-angiogenesis agent or inhibitor, an apoptosis-inducing agent or a chelator) or a pharmaceutical composition thereof. The components of the kit may be pre-complexed or each component may be in a separate distinct container prior to administration to a patient. The components of the kit may be provided in one or more liquid solutions, preferably, an aqueous solution, more preferably, a sterile aqueous solution. The components of the kit may also be provided as solids, which may be converted into liquids by addition of suitable solvents, which are preferably provided in another distinct container.

[0244] The container of a therapeutic kit may be a vial, test tube, flask, bottle, syringe, or any other means of enclosing a solid or liquid. Usually, when there is more than one component, the kit will contain a second vial or other container, which allows for separate dosing. The kit may also contain another container for a pharmaceutically acceptable liquid. Preferably, a therapeutic kit will contain an apparatus (e.g., one or more needles, syringes, eye droppers, pipette, etc.), which enables administration of the agents of the invention that are components of the present kit.

[0245] The present formulation is one that is suitable for administration of the peptides by any acceptable route such as oral (enteral), nasal, ophthal, subcutaneous, intradermal, intramuscular, intravenous or transdermal. Preferably, the administration is s.c., and most preferably i.d. administration may be by infusion pump.

[0246] Since the peptides of the invention were isolated from ovarian cancer, the medicament of the invention is preferably used to treat ovarian cancer.

[0247] The present invention will now be described in the following examples which describe preferred embodiments thereof, and with reference to the accompanying figures, nevertheless, without being limited thereto.FIGURES

[0248] Figures 1A to 1AE show the over-presentation of various peptides in normal tissues (white bars) and ovarian cancer (black bars). Figure 1A) Gene symbol: CLSR2, Peptide: VLVSDGVHSV (SEQ ID NO.: 6); Tissues from left to right: 1 adipose tissues, 3 adrenal glands, 6 arteries, 5 bone marrows, 7 brains, 3 breasts, 1 central nerve, 13 colons, 1 duodenum, 8 esophagi, 2 gallbladders, 5 hearts, 16 kidneys, 2 lymph nodes, 21 livers, 46 lungs, 1 lymph node metastasis, 4 leukocyte samples, 7 pancreas, 4 peripheral nerves, 1 peritoneum, 3 pituitary glands, 2 placentas, 3 pleuras, 3 prostates, 6 recti, 7 salivary glands, 3 skeletal muscles, 5 skins, 2 small intestines, 4 spleens, 7 stomachs, 4 testis, 3 thymi, 4 thyroid glands, 7 tracheas, 3 ureters, 6 urinary bladders, 2 uteri, 2 veins, 3 ovaries, 20 OC. The peptide has additionally been detected on 1 / 6 breast cancers, 1 / 2 Merkel cell carcinomas, 3 / 17 esophageal cancers, 3 / 91 lung cancers, 10 / 29 brain cancers, 1 / 22 renal cancers and 1 / 15 small cell lung cancers (not shown). Figure 1B) Gene symbol: CCNA1, Peptide: SLMEPPAVLLL (SEQ ID NO.: 1); Tissues from left to right: 1 adipose tissues, 3 adrenal glands, 6 arteries, 5 bone marrows, 7 brains, 3 breasts, 1 central nerve, 13 colons, 1 duodenum, 8 esophagi, 2 gallbladders, 5 hearts, 16 kidneys, 2 lymph nodes, 21 livers, 46 lungs, 1 lymph node metastasis, 4 leukocyte samples, 7 pancreas, 4 peripheral nerves, 1 peritoneum, 3 pituitary glands, 2 placentas, 3 pleuras, 3 prostates, 6 recti, 7 salivary glands, 3 skeletal muscles, 5 skins, 2 small intestines, 4 spleens, 7 stomachs, 4 testis, 3 thymi, 4 thyroid glands, 7 tracheas, 3 ureters, 6 urinary bladders, 2 uteri, 2 veins, 3 ovaries, 20 OC. The peptide has additionally been detected on 1 / 2 AMLs, 1 / 28 colorectal cancers, 2 / 17 esophageal cancers, 7 / 91 lung cancers, 1 / 29 brain cancers, 1 / 22 renal cancers and 2 / 15 small cell lung cancers (not shown). Figure 1C) Gene symbol: VTCN1, Peptide: ALLPLSPYL (SEQ ID NO.: 427); Tissues from left to right: 1 adipose tissues, 3 adrenal glands, 6 arteries, 5 bone marrows, 7 brains, 3 breasts, 1 central nerve, 13 colons, 1 duodenum, 8 esophagi, 2 gallbladders, 5 hearts, 16 kidneys, 2 lymph nodes, 21 livers, 46 lungs, 1 lymph node metastasis, 4 leukocyte samples, 7 pancreas, 4 peripheral nerves, 1 peritoneum, 3 pituitary glands, 2 placentas, 3 pleuras, 3 prostates, 6 recti, 7 salivary glands, 3 skeletal muscles, 5 skins, 2 small intestines, 4 spleens, 7 stomachs, 4 testis, 3 thymi, 4 thyroid glands, 7 tracheas, 3 ureters, 6 urinary bladders, 2 uteri, 2 veins, 3 ovaries, 20 OC. The peptide has additionally been detected on 4 / 43 prostate cancers, 3 / 6 breast cancers, 4 / 16 liver cancers, 1 / 17 esophageal cancers, 4 / 19 pancreatic cancers, 19 / 91 lung cancers, 1 / 15 small cell lung cancers, 1 / 4 urinary bladder cancers and 3 / 4 uterine cancers (not shown). Figure 1D) Gene symbol: AP1B1, Peptide: FLDTLKDLI SEQ ID NO.: 514); Tissues from left to right: 6 cell lines (1 lyphocytic, 1 kidney, 1 pancreatic, 2 PBMCs, K562-A2), 4 normal tissues (2 bone marrows, 2 spleens), 49 cancer tissues (1 breast cancer, 3 colon cancers, 2 esophageal cancers, 1 gallbladder cancer, 2 leukemias, 3 liver cancers, 21 lung cancers, 7 ovarian cancers,23 rectum cancers, 1 skin cancer, 4 stomach cancers, 1 testis cancer, 1 urinary bladder cancer). The normal tissue panel and the cancer cell lines and xenografts tested were the same as in Figure 1A-C, consisting of 1 adipose tissue, 3 adrenal glands, 6 arteries, 5 bone marrows, 7 brains, 3 breasts, 1 central nerve, 13 colons, 1 duodenum, 8 esophagi, 2 gallbladders, 5 hearts, 16 kidneys, 2 lymph nodes, 21 livers, 46 lungs, 1 lymph node metastasis, 4 leukocyte samples, 7 pancreas, 4 peripheral nerves, 1 peritoneum, 3 pituitary glands, 2 placentas, 3 pleuras, 3 prostates, 6 recti, 7 salivary glands, 3 skeletal muscles, 5 skins, 2 small intestines, 4 spleens, 7 stomachs, 4 testes, 3 thymi, 4 thyroid glands, 7 tracheas, 3 ureters, 6 urinary bladders, 2 uteri, 2 veins, 3 ovaries, 20 OC. The peptide has additionally been detected on 2 / 12 chronic lymphocytic leukemias, 5 / 28 colorectal cancers, 2 / 16 liver cancers, 1 / 2 melanomas, 2 / 17 esophageal cancers, 17 / 91 lung cancers, 4 / 46 stomach cancers, 4 / 15 small cell lung cancers and 1 / 4 urinary bladder cancers. Discrepancies regarding the list of tumor types between figure 1D and table 4 might be due to the more stringent selection criteria applied in table 4 (for details please refer to table 4). Figure 1D shows all samples with detectable presentation of the peptide Y, regardless of over-presentation parameters and technical sample quality check. Figure 1E) Gene symbol(s): CELSR2, Peptide: VLVSDGVHSV (SEQ ID NO.: 6). Tissues from left to right: 6 adipose tissues, 8 adrenal glands, 24 blood cells, 15 blood vessels, 10 bone marrows, 13 brains, 7 breasts, 9 esophagi, 2 eyes, 3 gallbladders, 16 hearts, 17 kidneys, 25 large intestines, 24 livers, 49 lungs, 7 lymph nodes, 12 nerves, 3 ovaries, 13 pancreases, 6 parathyroid glands, 1 peritoneum, 6 pituitary glands, 7 placentas, 1 pleura, 4 prostates, 7 salivary glands, 9 skeletal muscles, 11 skins, 9 small intestines, 12 spleens, 8 stomachs, 5 testes, 3 thymi, 5 thyroid glands, 16 tracheas, 7 ureters, 8 urinary bladders, 6 uteri, 20 ovarian cancer samples. The peptide has additionally been found on 15 / 34 brain cancers, 3 / 18 breast cancers, 3 / 18 esophageal cancers, 4 / 12 head and neck cancers, 1 / 23 kidney cancers, 6 / 107 lung cancers, 5 / 18 skin cancers, 5 / 15 urinary bladder cancers, 3 / 16 uterus cancers. Figure 1F) Gene symbol(s): SUCO, Peptide: LLLDITPEI (SEQ ID NO.: 143). Tissues from left to right: 6 adipose tissues, 8 adrenal glands, 24 blood cells, 15 blood vessels, 10 bone marrows, 13 brains, 7 breasts, 9 esophagi, 2 eyes, 3 gallbladders, 16 hearts, 17 kidneys, 25 large intestines, 24 livers, 49 lungs, 7 lymph nodes, 12 nerves, 3 ovaries, 13 pancreases, 6 parathyroid glands, 1 peritoneum, 6 pituitary glands, 7 placentas, 1 pleura, 4 prostates, 7 salivary glands, 9 skeletal muscles, 11 skins, 9 small intestines, 12 spleens, 8 stomachs, 5 testes, 3 thymi, 5 thyroid glands, 16 tracheas, 7 ureters, 8 urinary bladders, 6 uteri, 20 ovarian cancer samples. The peptide has additionally been found on 2 / 34 brain cancers, 4 / 18 breast cancers, 2 / 18 esophageal cancers, 1 / 12 head and neck cancers, 2 / 21 liver cancers, 6 / 107 lung cancers, 2 / 18 skin cancers, 1 / 45 stomach cancers, 2 / 15 urinary bladder cancers. Figure 1G) Gene symbol(s): PLAUR, Peptide: RLWEEGEELEL (SEQ ID NO.: 150). Tissues from left to right: 6 adipose tissues, 8 adrenal glands, 24 blood cells, 15 blood vessels, 10 bone marrows, 13 brains, 7 breasts, 9 esophagi, 2 eyes, 3 gallbladders, 16 hearts, 17 kidneys, 25 large intestines, 24 livers, 49 lungs, 7 lymph nodes, 12 nerves, 3 ovaries, 13 pancreases, 6 parathyroid glands, 1 peritoneum, 6 pituitary glands, 7 placentas, 1 pleura, 4 prostates, 7 salivary glands, 9 skeletal muscles, 11 skins, 9 small intestines, 12 spleens, 8 stomachs, 5 testes, 3 thymi, 5 thyroid glands, 16 tracheas, 7 ureters, 8 urinary bladders, 6 uteri, 20 ovarian cancer samples. The peptide has additionally been found on 4 / 17 gallbladder and bile duct cancers, 1 / 18 breast cancers, 1 / 29 colon cancers, 2 / 18 esophageal cancers, 1 / 12 head and neck cancers, 10 / 107 lung cancers, 2 / 18 skin cancers, 1 / 16 uterus cancers. Figure 1H) Gene symbol(s): HEATR2, Peptide: SLNDEVPEV (SEQ ID NO.: 157). Tissues from left to right: 6 adipose tissues, 8 adrenal glands, 24 blood cells, 15 blood vessels, 10 bone marrows, 13 brains, 7 breasts, 9 esophagi, 2 eyes, 3 gallbladders, 16 hearts, 17 kidneys, 25 large intestines, 24 livers, 49 lungs, 7 lymph nodes, 12 nerves, 3 ovaries, 13 pancreases, 6 parathyroid glands, 1 peritoneum, 6 pituitary glands, 7 placentas, 1 pleura, 4 prostates, 7 salivary glands, 9 skeletal muscles, 11 skins, 9 small intestines, 12 spleens, 8 stomachs, 5 testes, 3 thymi, 5 thyroid glands, 16 tracheas, 7 ureters, 8 urinary bladders, 6 uteri, 20 ovarian cancer samples. The peptide has additionally been found on 1 / 17 bile duct cancers, 5 / 34 brain cancers, 1 / 18 breast cancers, 1 / 29 colon cancers, 2 / 18 esophageal cancers, 1 / 12 head and neck cancers, 2 / 23 kidney cancers, 1 / 21 liver cancers, 4 / 107 lung cancers, 2 / 20 lymph node cancers, 1 / 18 skin cancers, 1 / 15 urinary bladder cancers, 1 / 16 uterus cancers. Figure 1I) Gene symbol(s): VTCN1, Peptide: ALLPLSPYL (SEQ ID NO.: 427). Tissues from left to right: 6 adipose tissues, 8 adrenal glands, 24 blood cells, 15 blood vessels, 10 bone marrows, 13 brains, 7 breasts, 9 esophagi, 2 eyes, 3 gallbladders, 16 hearts, 17 kidneys, 25 large intestines, 24 livers, 49 lungs, 7 lymph nodes, 12 nerves, 3 ovaries, 13 pancreases, 6 parathyroid glands, 1 peritoneum, 6 pituitary glands, 7 placentas, 1 pleura, 4 prostates, 7 salivary glands, 9 skeletal muscles, 11 skins, 9 small intestines, 12 spleens, 8 stomachs, 5 testes, 3 thymi, 5 thyroid glands, 16 tracheas, 7 ureters, 8 urinary bladders, 6 uteri, 20 ovarian cancer samples. The peptide has additionally been found on 7 / 17 gallbladder and bile duct cancers, 9 / 18 breast cancers, 2 / 18 esophageal cancers, 1 / 12 head and neck cancers, 7 / 21 liver cancers, 22 / 107 lung cancers, 4 / 19 pancreas cancers, 4 / 87 prostate cancers, 2 / 15 urinary bladder cancers, 11 / 16 uterus cancers. Figure 1J) Gene symbol(s): DDX11, DDX12P, LOC642846, Peptide: GLLRDEALAEV (SEQ ID NO.: 444). Tissues from left to right: 6 adipose tissues, 8 adrenal glands, 24 blood cells, 15 blood vessels, 10 bone marrows, 13 brains, 7 breasts, 9 esophagi, 2 eyes, 3 gallbladders, 16 hearts, 17 kidneys, 25 large intestines, 24 livers, 49 lungs, 7 lymph nodes, 12 nerves, 3 ovaries, 13 pancreases, 6 parathyroid glands, 1 peritoneum, 6 pituitary glands, 7 placentas, 1 pleura, 4 prostates, 7 salivary glands, 9 skeletal muscles, 11 skins, 9 small intestines, 12 spleens, 8 stomachs, 5 testes, 3 thymi, 5 thyroid glands, 16 tracheas, 7 ureters, 8 urinary bladders, 6 uteri, 20 ovarian cancer samples. The peptide has additionally been found on 2 / 18 breast cancers, 3 / 29 colon or rectum cancers, 1 / 18 esophageal cancers, 1 / 12 head and neck cancers, 1 / 23 kidney cancers, 2 / 17 leukocytic leukemia cancers, 9 / 107 lung cancers, 6 / 20 lymph node cancers, 1 / 18 myeloid cells cancer, 2 / 18 skin cancers, 2 / 15 urinary bladder cancers, 1 / 16 uterus cancers. Figure 1K) Gene symbol(s): KDM1B, Peptide: KLAEGLDIQL (SEQ ID NO.: 449). Tissues from left to right: 6 adipose tissues, 8 adrenal glands, 24 blood cells, 15 blood vessels, 10 bone marrows, 13 brains, 7 breasts, 9 esophagi, 2 eyes, 3 gallbladders, 16 hearts, 17 kidneys, 25 large intestines, 24 livers, 49 lungs, 7 lymph nodes, 12 nerves, 3 ovaries, 13 pancreases, 6 parathyroid glands, 1 peritoneum, 6 pituitary glands, 7 placentas, 1 pleura, 4 prostates, 7 salivary glands, 9 skeletal muscles, 11 skins, 9 small intestines, 12 spleens, 8 stomachs, 5 testes, 3 thymi, 5 thyroid glands, 16 tracheas, 7 ureters, 8 urinary bladders, 6 uteri, 20 ovarian cancer samples. The peptide has additionally been found on 3 / 29 colon or rectum cancers, 6 / 107 lung cancers, 1 / 20 lymph node cancers. Figure 1L) Gene symbol(s): CCNA1, Peptide: SLMEPPAVLLL (SEQ ID NO.: 1). Tissues from left to right: 1 cancer cell line, 1 normal tissue (1 lymph node), 45 cancer tissues (3 bone marrow cancers, 1 brain cancer, 1 breast cancer, 2 esophageal cancers, 1 head and neck cancer, 1 kidney cancer, 3 leukocytic leukemia cancers, 12 lung cancers, 1 myeloid cell cancer, 11 ovarian cancers, 2 urinary bladder cancers, 7 uterus cancers. The normal tissue panel tested was the same as in Figure 1E-K. Figure 1M) Gene symbol(s): CT45A5, LOC101060208, CT45A3, CT45A1, LOC101060211, CT45A6, CT45A4, LOC101060210, CT45A2, Peptide: KIFEMLEGV (SEQ ID NO.: 11). Tissues from left to right: 3 normal tissues (1 brain, 1 lung, 1 ureter), 21 cancer tissues (1 bile duct cancer, 1 esophageal cancer, 1 liver cancer, 10 lung cancers, 1 lymph node cancer, 5 ovarian cancers, 2 uterus cancers). The normal tissue panel tested was the same as in Figure 1E-K. Figure 1N) Gene symbol(s): FGFR1OP, Peptide: KLDDLTQDLTV (SEQ ID NO.: 32). Tissues from left to right: 1 cell line, 1 normal tissue (1 liver), 29 cancer tissues (2 bile duct cancers, 1 esophageal cancer, 2 head and neck cancers, 4 liver cancers, 4 lung cancers, 3 lymph node cancers, 8 ovarian cancers, 1 prostate cancer, 1 rectum cancer, 2 urinary bladder cancers, 1 uterus cancer). The normal tissue panel tested was the same as in Figure 1E-K. Figure 1O) Gene symbol(s): TSEN15, Peptide: FLLEDDIHVS (SEQ ID NO.: 38). Tissues from left to right: 1 primary culture, 1 normal tissue (1 trachea), 28 cancer tissues (2 breast cancers, 1 head and neck cancer, 4 leukocytic leukemia cancers, 5 lung cancers, 6 lymph node cancers, 1 myeloid cell cancer, 2 ovarian cancers, 1 rectum cancer, 3 skin cancers, 2 urinary bladder cancers, 1 uterus cancer). The normal tissue panel tested was the same as in Figure 1E-K. Figure 1P) Gene symbol(s): ZNF527, ZNF829, ZNF383, ZNF850, ZNF583, Peptide: SLLEQGKEPWMV (SEQ ID NO.: 54). Tissues from left to right: 1 cell line, 18 cancer tissues (2 brain cancers, 1 breast cancer, 1 gallbladder cancer, 1 leukocytic leukemia cancer, 2 liver cancers, 7 lung cancers, 1 lymph node cancer, 2 ovarian cancers, 1 urinary bladder cancer). The normal tissue panel tested was the same as in Figure 1E-K. Figure 1Q) Gene symbol(s): CAMSAP1, Peptide: TLAELQPPVQL (SEQ ID NO.: 57). Tissues from left to right: 4 cell lines and primary cultures, 32 cancer tissues (1 bile duct cancer, 1 brain cancer, 2 esophageal cancers, 3 head and neck cancers, 2 leukocytic leukemia cancers, 1 liver cancer, 9 lung cancers, 4 lymph node cancers, 5 ovarian cancers, 2 skin cancers, 1 urinary bladder cancer, 1 uterus cancer). The normal tissue panel tested was the same as in Figure 1E-K. Figure 1R) Gene symbol(s): STK38L, Peptide: ILVEADGAWVV (SEQ ID NO.: 77). Tissues from left to right: 4 cell lines, 19 cancer tissues (1 brain cancer, 2 breast cancers, 1 colon cancer, 1 leukocytic leukemia cancer, 4 lung cancers, 3 lymph node cancers, 3 ovarian cancers, 1 prostate cancer, 1 skin cancer, 1 urinary bladder cancer, 1 uterus cancer). The normal tissue panel tested was the same as in Figure 1E-K. Figure 1S) Gene symbol(s): PIGA, Peptide: ALNPEIVSV (SEQ ID NO.: 148). Tissues from left to right: 3 cell lines, 20 cancer tissues (1 esophageal cancer, 2 head and neck cancers, 1 leukocytic leukemia cancer, 5 lung cancers, 3 lymph node cancers, 2 ovarian cancers, 2 skin cancers, 4 urinary bladder cancers). The normal tissue panel tested was the same as in Figure 1E-K. Figure 1T) Gene symbol(s): NPLOC4, Peptide: YLNHLEPPV (SEQ ID NO.: 166). Tissues from left to right: 2 cell lines, 20 cancer tissues (3 brain cancers, 1 breast cancer, 1 esophageal cancer, 3 leukocytic leukemia cancers, 2 liver cancers, 4 lung cancers, 2 lymph node cancers, 1 myeloid cells cancer, 3 ovarian cancers). The normal tissue panel tested was the same as in Figure 1E-K. Figure 1U) Gene symbol(s): RNF213, Peptide: YLMDINGKMWL (SEQ ID NO.: 184). Tissues from left to right: 1 cell line, 19 cancer tissues (1 breast cancer, 1 gallbladder cancer, 1 leukocytic leukemia cancer, 6 lung cancers, 2 lymph node cancers, 5 ovarian cancers, 2 skin cancers, 1 uterus cancer). The normal tissue panel tested was the same as in Figure 1E-K. Figure 1V) Gene symbol(s): SKIL, Peptide: KTINKVPTV (SEQ ID NO.: 198). Tissues from left to right: 2 cell lines and primary cultures, 1 normal tissue (1 lung), 36 cancer tissues (3 brain cancers, 2 breast cancers, 2 colon cancers, 1 head and neck cancer, 1 liver cancer, 14 lung cancers, 1 lymph node cancer, 8 ovarian cancers, 1 rectum cancer, 2 urinary bladder cancers, 1 uterus cancer). The normal tissue panel tested was the same as in Figure 1E-K. Figure 1W) Gene symbol(s): SEC24C, Peptide: FLFPNQYVDV (SEQ ID NO.: 248). Tissues from left to right: 3 cell lines and primary cultures, 1 normal tissue (1 spleen), 24 cancer tissues (1 bile duct cancer, 2 breast cancers, 2 leukocytic leukemia cancers, 1 liver cancer, 9 lung cancers, 2 lymph node cancers, 3 ovarian cancers, 1 prostate cancer, 2 skin cancers, 1 uterus cancer). The normal tissue panel tested was the same as in Figure 1E-K. Figure 1X) Gene symbol(s): PDIK1L, STK35, Peptide: ALLENPKMEL (SEQ ID NO.: 441). Tissues from left to right: 5 cell lines and primary cultures, 1 normal tissue (1 adrenal gland), 26 cancer tissues (1 breast cancer, 1 colon cancer, 1 esophageal cancer, 1 head and neck cancer, 2 liver cancers, 10 lung cancers, 5 ovarian cancers, 1 prostate cancer, 1 rectum cancer, 2 urinary bladder cancers, 1 uterus cancer). The normal tissue panel tested was the same as in Figure 1E-K. Figure 1Y) Gene symbol(s): EMC10, Peptide: SLVESHLSDQLTL (SEQ ID NO.: 463). Tissues from left to right: 1 primary culture, 32 cancer tissues (1 bile duct cancer, 2 brain cancers, 2 breast cancers, 2 head and neck cancers, 3 leukocytic leukemia cancers, 1 liver cancer, 8 lung cancers, 3 lymph node cancers, 5 ovarian cancers, 2 skin cancers, 2 urinary bladder cancers, 1 uterus cancer). The normal tissue panel tested was the same as in Figure 1E-K. Figure 1Z) Gene symbol(s): ZYG11A, Peptide: VLIANLEKL (SEQ ID NO.: 466). Tissues from left to right: 5 cell lines, 17 cancer tissues (3 breast cancers, 2 esophageal cancers, 1 liver cancer, 2 lung cancers, 5 lymph node cancers, 3 ovarian cancers, 1 urinary bladder cancer). The normal tissue panel tested was the same as in Figure 1E-K. Figure 1AA) Gene symbol(s): CEP192, Peptide: SLFGNSGILENV (SEQ ID NO.: 479). Tissues from left to right: 7 cell lines, 1 normal tissue (1 spleen), 33 cancer tissues (1 breast cancer, 1 colon cancer, 1 esophageal cancer, 1 head and neck cancer, 1 leukocytic leukemia cancer, 3 liver cancers, 10 lung cancers, 1 lymph node cancer, 1 myeloid cell cancer, 7 ovarian cancers, 2 skin cancers, 3 urinary bladder cancers, 1 uterus cancer). The normal tissue panel tested was the same as in Figure 1E-K. Figure 1AB) Gene symbol(s): CCNA1, Peptide: SLSEIVPCL (SEQ ID NO.: 512). Tissues from left to right: 9 cancer tissues (1 head and neck cancer, 2 lung cancers, 1 myeloid cell cancer, 3 ovarian cancers, 2 uterus cancers). The normal tissue panel tested was the same as in Figure 1E-K. Figure 1AC) Gene symbol(s): GNB1, Peptide: ALWDIETGQQTTT (SEQ ID NO.: 560), Tissues from left to right: 5 cell lines and primary cultures, 26 cancer tissues (1 brain cancer, 1 esophageal cancer, 1 esophageal and stomach cancer, 1 gallbladder cancer, 2 head and neck cancers, 1 leukocytic leukemia cancer, 1 liver cancer, 5 lung cancers, 6 lymph node cancers, 3 ovarian cancers, 1 prostate cancer, 1 skin cancer, 1 urinary bladder cancer, 1 uterus cancer). The normal tissue panel tested was the same as in Figure 1E-K. Figure 1AD) Gene symbol(s): KLHL14, Peptide: VMNDRLYAI (SEQ ID NO.: 587), Tissues from left to right: 5 normal tissues (1 pancreas, 3 spleens, 1 thyroid gland), 38 cancer tissues (14 leukocytic leukemia cancers, 10 lymph node cancers, 9 ovarian cancers, 1 prostate cancer, 4 uterus cancers). The normal tissue panel tested was the same as in Figure 1E-K. Figure 1AE) Gene symbol(s): URB1, Peptide: KLLNKIYEA (SEQ ID NO.: 620), Tissues from left to right: 3 cell lines and primary cultures, 2 normal tissues (1 lung, 1 uterus), 27 cancer tissues (5 brain cancers, 2 breast cancers, 2 esophageal cancers, 5 lung cancers, 1 lymph node cancer, 1 myeloid cell cancer, 5 ovarian cancers, 3 prostate cancers, 1 rectum cancer, 1 urinary bladder cancer, 1 uterus cancer). The normal tissue panel tested was the same as in Figure 1E-K. Figures 2A to 2D show exemplary expression profiles of source genes as disclosed that are highly over-expressed or exclusively expressed in ovarian cancer in a panel of normal tissues (white bars) and 20 ovarian cancer samples (black bars). Tissues from left to right: 7 arteries, 1 brain, 1 heart, 2 livers, 2 lungs, 2 veins, 1 adipose tissue, 1 adrenal gland, 4 bone marrows, 1 colon, 2 esophagi, 2 gallbladders, 1 kidney, 6 lymph nodes, 1 pancreas, 1 pituitary gland, 1 rectum, 1 skeletal muscle, 1 skin, 1 small intestine, 1 spleen, 1 stomach, 1 thymus, 1 thyroid gland, 5 tracheae, 1 urinary bladder, 1 breast, 3 ovaries, 3 placentae, 1 prostate, 1 testis, 1 uterus. Figure 2A) CT45A1, CT45A3, CT45A5, CT45A6, CT45A2, RP11-342L5.1, Figure 2B) CLDN16; Figure 2C) ESR1; Figure 2D) IDO1. Figure 3A to F shows exemplary immunogenicity data: flow cytometry results after peptide-specific multimer staining. CD8+ T cells were primed using artificial APCs coated with anti-CD28 mAb and HLA-A*02 in complex with SeqID No 662 (A, left panel), SeqID No 663 (B, left panel), SeqID No 11 peptide (C, left panel), SeqID No 198 peptide (D, left panel), SeqID No 587 peptide (E, left panel) and SeqID No 427 peptide (F, left panel), respectively. After three cycles of stimulation, the detection of peptide-reactive cells was performed by 2D multimer staining with A*02 / SeqID No 662 (A), A*02 / SeqID No 663 (B), A*02 / SeqID No 11 (C), A*02 / SeqID No 198 (D), A*02 / SeqID No 587 (E) or A*02 / SeqID No 427 (F). Right panels (A, B, C, D, E, and F) show control staining of cells stimulated with irrelevant A*02 / peptide complexes. Viable singlet cells were gated for CD8+ lymphocytes. Boolean gates helped excluding false-positive events detected with multimers specific for different peptides. Frequencies of specific multimer+ cells among CD8+ lymphocytes are indicated. EXAMPLESEXAMPLE 1Identification and quantitation of tumor associated peptides presented on the cell surfaceTissue samples

[0249] Patients' tumor tissues were obtained from Asterand (Detroit, USA and Royston, Herts, UK); Val d'Hebron University Hospital (Barcelona); ProteoGenex Inc., (Culver City, CA, USA); Stanford Cancer Center (Stanford, CA, USA); University Hospital of Tubingen. Normal (healthy) tissues were obtained from Asterand (Detroit, USA and Royston, Herts, UK); Bio-Options Inc., CA, USA; BioServe, Beltsville, MD, USA; Capital BioScience Inc., Rockville, MD, USA; Geneticist Inc., Glendale, CA, USA; University Hospital of Geneva; University Hospital of Heidelberg; University Hospital Munich; ProteoGenex Inc., Culver City, CA, USA; University Hospital of Tubingen, Kyoto Precatural University if Medicine (KPUM). Written informed consents of all patients had been given before surgery or autopsy. Tissues were shock-frozen immediately after excision and stored until isolation of TUMAPs at -70°C or below.Isolation of HLA peptides from tissue samples

[0250] HLA peptide pools from shock-frozen tissue samples were obtained by immune precipitation from solid tissues according to a slightly modified protocol (Falk et al., 1991; Seeger et al., 1999) using the HLA-A*02-specific antibody BB7.2, the HLA-A, -B, - C-specific antibody W6 / 32, CNBr-activated sepharose, acid treatment, and ultrafiltration.Mass spectrometry analyses

[0251] The HLA peptide pools as obtained were separated according to their hydrophobicity by reversed-phase chromatography (nanoAcquity UPLC system, Waters) and the eluting peptides were analyzed in LTQ- velos and fusion hybrid mass spectrometers (ThermoElectron) equipped with an ESI source. Peptide pools were loaded directly onto the analytical fused-silica micro-capillary column (75 µm i.d. x 250 mm) packed with 1.7 µm C18 reversed-phase material (Waters) applying a flow rate of 400 nL per minute. Subsequently, the peptides were separated using a two-step 180 minute-binary gradient from 10% to 33% B at a flow rate of 300 nL per minute. The gradient was composed of Solvent A (0.1% formic acid in water) and solvent B (0.1% formic acid in acetonitrile). A gold coated glass capillary (PicoTip, New Objective) was used for introduction into the nanoESI source. The LTQ-Orbitrap mass spectrometers were operated in the data-dependent mode using a TOP5 strategy. In brief, a scan cycle was initiated with a full scan of high mass accuracy in the Orbitrap (R = 30 000), which was followed by MS / MS scans also in the Orbitrap (R = 7500) on the 5 most abundant precursor ions with dynamic exclusion of previously selected ions. Tandem mass spectra were interpreted by SEQUEST and additional manual control. The identified peptide sequence was assured by comparison of the generated natural peptide fragmentation pattern with the fragmentation pattern of a synthetic sequence-identical reference peptide.

[0252] Label-free relative LC-MS quantitation was performed by ion counting i.e. by extraction and analysis of LC-MS features (Mueller et al., 2007). The method assumes that the peptide's LC-MS signal area correlates with its abundance in the sample. Extracted features were further processed by charge state deconvolution and retention time alignment (Mueller et al., 2008; Sturm et al., 2008). Finally, all LC-MS features were cross-referenced with the sequence identification results to combine quantitative data of different samples and tissues to peptide presentation profiles. The quantitative data were normalized in a two-tier fashion according to central tendency to account for variation within technical and biological replicates. Thus each identified peptide can be associated with quantitative data allowing relative quantification between samples and tissues. In addition, all quantitative data acquired for peptide candidates was inspected manually to assure data consistency and to verify the accuracy of the automated analysis. For each peptide a presentation profile was calculated showing the mean sample presentation as well as replicate variations. The profiles juxtapose ovarian cancer samples to a baseline of normal tissue samples. Presentation profiles of exemplary over-presented peptides are shown in Figure 1. Presentation scores for exemplary peptides are shown in Table 8. Table 8: Presentation scores. The table lists peptides that are very highly over-presented on tumors compared to a panel of normal tissues (+++), highly over-presented on tumors compared to a panel of normal tissues (++) or over-presented on tumors compared to a panel of normal tissues (+). The panel of normal tissues consisted of: adipose tissue, adrenal gland, artery, vein, bone marrow, brain, central and peripheral nerve, colon, rectum, small intestine incl. duodenum, esophagus, gallbladder, heart, kidney, liver, lung, lymph node, mononuclear white blood cells, pancreas, peritoneum, pituitary, pleura, salivary gland, skeletal muscle, skin, spleen, stomach, thymus, thyroid gland, trachea, ureter, urinary bladder.SEQ ID No.SequencePeptide Presentation1SLMEPPAVLLL+++2SLLEADPFL+++3SLASKLTTL+++4GIMEHITKI+++5HLTEVYPEL+++6VLVSDGVHSV+++7SLVGLLLYL+++8FTLGNVVGMYL+++9GAAKDLPGV++10FLATFPLAAV+++11KIFEMLEGV+++12SLWPDPMEV+++13YLMDESLNL+++14AAYGGLNEKSFV+++15VLLTFKIFL+++16VLFQGQASL++17GLLPGDRLVSV+++18YLVAKLVEV+++20RMIEYFIDV+++21VLDELDMEL+++23VLLDDIFAQL+++24SLSDGLEEV++25FLPDEPYIKV+++26ALLELAEEL+++27ILADIVISA+28QLLDETSAITL+++29KMLGIPISNILMV++30LILDWVPYI++31YLAPELFVNV+++32KLDDLTQDLTV+++33VLLSLLEKV++34ILVEADSLWVV+++35KINDTIYEV+++36YVLEDLEVTV+++37LLWDVVTGQSV+++38FLLEDDIHVS+++39SVAPNLPAV+++40TLLVKVFSV+++41SLMPHIPGL+++42VLLQKIVSA+++43VLSSLEINI+44ILDPISSGFLL+++45SLWQDIPDV+++46ILTEENIHL+++47ILLSVPLLVV+++48ALAELYEDEV+++50SLSELEALM+++51LLPDLEFYV+++52FLLAHGLGFLL+++53KMIETDILQKV+++54SLLEQGKEPWMV+++55SLLDLETLSL+++56KLYEGIPVLL+++57TLAELQPPVQL+++58FLDTLKDLI++59IMEDIILTL+++60SLTIDGIYYV+++61FLQGYQLHL+++62VLLDVSAGQLLM+++63YLLPSGGSVTL+++64YAAPGGLIGV+65LKVNQGLESL+++67TLLAEALVTV+++68SLMELPRGLFL+++69FQLDPSSGVLVTV+++70GLLDYPVGV+++71GILARIASV+++72SLLELDGINL+++73NIFDLQIYV+++74ALLDPEVLSIFV+++75GLLEVMVNL+++76ILIDSIYKV+++77I LVEADGAWVV+++78SLFSSLEPQIQPV+++79SLFIGEKAVLL++81FLFSQLQYL+++82FLSSVTYNL+++83ILAPTVMMI+++84VTFGEKLLGV+++86NLIGKIENV+87ALPEAPAPLLPHIT+++88FLLVGDLMAV+++89YILPTETIYV+++90TLLQIIETV+++91IMQDFPAEIFL+++92YLIPFTGIVGL+++93LLQAIKLYL+++94YLIDIKTIAI+++96YIFTDNPAAV+++97SLINGSFLV+++98LIIDQADIYL+++99ALVSKGLATV+++100YLLSTNAQL+++101ILVGGGALATV+++102YLFESEGLVL+++103TLAEEVVAL+++105LLLEHSFEI++106LLYDAVHIVSV+++107FLQPVDDTQHL+++108ALFPGVALLLA+++109IILSILEQA+++110FLSQVDFEL+++111YVWGFYPAEV+++112FLITSNNQL+++113GLLPTPLFGV+++114SLVGEPILQNV+++116YHIDEEVGF+++117ILPDGEDFLAV+++118KLIDNNINV+++119FLYIGDIVSL++120ALLGIPLTLV+++122FLLAEDDIYL+++123NLWDLTDASVV+++124ALYETELADA+++125VQIHQVAQV+++126VLAYFLPEA+127KIGDEPPKV++129GLLDGGVDILL++130FLWNGEDSALL+++131FVPPVTVFPSL+++132LLVEQPPLAGV+++134YLQELIFSV+++135ALSEVDFQL+++136YLADPSNLFVV+++137TLVLTLPTV+++138YQYPRAILSV+++139SVMEVNSGIYRV+++141YLDFSNNRL+++142FLFATPVFI+++143LLLDITPEI+++144YIMEPSIFNTL++145FLATSGTLAGI+++146SLATAGDGLIEL+++147SLLEAVSFL+148ALNPEIVSV+++149NLLELFVQL+++150RLWEEGEELEL+++151KILQQLVTL+++152ILFEDIFDV+++153FLIANVLYL+++155RVANLHFPSV+156AISQGITLPSL+++157SLNDEVPEV+++158KLFDVDEDGYI+++159GLVGNPLPSV+++160FLFDEEIEQI++161ALLEGVNTV+++162YQQAQVPSV+++163ALDEMGDLLQL+++164ALLPQPKNLTV+++165SLLDEIRAV+++166YLNHLEPPV+++167KVLEVTEEFGV++168KILDADIQL+++169NLPEYLPFV+++170RLQETLSAA+++171LLLPLQILL+++172VLYSYTIITV+++173LLDSASAGLYL+++174ALAQYLITA++175YLFENISQL+++176YLMEGSYNKVFL+++177YLLPEEYTSTL+++178ALTEIAFVV+179KVLNELYTV+++180FQIDPHSGLVTV+++181LLWAGTAFQV+++182MLLEAPGIFL+++183FGLDLVTEL++184YLMDINGKMWL+++185FLIDDKGYTL+++186TLFFQQNAL+187RQISIRGIVGV+++188GLFPVTPEAV+189ALQRKLPYV+++190FLSSLTETI+++191LLQEGQALEYV+++192KMLDGASFTL+++193QLLDADGFLNV+++194ALPLFVITV+++196YLYSVEIKL+++197ALGPEGGRV++198KTINKVPTV+++199ALQDVPLSSV+++200LLFGSVQEV+++201RLVDYLEGI+++202ALLDQQGSRWTL+++203VLLEDAHSHTL+++204KIAENVEEV+++205SLYPGTETMGL+++206VLQEGKLQKLAQL+++208KISPVTFSV+++209KLIESKHEV+++210LLLNAVLTV++211LLWPGAALL+++212ALWDQDNLSV+++213VTAAYMDTVSL++215QLINHLHAV+++216NLWEDPYYL+++217ALIHPVSTV+++218SALEELVNV+++219KLSDIGITV+++220LLQKFVPEI+++221ALYEEGLLL+++222NLIENVQRL++223ALLENIALYL+++224TLIDAQWVL+++225SLLKVLPAL+++226MLYVVPIYL+++227ALMNTLLYL+++228AMQEYIAVV+229RLPGPLGTV++230ILVDWLVEV+++231FLSPQQPPLLL+++232ALLEAQDVELYL+++233VLSETLYEL++234ALMEDTGRQML+++235YLNDLHEVLL+++236GLLEAKVSL+++237ALLEASGTLLL+++238YLISFQTHI+++239AAFAGKLLSV+++240ILLEQAFYL+++241SLVEVNPAYSV+++242AIAYILQGV+++243LLLNELPSV++244SLFGGTEITI+++245SMIDDLLGV+++246LLWEVVSQL+++247VLLPNDLLEKV+++248FLFPNQYVDV+249LLDGFLVNV+++251ALYTGFSILV+++252LLIGTDVSL+++253GLDAATATV+++254TLLAFIMEL+++255VLASYNLTV+++256FLPPEHTIVYI+++257SIFSAFLSV+++259TLMRQLQQV++261YVLEFLEEI+263LLVSNLDFGV+++267ALQDFLLSV+++271LVYPLELYPA++274SLLFSLFEA+275YLVYILNEL+277LLPPLESLATV+278QLLDVVLTI+279ALWGGTQPLL++280VLPDPEVLEAV+281ILRESTEEL+282LLADVVPTT+285QLLHVGVTV+288NLINEINGV+++289VLLEIEDLQV+292LLWEAGSEA+296FMEGAIIYV++298VMITKLVEV++303AILPQLFMV+307ALPVSLPQI+308SQYSGQLHEV+311RLYTGMHTV+315YLQDVVEQA++318GLINTGVLSV+319SLEPQIQPV+320KMFEFVEPLL+321GLFEDVTQPGILL++322TLMTSLPAL++323IQIGEETVITV+325FIMPATVADATAV+++327GLAPFTEGISFV++328ALNDQVFEI+331KVDTVWVNV+332YLISELEAA+333FLPDANSSV++334TLTKVLVAL+338SVLEDPVHAV+341SQIALNEKLVNL+342HIYDKVMTV+343SLLEVNEESTV+345VIWKALIHL++346LLDSKVPSV++348ILLDVKTRL+++351SLIPNLRNV+++352SLLELLHIYV+356KLLGKLPEL++357SMHDLVLQV++358ALDEYTSEL+359YLLPESVDL+360ALDJGASLLHL+363KVLDVSDLESV++368ILLEEVSPEL+370SLLQDLVSV+372TMLLNIPLV+++373SLLEDKGLAEV+375SLTETIEGV+++379IMEGTLTRV+382ALQNYIKEA+384ILFANPNIFV+385SLLEQGLVEA+386ILFRYPLTI++390ALFMKQIYL++394LLAVIGGLVYL+395ALALGGIAVV++396ALLPDLPAL++397YLFGERLLEC+398KLLEEDGTIITL+399YLFEPLYHV+++401ILLDDTGLAYI+403KLYDRILRV++404AIDIJGRDPAV+406SVQGEDLYLV++410VLSDVIPJI++411LLAHLSPEL+413TLLEKVEGC++414YVDDIFLRV+415LLDKVYSSV+418ALAELENIEV+419GQYEGKVSSV+420FMYDTPQEV++421RLPETLPSL++423GLDGPPPTV+++424TLLDALYEI+425FLYEKSSQV+427ALLPLSPYL+++428KLGHTDILVGV++429GLVNDLARV+430HLYSSIEHLTT+431SLVNVVPKL+432TLIEESAKV+++433AMLNEPWAV+++434KVSNSGITRV+++435WLMPVIPAL+++436HLAEVSAEV+++437SMAPGLVIQAV+++438KLLPLAGLYL+++439YLLQEIYGI+++440ALADGVTMQV+++441ALLENPKMEL+++442GLLGGGGVLGV+++443GLWEIENNPTV++444GLLRDEALAEV+++446QLIPALAKV+++447QLVPALAKV+++448NLLETKLQL++450FMIDASVHPTL+++451LLLLDTVTMQV+++454KLPPPPPQA+++455SLLKEPQKVQL+456LLIGHLERV++457SLLPGNLVEKV+++458SLIDKLYNI+++459ALITEVVRL+++460AMLEKNYKL+++461VMFRTPLASV+++462KLAKQPETV+++463SLVESHLSDQLTL+++464ALNDCIYSV+++465QLCDLNAEL+++466VLIANLEKL+++468YLRSVGDGETV+470MLQDSIHVV+++471YLYNNMIAKI+++472KLLEVSDDPQV++473AMATESILHFA+++474YLDPALELGPRNV+475LLLNEEALAQI+++476ALMERTGYSMV+++477ALLPASGQIAL+++478YLLHEKLNL+++479SLFGNSGILENV+480ALLEDSCHYL+481GLIEDYEALL+++482SLAPAGIADA+++483ALTDIVSQV+486AVMESIQGV++487LLINSVFHV+488FLAEDPKVTL+489KMWEELPEVV+++490FLLQHVQEL+++491GLNDRSDAV+++492SLFDGFADGLGV+++494ALQPEPIKV+++495FIFSEKPVFV+496FLVEKQPPQV+++497GLLEKLTAI+498KLWTGGLDNTV+499KIFDIDEAEEGV+++500SLMEDQVLQL+501LLDPNVKSIFV++502RLLAQVPGL+++503SLNHFTHSV+504GLSDGNPSL+++505SLAPGDVVRQV+++506KLLGKVETA+++507KLIDDQDISISL+508ILAQEQLVVGV+++509FLFDTKPLIV+++510KLYSVVSQL+++511FLDPYCSASV+++512SLSEIVPCL+++513SLWPSPEQL+++514ILVDWLVQV+++515LLQELVLFL+++516AVGPASILKEV+++517LLMPIPEGLTL+518KLNAEVACV+++519GLLHL TLLL+++520LAVHPSGVAL++521MLLTKLPTI++522TLWYRSPEV+++523YQIPRTFTL+525VLLEAGEGLVTI+526RLAEVGQYEQV+527FLLEPGNLEV+++528SVAEGRALMSV+529LLADELITV++530VMYADIGGMDI+531YTLPIASSIRL+538LLLAHIIAL++539ALFDAQAQV++540ALI PETTTLTV++541SMLEPVPEL+543GLLPTPITQQASL+545LLADLLHNV+546VMIAGKVAVV+550FLYDEIEAEVNL+551KLYESLLPFA++554LLMPSSEDLLL++557KLYDDMIRL+558GLLENIPRV++560ALWDIETGQQTTT+561YLQLTQSEL+++563WLLPYNGVTV+564TVTNAVVTV++565ALQETPTSV++566VIADGGIQNV++568TLYDIAHTPGV++570ALANQIPTV+574YLLQEPPRTV+575YLISQVEGHQV+576ILLNNSGQIKL++579NLMEMVAQL++586KLKPGDLVGV+588SLLPLSHLV+589KLYPQLPAEI+590SLIEKLWQT+591SMAELDIKL++593GLPRFGIEMV+595VLLSIYPRV+597KLLEGQVIQL+599YLLNDASLISV++601SAFPFPVTV+603FLIEPEHVNTV+606ALWETEVYI++610LLAPTPYIIGV+613RLLPPGAVVAV++618VLFDSESIGIYV+619ALQDRVPLA+625VVLEGASLETV+626LLMATILHL++627KLLETELLQEI+629HLLNESPML++630LLSHVIVAL+631FLDVFLPRV+632YLIPDIDLKL++634VVAEFVPLI+637SIYGGFLLGV++638KLIQESPTV+639SLFQNCFEL+640YLFSEALNAA+ EXAMPLE 2Expression profiling of genes encoding the peptides as disclosed

[0253] Over-presentation or specific presentation of a peptide on tumor cells compared to normal cells is sufficient for its usefulness in immunotherapy, and some peptides are tumor-specific despite their source protein occurring also in normal tissues. Still, mRNA expression profiling adds an additional level of safety in selection of peptide targets for immunotherapies. Especially for therapeutic options with high safety risks, such as affinity-matured TCRs, the ideal target peptide will be derived from a protein that is unique to the tumor and not found on normal tissues.RNA sources and preparation

[0254] Surgically removed tissue specimens were provided as indicated above (see Example 1) after written informed consent had been obtained from each patient. Tumor tissue specimens were snap-frozen immediately after surgery and later homogenized with mortar and pestle under liquid nitrogen. Total RNA was prepared from these samples using TRI Reagent (Ambion, Darmstadt, Germany) followed by a cleanup with RNeasy (QIAGEN, Hilden, Germany); both methods were performed according to the manufacturer's protocol.

[0255] Total RNA from healthy human tissues for RNASeq experiments was obtained from: Asterand, Detroit, USA and Royston, Herts, UK; ProteoGenex Inc. Culver City, CA, USA, Geneticist Inc., Glendale, CA, USA, Istituto Nazionale Tumori "Pascale", Molecular Biology and Viral Oncology Unit (IRCCS), Naples, Italy, University Hospital of Heidelberg, Germany, BioCat GmbH, Heidelberg, Germany.

[0256] Quality and quantity of all RNA samples were assessed on an Agilent 2100 Bioanalyzer (Agilent, Waldbronn, Germany) using the RNA 6000 Pico LabChip Kit (Agilent).RNAseq experiments

[0257] Gene expression analysis of - tumor and normal tissue RNA samples was performed by next generation sequencing (RNAseq) by CeGaT (Tübingen, Germany). Briefly, sequencing libraries are prepared using the Illumina HiSeq v4 reagent kit according to the provider's protocol (Illumina Inc., San Diego, CA, USA), which includes RNA fragmentation, cDNA conversion and addition of sequencing adaptors. Libraries derived from multiple samples are mixed equimolar and sequenced on the Illumina HiSeq 2500 sequencer according to the manufacturer's instructions, generating 50 bp single end reads. Processed reads are mapped to the human genome (GRCh38) using the STAR software. Expression data are provided on transcript level as RPKM (Reads Per Kilobase per Million mapped reads, generated by the software Cufflinks) and on exon level (total reads, generated by the software Bedtools), based on annotations of the ensembl sequence database (Ensembl77). Exon reads are normalized for exon length and alignment size to obtain RPKM values.

[0258] Exemplary expression profiles of source genes as disclosed that are highly over-expressed or exclusively expressed in ovarian cancer are shown in Figures 2A to 2D. Expression scores for further exemplary genes are shown in Table 9. Table 9: Expression scores. The table lists peptides from genes that are very highly over-expressed in tumors compared to a panel of normal tissues (+++), highly over-expressed in tumors compared to a panel of normal tissues (++) or over-expressed in tumors compared to a panel of normal tissues (+). The baseline for this score was calculated from measurements of the following normal tissues: adipose tissue, adrenal gland, artery, bone marrow, brain, colon, esophagus, gallbladders, heart, kidney, liver, lung, lymph node, pancreas, pituitary, rectum, skeletal muscle, skin, small intestine, spleen, stomach, thymus, thyroid gland, trachea, urinary bladder, vein.SEQ ID No.Gene NameSequenceGene Expression1CCNA1SLMEPPAVLLL+++2CCNA1SLLEADPFL+++3MUC16SLASKLTTL+++4MUC16GIMEHITKI+++5MUC16HLTEVYPEL+++11CT45A1, CT45A3, CT45A5, CT45A6, CT45A2, RP11-342L5.1KIFEMLEGV+++15GPR64VLLTFKIFL+++21IFI30VLDELDMEL+25CLDN16FLPDEPYIKV+++41TDRD9SLMPHIPGL+42TDRD9VLLQKIVSA+45ARHGEF19SLWQDIPDV++67MUC20TLLAEALVTV+69FAT2FQLDPSSGVLVTV+++72VWDESLLELDGINL+++81NUP205FLFSQLQYL+101GPD2ILVGGGALATV+102GAS2L3YLFESEGLVL++113BPIFB3GLLPTPLFGV+++114BPIFB3SLVGEPILQNV+++115AQP5AIAGAGILYGV++116IDO1YHIDEEVGF+++118ITGB8KLIDNNINV++126MCM2VLAYFLPEA+171KLK7LLLPLQILL+++173KIF15LLDSASAGLYL+++181KIAA1324LLWAGTAFQV+183RNF213FGLDLVTEL++184RNF213YLMDINGKMWL++193CLSPNQLLDADGFLNV+++194SLC28A3ALPLFVITV++195MROH6GLFADLLPRL+197SOX17ALGPEGGRV++210UNGLLLNAVLTV+215BHLHE41QLINHLHAV++230CCNA2, CCNA1, CCNB3ILVDWLVEV+++233TIMELESSVLSETLYEL++235CCNE1YLNDLHEVLL++239RSAD2AAFAGKLLSV+244PKHD1L1SLFGGTEITI+++258NCAPD2ELAERVPAI++259C20orf96TLMRQLQQV+266ESR1KITDTLIHL+++310GGT6FLVDTPLARA+311SGPP2RLYTGMHTV+317FAT2SLAALVVHV++327APOL2GLAPFTEGISFV++335IGHG1, IGHG4, IGHG3, IGHG2YSLSSVVTV+++339HDGFGLWEIENNPTVKA+342VWA2HIYDKVMTV++350LAMA5ALLDVTHSELTV++371RNF213FLQAHLHTA++372RNF213TMLLNIPLV++387ALMS1ALFQATAEV+393EPPK1GLLDTQTSQVLTA++395ARID5BALALGGIAVV+408KLHL14VLDDSIYLV+++409KLHL14LLDAMNYHL+++421SCNN1ARLPETLPSL+++423TNFAIP2GLDGPPPTV++426NCAPD2RLADKSVLV+427VTCN1ALLPLSPYL+++432ABCC4TLIEESAKV+442BPIFB4GLLGGGGVLGV++443HDGF, HDGFL1GLWEIENNPTV+446EYA4, EYA1, EYA2QLIPALAKV+++456NUP205LLIGHLERV+465KIFC1QLCDLNAEL++466ZYG11AVLIANLEKL++467MX2FLAKDFNFL++484KIF15SLIEKVTQL+++494SORL1ALQPEPIKV++495SORL1FIFSEKPVFV+509CANXFLFDTKPLIV+512CCNA1SLSEIVPCL+++519NFE2L3GLLHLTLLL+++523GAB2YQIPRTFTL+++551NCAPD3KLYESLLPFA+579CHD7NLMEMVAQL++580ASUNLLMENAERV+587KLHL14VMNDRLYAI+++588RNF213SLLPLSHLV+595TAP1VLLSIYPRV++602ERMP1YLLEQIKLIEV++609HELZ2ALWKQLLEL+614UBE2L6LLLPDQPPYHL++616TRIP13VLIDEVESL++629NUP205HLLNESPML+631PRKDCFLDVFLPRV+632SMARCC1YLIPDIDLKL+ EXAMPLE 3In vitro immunogenicity for MHC class I presented peptides

[0259] In order to obtain information regarding the immunogenicity of the TUMAPs as disclosed, the inventors performed investigations using an in vitro T-cell priming assay based on repeated stimulations of CD8+ T cells with artificial antigen presenting cells (aAPCs) loaded with peptide / MHC complexes and anti-CD28 antibody. This way the inventors could show immunogenicity for 22 HLA-A*0201 restricted TUMAPs as disclosed so far, demonstrating that these peptides are T-cell epitopes against which CD8+ precursor T cells exist in humans (Table 10).In vitro priming of CD8+ T cells

[0260] In order to perform in vitro stimulations by artificial antigen presenting cells loaded with peptide-MHC complex (pMHC) and anti-CD28 antibody, the inventors first isolated CD8+ T cells from fresh HLA-A*02 leukapheresis products via positive selection using CD8 microbeads (Miltenyi Biotec, Bergisch-Gladbach, Germany) of healthy donors obtained from the University clinics Mannheim, Germany, after informed consent.

[0261] PBMCs and isolated CD8+ lymphocytes were incubated in T-cell medium (TCM) until use consisting of RPMI-Glutamax (Invitrogen, Karlsruhe, Germany) supplemented with 10% heat inactivated human AB serum (PAN-Biotech, Aidenbach, Germany), 100 U / ml Penicillin / 100 µg / ml Streptomycin (Cambrex, Cologne, Germany), 1 mM sodium pyruvate (CC Pro, Oberdorla, Germany), 20 µg / ml Gentamycin (Cambrex). 2.5 ng / ml IL-7 (PromoCell, Heidelberg, Germany) and 10 U / ml IL-2 (Novartis Pharma, Nürnberg, Germany) were also added to the TCM at this step.

[0262] Generation of pMHC / anti-CD28 coated beads, T-cell stimulations and readout was performed in a highly defined in vitro system using four different pMHC molecules per stimulation condition and 8 different pMHC molecules per readout condition.

[0263] The purified co-stimulatory mouse IgG2a anti human CD28 Ab 9.3 (Jung et al., 1987) was chemically biotinylated using Sulfo-N-hydroxysuccinimidobiotin as recommended by the manufacturer (Perbio, Bonn, Germany). Beads used were 5.6 µm diameter streptavidin coated polystyrene particles (Bangs Laboratories, Illinois, USA).

[0264] pMHC used for positive and negative control stimulations were A*0201 / MLA-001 (peptide ELAGIGILTV (SEQ ID NO. 664) from modified Melan-A / MART-1) and A*0201 / DDX5-001 (YLLPAIVHI from DDX5, SEQ ID NO. 665), respectively.

[0265] 800.000 beads / 200 µl were coated in 96-well plates in the presence of 4 x 12.5 ng different biotin-pMHC, washed and 600 ng biotin anti-CD28 were added subsequently in a volume of 200 µl. Stimulations were initiated in 96-well plates by co-incubating 1x10 6< CD8+ T cells with 2x10 5< washed coated beads in 200 µl TCM supplemented with 5 ng / ml IL-12 (PromoCell) for 3 days at 37°C. Half of the medium was then exchanged by fresh TCM supplemented with 80 U / ml IL-2 and incubating was continued for 4 days at 37°C. This stimulation cycle was performed for a total of three times. For the pMHC multimer readout using 8 different pMHC molecules per condition, a two-dimensional combinatorial coding approach was used as previously described (Andersen et al., 2012) with minor modifications encompassing coupling to 5 different fluorochromes.

[0266] Finally, multimeric analyses were performed by staining the cells with Live / dead near IR dye (Invitrogen, Karlsruhe, Germany), CD8-FITC antibody clone SK1 (BD, Heidelberg, Germany) and fluorescent pMHC multimers. For analysis, a BD LSRII SORP cytometer equipped with appropriate lasers and filters was used. Peptide specific cells were calculated as percentage of total CD8+ cells. Evaluation of multimeric analysis was done using the FlowJo software (Tree Star, Oregon, USA). In vitro priming of specific multimer+ CD8+ lymphocytes was detected by comparing to negative control stimulations. Immunogenicity for a given antigen was detected if at least one evaluable in vitro stimulated well of one healthy donor was found to contain a specific CD8+ T-cell line after in vitro stimulation (i.e. this well contained at least 1% of specific multimer+ among CD8+ T-cells and the percentage of specific multimer+ cells was at least 10x the median of the negative control stimulations).In vitro immunogenicity for ovarian cancer peptides

[0267] For tested HLA class I peptides, in vitro immunogenicity could be demonstrated by generation of peptide specific T-cell lines. Exemplary flow cytometry results after TUMAP-specific multimer staining for two peptides as disclosed are shown in Figure 3 together with corresponding negative controls. Results for six peptides as disclosed are summarized in Table 10 A and B. Table 10A: in vitro immunogenicity of HLA class I peptides as disclosed. Exemplary results of in vitro immunogenicity experiments conducted by the applicant for the peptides as disclosed. <20 % = +; 20 % - 49 % = ++; 50 % - 69 %= +++; >= 70 % = ++++SEQ ID NO:Sequencewellsdonors283ALYIGDGYVIHLA++++648LLWGNAIFL+++++652TLWYRAPEV+++++++659ILFPDIIARA++++662KIQEILTQV++++663KIQEMQHFL++++ Table 10B: in vitro immunogenicity of additional HLA class I peptides as disclosed. Exemplary results of in vitro immunogenicity experiments conducted by the applicant for HLA-A*02 restricted peptides as disclosed. Results of in vitro immunogenicity experiments are indicated. Percentage of positive wells and donors (among evaluable) are summarized as indicated <20 % = +; 20 % - 49 % = ++; 50 % - 69 %= +++; >= 70 %= ++++ SEQ ID NO:SequenceWells positive [%]2SLLEADPFL"+"3SLASKLTTL"+"5HLTEVYPEL"+++"7SLVGLLLYL"++"8FTLGNVVGMYL"+"11KIFEMLEGV"+"17GLLPGDRLVSV"++"19FMVDNEAIYDI"++"36YVLEDLEVTV"+"38FLLEDDIHVS"+"40TLLVKVFSV"++"48ALAELYEDEV"+"49YLPAVFEEV"++"56KLYEGIPVLL"+"60SLTIDGIYYV"++++"61FLQGYQLHL"++"79SLFIGEKAVLL"+"108ALFPGVALLLA"++"113GLLPTPLFGV"+"118KLIDNNINV"+"141YLDFSNNRL"+"143LLLDITPEI"+"150RLWEEGEELEL"+"152ILFEDIFDV"++"157SLNDEVPEV"+++"166YLNHLEPPV"++++"191LLQEGQALEYV"+++"198KTINKVPTV"++"199ALQDVPLSSV"+"215QLINHLHAV"++"242AIAYI LQGV"+++"247VLLPNDLLEKV"+"319SLEPQIQPV"+"384ILFANPNIFV"+"395ALALGGIAVV"+++"443GLWEIENNPTV"+"446QLI PALAKV"++"454KLPPPPPQA"++"460AMLEKNYKL"+"463SLVESHLSDQLTL"++"489KMWEELPEVV"+"499KIFDIDEAEEGV"+"511FLDPYCSASV"+"518KLNAEVACV"++"603FLIEPEHVNTV"+" EXAMPLE 4Synthesis of peptides

[0268] All peptides were synthesized using standard and well-established solid phase peptide synthesis using the Fmoc-strategy. Identity and purity of each individual peptide have been determined by mass spectrometry and analytical RP-HPLC. The peptides were obtained as white to off-white lyophilizates (trifluoro acetate salt) in purities of >50%. All TUMAPs are preferably administered as trifluoroacetate salts or acetate salts, other salt-forms are also possible.EXAMPLE 5MHC Binding Assays

[0269] Candidate peptides for T cell based therapies as disclosed were further tested for their MHC binding capacity (affinity). The individual peptide-MHC complexes were produced by UV-ligand exchange, where a UV-sensitive peptide is cleaved upon UV-irradiation, and exchanged with the peptide of interest as analyzed. Only peptide candidates that can effectively bind and stabilize the peptide-receptive MHC molecules prevent dissociation of the MHC complexes. To determine the yield of the exchange reaction, an ELISA was performed based on the detection of the light chain (β2m) of stabilized MHC complexes. The assay was performed as generally described in Rodenko et al. (Rodenko et al., 2006).

[0270] 96 well MAXISorp plates (NUNC) were coated over night with 2ug / ml streptavidin in PBS at room temperature, washed 4x and blocked for1h at 37°C in 2% BSA containing blocking buffer. Refolded HLA-A*02:01 / MLA-001 monomers served as standards, covering the range of 15-500 ng / ml. Peptide-MHC monomers of the UV-exchange reaction were diluted 100 fold in blocking buffer. Samples were incubated for 1h at 37°C, washed four times, incubated with 2ug / ml HRP conjugated anti-β2m for 1h at 37°C, washed again and detected with TMB solution that is stopped with NH2SO4. Absorption was measured at 450nm. Candidate peptides that show a high exchange yield (preferably higher than 50%, most preferred higher than 75 %) are generally preferred for a generation and production of antibodies or fragments thereof, and / or T cell receptors or fragments thereof, as they show sufficient avidity to the MHC molecules and prevent dissociation of the MHC complexes. Table 11: MHC class I binding scores. Binding of HLA-class I restricted peptides to HLA-A*02:01 was ranged by peptide exchange yield: ≥10% = +; ≥20% = ++; ≥50 = +++; ≥ 75% = ++++SEQID Sequence Peptide exchange 1SLMEPPAVLLL"+++"2SLLEADPFL"+++"3SLASKLTTL"++++"4GIMEHITKI"++++"5HLTEVYPEL"+++"6VLVSDGVHSV"+++"7SLVGLLLYL"++++"8FTLGNVVGMYL"++++"9GAAKDLPGV"++"10FLATFPLAAV"++++"11KIFEMLEGV"+++"12SLWPDPMEV"+++"13YLMDESLNL"+++"14AAYGGLNEKSFV"+++"15VLLTFKIFL"++"16VLFQGQASL"+++"17GLLPGDRLVSV"+++"18YLVAKLVEV"++"19FMVDNEAIYDI"++++"20RMIEYFIDV"+++"21VLDELDMEL"++"22IMEENPGIFAV"+++"23VLLDDIFAQL"+++"24SLSDGLEEV"++"25FLPDEPYIKV"+++"26ALLELAEEL"+++"27ILADIVISA"+++"28QLLDETSAITL"+++"29KMLGIPISNILMV"+++"30LILDWVPYI"+++"31YLAPELFVNV"++"32KLDDLTQDLTV"++"33VLLSLLEKV"++"34ILVEADSLWVV"+++"35KINDTIYEV"+++"36YVLEDLEVTV"++"38FLLEDDIHVS"+++"39SVAPNLPAV"+++"40TLLVKVFSV"+++"41SLMPHIPGL"+++"42VLLQKIVSA"+++"43VLSSLEINI"++"44ILDPISSGFLL"++"45SLWQDIPDV"+++"46ILTEENIHL"+++"47ILLSVPLLVV"++"48ALAELYEDEV"+++"49YLPAVFEEV"+++"50SLSELEALM"+++"51LLPDLEFYV"++++"52FLLAHGLGFLL"++++"53KMIETDILQKV"++++"54SLLEQGKEPWMV"+++"55SLLDLETLSL"++++"56KLYEGIPVLL"++++"57TLAELQPPVQL"+++"58FLDTLKDLI"+++"59IMEDIILTL"+++"60SLTIDGIYYV"++++"61FLQGYQLHL"++++"62VLLDVSAGQLLM"++++"63YLLPSGGSVTL"++"64YAAPGGLIGV"++"66FLDENIGGVAV"+++"67TLLAEALVTV"+++"68SLMELPRGLFL"++++"69FQLDPSSGVLVTV"+++"70GLLDYPVGV"+++"71GILARIASV"+++"72SLLELDGINL"+++"73NIFDLQIYV"+++"74ALLDPEVLSIFV"+++"75GLLEVMVNL"+++"76ILIDSIYKV"+++"77ILVEADGAWVV"++++"78SLFSSLEPQIQPV"+++"79SLFIGEKAVLL"+++"80FLYDNLVESL"++"81FLFSQLQYL"++"82FLSSVTYNL"+++"83ILAPTVMMI"+++"84VTFGEKLLGV"++"85KMSELRVTL"+++"86NLIGKIENV"+++"87ALPEAPAPLLPHIT"++"88FLLVGDLMAV"+++"89YILPTETIYV"++++"90TLLQIIETV"+++"91IMQDFPAEIFL"++++"92YLIPFTGIVGL"++"93LLQAIKLYL"++"94YLIDIKTIAI"++"95SVIPQIQKV"+++"96YIFTDNPAAV"+++"97SLINGSFLV"+++"98LIIDQADIYL"+++"99ALVSKGLATV"++"100YLLSTNAQL"++++"101ILVGGGALATV"+++"102YLFESEGLVL"+++"103TLAEEVVAL"+++"104STMEQNFLL"++++"106LLYDAVHIVSV"+++"107FLQPVDDTQHL"+++"108ALFPGVALLLA"++++"109IILSILEQA"++++"110FLSQVDFEL"+++"111YVWGFYPAEV"+++"113GLLPTPLFGV"+++"114SLVGEPILQNV"++"115AIAGAGILYGV"++"116YHIDEEVGF"+"117ILPDGEDFLAV"+++"118KLIDNNINV"+++"119FLYIGDIVSL"++++"120ALLGIPLTLV"+++"121GVVDPRAISVL"++"122FLLAEDDIYL"+++"123NLWDLTDASVV"+++"124ALYETELADA"++"125VQIHQVAQV"+++"126VLAYFLPEA"++++"127KIGDEPPKV"++"128YLFDDPLSAV"++"129GLLDGGVDILL"+++"130FLWNGEDSALL"+++"131FVPPVTVFPSL"++"132LLVEQPPLAGV"+++"133KVLSNIHTV"++"134YLQELIFSV"+++"135ALSEVDFQL"+++"136YLADPSNLFVV"+++"137TLVLTLPTV"++++"138YQYPRAILSV"+++"139SVMEVNSGIYRV"+++"140YMDAPKAAL"++"141YLDFSNNRL"++"142FLFATPVFI"+++"143LLLDITPEI"++++"144YIMEPSIFNTL"+++"145FLATSGTLAGI"++"146SLATAGDGLIEL"++"147SLLEAVSFL"+++"148ALNPEIVSV"++"149NLLELFVQL"+++"150RLWEEGEELEL"+++"151KILQQLVTL"+++"152ILFEDIFDV"+++"153FLIANVLYL"+"154ALDDGTPAL"++"155RVANLHFPSV"+++"157SLNDEVPEV"++"158KLFDVDEDGYI"+++"159GLVGNPLPSV"++++"160FLFDEEIEQI"+++"161ALLEGVNTV"+++"162YQQAQVPSV"+++"163ALDEMGDLLQL"+++"164ALLPQPKNLTV"+++"165SLLDEIRAV"+++"166YLNHLEPPV"+++"167KVLEVTEEFGV"+++"168KILDADIQL"++++"169NLPEYLPFV"+++"170RLQETLSAA"+++"171LLLPLQILL"+++"172VLYSYTIITV"++"173LLDSASAGLYL"+++"174ALAQYLITA"+++"175YLFENISQL"+++"176YLMEGSYNKVFL"++"177YLLPEEYTSTL"++++"178ALTEIAFVV"++++"179KVLNELYTV"+++"180FQIDPHSGLVTV"++"181LLWAGTAFQV"+++"182MLLEAPGIFL"+++"183FGLDLVTEL"+++"184YLMDINGKMWL"+++"185FLIDDKGYTL"++"186TLFFQQNAL"++"187RQISIRGIVGV"+++"188GLFPVTPEAV"+++"189ALQRKLPYV"+++"190FLSSLTETI"+++"191LLQEGQALEYV"++"192KMLDGASFTL"+++"193QLLDADGFLNV"+++"194ALPLFVITV"+++"195GLFADLLPRL"+++"196YLYSVEIKL"++++"197ALGPEGGRV"++"198KTINKVPTV"+++"199ALQDVPLSSV"+++"200LLFGSVQEV"+++"201RLVDYLEGI"+++"202ALLDQQGSRWTL"+++"204KIAENVEEV"++"205SLYPGTETMGL"+++"206VLQEGKLQKLAQL"+++"207GLTSTNAEV"++"208KISPVTFSV"+++"209KLIESKHEV"++"210LLLNAVLTV"++"211LLWPGAALL"++"212ALWDQDNLSV"++"214FLLDLDPLLL"+++"215QLINHLHAV"+++"216NLWEDPYYL"+++"217ALIHPVSTV"++"218SALEELVNV"++"219KLSDIGITV"+++"220LLQKFVPEI"++"221ALYEEGLLL"++"222NLIENVQRL"++"223ALLENIALYL"+++"224TLIDAQWVL"+++"225SLLKVLPAL"+++"226MLYVVPIYL"++"227ALMNTLLYL"++"228AMQEYIAVV"++"229RLPGPLGTV"++"230ILVDWLVEV"+"231FLSPQQPPLLL"++"232ALLEAQDVELYL"++"233VLSETLYEL"++"234ALMEDTGRQML"++"235YLNDLHEVLL"++++"236GLLEAKVSL"+++"237ALLEASGTLLL"++++"238YLISFQTHI"+++"239AAFAGKLLSV"+++"240ILLEQAFYL"+++"241SLVEVNPAYSV"+++"242AIAYILQGV"++"243LLLNELPSV"+++"244SLFGGTEITI"+++"245SMIDDLLGV"+++"246LLWEVVSQL"+++"247VLLPNDLLEKV"+++"248FLFPNQYVDV"+++"249LLDGFLVNV"+++"250ALSEEGLLVYL"+++"251ALYTGFSILV"++"252LLIGTDVSL"+++"253GLDAATATV"++"254TLLAFIMEL"+++"255VLASYNLTV"+++"256FLPPEHTIVYI"+++"257SIFSAFLSV"+++"258ELAERVPAI"++"261YVLEFLEEI"++"262LLWGDLIWL"+++"263LLVSNLDFGV"+++"264SLQEQLHSV"+++"265LLFGGTKTV"++"266KITDTLIHL"+++"267ALQDFLLSV"+++"269RVLEVGALQAV"++"270LLLDEEGTFSL"++"271LVYPLELYPA"+++"272ALGNTVPAV"+++"273NLFQSVREV"++"274SLLFSLFEA"++"275YLVYILNEL"++"276ALFTFSPLTV"+++"277LLPPLESLATV"++"278QLLDVVLTI"++"279ALWGGTQPLL"++"280VLPDPEVLEAV"+++"281ILRESTEEL"+++"282LLADVVPTT"+++"283ALYIGDGYVIHLA"+++"284ILLSQTTGV"+++"285QLLHVGVTV"+++"286YLFPGIPEL"+++"287FLNEFFLNV"+++"288NLINEINGV"+++"289VLLEIEDLQV"++++"295VLDRESPNV"+++"296FMEGAIIYV"+++"297VLADIELAQA"+++"298VMITKLVEV"+++"299YLLETSGNL"+++"300ALLGQTFSL"+++"301FLVEDLVDSL"+++"302ALLQEGEVYSA"+++"303AILPQLFMV"++++"304MTLGQIYYL"+++"305SIANFSEFYV"++++"306ALVNVQIPL"+++"307ALPVSLPQI"+++"308SQYSGQLHEV"+++"309GLFDGVPTTA"+++"310FLVDTPLARA"++++"311RLYTGMHTV"+++"312IISDLTIAL"+++"313VLFDDELLMV"+++"314ALIAEGIALV"+++"315YLQDVVEQA"+++"316ILLERLWYV"+++"317SLAALVVHV"+++"318GLINTGVLSV"++"319SLEPQIQPV"++"320KMFEFVEPLL"++++"321GLFEDVTQPGILL"++++"322TLMTSLPAL"+++"324FLYDEIEAEV"+++"325FIMPATVADATAV"+++"326FLPEALDFV"+++"327GLAPFTEGISFV"+++"328ALNDQVFEI"+++"329FLVTLNNVEV"++++"330QLALKVEGV"+++"331KVDTVWVNV"+++"332YLISELEAA"+++"333FLPDANSSV"++"334TLTKVLVAL"+++"335YSLSSVVTV"+++"336ILLTAIVQV"+++"337HLLSELEAAPYL"++++"339GLWEIENNPTVKA"++++"340ALLSMTFPL"++++"341SQIALNEKLVNL"+++"342HIYDKVMTV"+++"343SLLEVNEESTV"+++"344YLQDQHLLLTV"+++"345VIWKALIHL"+++"346LLDSKVPSV"+++"347SLFKHDPAAWEA"++++"348ILLDVKTRL"++++"349SLTEYLQNV"++++"350ALLDVTHSELTV"+++"351SLIPNLRNV"+++"352SLLELLHIYV"+++"353YLFEMDSSL"++"354LILEGVDTV"++"355SIQQSIERLLV"++"356KLLGKLPEL"+++"357SMHDLVLQV"+++"358ALDEYTSEL"++++"359YLLPESVDL"+++"361ALYELEGTTV"+++"362TLYGLSVLL"+++"363KVLDVSDLESV"++"364LLQNEQFEL"+++"365YVIDQGETDVYV"+++"366RLLDMGETDLML"+++"367SLQNHNHQL"+++"369GLFPEHLIDV"+++"370SLLQDLVSV"+++"371FLQAHLHTA"++++"372TMLLNIPLV"++"373SLLEDKGLAEV"++"374FLLQQHLISA"++"375SLTETIEGV"++"376AMFESSQNVLL"++"377FLLDSSASV"++"378ALGYFVPYV"+++"379IMEGTLTRV"++"380TLIEDEIATI"++"381FIDEAYVEV"++"382ALQNYIKEA"++"383ALLELENSVTL"+++"384ILFANPNIFV"+++"385SLLEQGLVEA"++"386ILFRYPLTI"+++"387ALFQATAEV"++++"388SLTIDGIRYV"+++"389LLADVTHLL"++"390ALFMKQIYL"+++"391YVYPQRLNFV"+++"392ALLHPQGFEV"++"393GLLDTQTSQVLTA"++"394LLAVIGGLVYL"+++"395ALALGGIAVV"++++"396ALLPDLPAL"+++"397YLFGERLLEC"+++"398KLLEEDGTIITL"++"399YLFEPLYHV"+++"400SLLTEQDLWTV"++"401ILLDDTGLAYI"+++"402VLFSGALLGL"++"403KLYDRILRV"++"405ALYDVFLEV"++"407YLMDLINFL"+++"408VLDDSIYLV"++"409LLDAMNYHL"++"412YLDDLNEGVYI"++"426RLADKSVLV"+++"427ALLPLSPYL"+++"428KLGHTDILVGV"++"429GLVNDLARV"++"430HLYSSIEHLTT"+++"431SLVNVVPKL"++"432TLIEESAKV"++"433AMLNEPWAV"+++"434KVSNSGITRV"++"436HLAEVSAEV"+++"437SMAPGLVIQAV"+++"438KLLPLAGLYL"++++"439YLLQEIYGI"+++"440ALADGVTMQV"++"441ALLENPKMEL"+++"442GLLGGGGVLGV"+++"443GLWEIENNPTV"+++"444GLLRDEALAEV"+++"446QLIPALAKV"+++"447QLVPALAKV"++"448NLLETKLQL"+++"449KLAEGLDIQL"+++"450FMIDASVHPTL"+++"451LLLLDTVTMQV"++"452ILLEHGADPNL"+++"453KLLEATSAV"++"454KLPPPPPQA"+++"455SLLKEPQKVQL"++"456LLIGHLERV"+++"457SLLPGNLVEKV"+++"458SLIDKLYNI"++"459ALITEVVRL"++"460AMLEKNYKL"++++"461VMFRTPLASV"++"462KLAKQPETV"+++"463SLVESHLSDQLTL"+++"464ALNDCIYSV"+++"465QLCDLNAEL"+++"466VLIANLEKL"++++"467FLAKDFNFL"+++"468YLRSVGDGETV"+++"469YLASDEITTV"+++"471YLYNNMIAKI"+++"472KLLEVSDDPQV"+++"473AMATESILHFA"+++"474YLDPALELGPRNV"+++"475LLLNEEALAQI"+++"476ALMERTGYSMV"+++"477ALLPASGQIAL"+++"478YLLHEKLNL"+++"479SLFGNSGILENV"+++"480ALLEDSCHYL"+++"481GLIEDYEALL"+++"484SLIEKVTQL"+++"485NVPDSFNEV"+++"486AVMESIQGV"+++"487LLINSVFHV"+++"488FLAEDPKVTL"+++"489KMWEELPEVV"+++"490FLLQHVQEL"+++"491GLNDRSDAV"++"492SLFDGFADGLGV"+++"493GLLGEKTQDLIGV"+++"494ALQPEPIKV"++"495FIFSEKPVFV"+++"496FLVEKQPPQV"+++"497GLLEKLTAI"+++"498KLWTGGLDNTV"+++"499KIFDIDEAEEGV"++"500SLMEDQVLQL"+++"501LLDPNVKSIFV"+++"502RLLAQVPGL"+++"503SLNHFTHSV"+++"504GLSDGNPSL"++"505SLAPGDVVRQV"++"506KLLGKVETA"+++"507KLIDDQDISISL"+++"508ILAQEQLVVGV"+++"509FLFDTKPLIV"+++"510KLYSVVSQL"++"511FLDPYCSASV"++"512SLSEIVPCL"+++"513SLWPSPEQL"++"514ILVDWLVQV"+++"515LLQELVLFL"+++"516AVGPASILKEV"++"517LLMPIPEGLTL"+++"518KLNAEVACV"+++"519GLLHL TLLL"+++"520LAVHPSGVAL"+"521MLLTKLPTI"+++"522TLWYRSPEV"++"523YQIPRTFTL"++"524ALIENLTHQI"++"525VLLEAGEGLVTI"+++"526RLAEVGQYEQV"++"527FLLEPGNLEV"++++"528SVAEGRALMSV"+++"529LLADELITV"+++"530VMYADIGGMDI"+++"531YTLPIASSIRL"+++"537TLAPGEVLRSV"+++"538LLLAHIIAL"++"539ALFDAQAQV"+++"541SMLEPVPEL"+++"542RVWDISTVSSV"+++"543GLLPTPITQQASL"+++"544LLWDVPAPSL"+++"545LLADLLHNV"+++"546VMIAGKVAVV"+++"547TLDITPHTV"+++"548ALWENPESGEL"++"549AMLENASDIKL"+++"550FLYDEIEAEVNL"+++"551KLYESLLPFA"+++"552GLLDLPFRVGV"++++"553SLLNQDLHWSL"++++"554LLMPSSEDLLL"+++"555YVLEGLKSV"+++"556FLTDLEDLTL"+++"557KLYDDMIRL"+++"558GLLENIPRV"+++"559VTVPPGPSL"++"560ALWDIETGQQTTT"+++"561YLQLTQSEL"+++"562YLEELPEKLKL"+++"563WLLPYNGVTV"+++"564TVTNAVVTV"+++"565ALQETPTSV"++"566VIADGGIQNV"++"567SLLPLDDIVRV"+++"568TLYDIAHTPGV"++++"569KLVDRTWTL"+++"570ALANQIPTV"++"571LLLTTIPQI"+++"572ALADLIEKELSV"+++"573ILVANAIVGV"+++"574YLLQEPPRTV"++"575YLISQVEGHQV"+++"576ILLNNSGQIKL"++++"577VMFEDGVLMRL"+++"578FLDPGGPMMKL"+++"579NLMEMVAQL"++"580LLMENAERV"++"582TLCDVILMV"+++"583ILANDGVLLAA"+++"584ALAEVAAMENV"+++"585ALWDLAADKQTL"++++"586KLKPGDLVGV"+++"587VMNDRLYAI"+++"588SLLPLSHLV"+++"589KLYPQLPAEI"+++"590SLIEKLWQT"++"591SMAELDIKL"+++"592RLLJAAENFL"+++"593GLPRFGIEMV"+++"594IMLKGDNITL"+++"595VLLSIYPRV"+++"596ALLDQTKTLAESAL"+++"597KLLEGQVIQL"+++"598FLFPHSVLV"+++"599YLLNDASLISV"+++"600ALAAPDIVPAL"+++"601SAFPFPVTV"+++"602YLLEQIKLIEV"++++"603FLIEPEHVNTV"++"604SILDRDDIFV"+++"605KLYEAVPQL"+++"606ALWETEVYI"+++"607RLYSGISGLEL"+++"608SLLSVSHAL"+++"609ALWKQLLEL"+++"610LLAPTPYIIGV"+++"611YLLDDGTLVV"++++"612YLYNEGLSV"+++"613RLLPPGAVVAV"+++"614LLLPDQPPYHL"+++"615VLPPDTDPA"++"616VLIDEVESL"+++"617ALMYESEKVGV"+++"618VLFDSESIGIYV"+++"619ALQDRVPLA"+++"620KLLNKIYEA"++++"621VLMDRLPSLL"++++"622RLLGEEVVRVLQA"+++"623YLVEDIQHI"+++"635SLDSTLHAV"+++" EXAMPLE 6Absolute quantitation of tumor associated peptides presented on the cell surface

[0271] The generation of binders, such as antibodies and / or TCRs, is a laborious process, which may be conducted only for a number of selected targets. In the case of tumor-associated and -specific peptides, selection criteria include but are not restricted to exclusiveness of presentation and the density of peptide presented on the cell surface. In addition to the isolation and relative quantitation of peptides as described in EXAMPLE 1, the inventors did analyze absolute peptide copies per cell as described in patent application PCT / EP2015 / 79873. The quantitation of TUMAP copies per cell in solid tumor samples requires the absolute quantitation of the isolated TUMAP, the efficiency of TUMAP isolation, and the cell count of the tissue sample analyzed. Experimental steps are described below.Peptide quantitation by nanoLC-MS / MS

[0272] For an accurate quantitation of peptides by mass spectrometry, a calibration curve was generated for each peptide using the internal standard method. The internal standard is a double-isotope-labelled variant of each peptide, i.e. two isotope-labelled amino acids were included in TUMAP synthesis. It differs from the tumor-associated peptide only in its mass but shows no difference in other physicochemical properties (Anderson et al., 2012). The internal standard was spiked to each MS sample and all MS signals were normalized to the MS signal of the internal standard to level out potential technical variances between MS experiments.

[0273] The calibration curves were prepared in at least three different matrices, i.e. HLA peptide eluates from natural samples similar to the routine MS samples, and each preparation was measured in duplicate MS runs. For evaluation, MS signals were normalized to the signal of the internal standard and a calibration curve was calculated by logistic regression.

[0274] For the quantitation of tumor-associated peptides from tissue samples, the respective samples were also spiked with the internal standard; the MS signals were normalized to the internal standard and quantified using the peptide calibration curve.Efficiency of peptide / MHC isolation

[0275] As for any protein purification process, the isolation of proteins from tissue samples is associated with a certain loss of the protein of interest. To determine the efficiency of TUMAP isolation, peptide / MHC complexes were generated for all TUMAPs selected for absolute quantitation. To be able to discriminate the spiked from the natural peptide / MHC complexes, single-isotope-labelled versions of the TUMAPs were used, i.e. one isotope-labelled amino acid was included in TUMAP synthesis. These complexes were spiked into the freshly prepared tissue lysates, i.e. at the earliest possible point of the TUMAP isolation procedure, and then captured like the natural peptide / MHC complexes in the following affinity purification. Measuring the recovery of the single-labelled TUMAPs therefore allows conclusions regarding the efficiency of isolation of individual natural TUMAPs.

[0276] The efficiency of isolation was analyzed in a low number of samples and was comparable among these tissue samples. In contrast, the isolation efficiency differs between individual peptides. This suggests that the isolation efficiency, although determined in only a limited number of tissue samples, may be extrapolated to any other tissue preparation. However, it is necessary to analyze each TUMAP individually as the isolation efficiency may not be extrapolated from one peptide to others.Determination of the cell count in solid, frozen tissue

[0277] In order to determine the cell count of the tissue samples subjected to absolute peptide quantitation, the inventors applied DNA content analysis. This method is applicable to a wide range of samples of different origin and, most importantly, frozen samples (Alcoser et al., 2011; Forsey and Chaudhuri, 2009; Silva et al., 2013). During the peptide isolation protocol, a tissue sample is processed to a homogenous lysate, from which a small lysate aliquot is taken. The aliquot is divided in three parts, from which DNA is isolated (QiaAmp DNA Mini Kit, Qiagen, Hilden, Germany). The total DNA content from each DNA isolation is quantified using a fluorescence-based DNA quantitation assay (Qubit dsDNA HS Assay Kit, Life Technologies, Darmstadt, Germany) in at least two replicates.

[0278] In order to calculate the cell number, a DNA standard curve from aliquots of single healthy blood cells, with a range of defined cell numbers, has been generated. The standard curve is used to calculate the total cell content from the total DNA content from each DNA isolation. The mean total cell count of the tissue sample used for peptide isolation is extrapolated considering the known volume of the lysate aliquots and the total lysate volume.Peptide copies per cell

[0279] With data of the aforementioned experiments, the inventors calculated the number of TUMAP copies per cell by dividing the total peptide amount by the total cell count of the sample, followed by division through isolation efficiency. Copy cell number for selected peptides are shown in Table 12 Table 12: Absolute copy numbers. The table lists the results of absolute peptide quantitation in NSCLC tumor samples. The median number of copies per cell are indicated for each peptide: <100 = +; >=100 = ++; >=1,000 +++; >=10,000 = ++++. The number of samples, in which evaluable, high quality MS data are available, is indicated.Seq IDSequenceCopy Number CategoryNumber of quantifiable samples11KIFEMLEGV++32198KTINKVPTV++14408VLDDSIYLV++17427ALLPLSPYL+++13587VMNDRLYAI++18 Reference List

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Claims

1. A peptide consisting of the amino acid sequence according to SEQ ID No. 11; or a pharmaceutical acceptable salt thereof.

2. The peptide according to claim 1, wherein said peptide includes non-peptide bonds.

3. The peptide according to claim 1 or 2, wherein said peptide is fused to the N-terminal amino acids of the HLA-DR antigen-associated invariant chain (Ii).

4. A T-cell receptor, preferably a recombinant, soluble or membrane-bound T-cell receptor that is specifically reactive with an HLA ligand, wherein said ligand consists of the amino acid sequence of SEQ ID No. 11.

5. An antibody, in particular a soluble or membrane-bound antibody, that specifically recognizes the peptide according to any of claims 1 or 2 when bound to an MHC molecule.

6. A nucleic acid, encoding for a peptide according to any one of claims 1 to 3 or for a TCR according to claim 4, or an antibody according to claim 5, optionally linked to a heterologous promoter sequence, or an expression vector expressing said nucleic acid.

7. A recombinant host cell comprising the peptide according to claim 1 to 3, or the nucleic acid or the expression vector according to claim 6, wherein said host cell preferably is an antigen presenting cell such as a dendritic cell, or wherein said host cell preferably is a T cell or NK cell.

8. A method for producing the peptide according to any one of claims 1 to 3, or for producing the T cell receptor according to claim 4, or an antibody according to claim 5, the method comprising culturing the host cell according to claim 7 that presents the peptide according to claim 1 to 3, or expresses the nucleic acid or expression vector according to claim 6, and isolating the peptide or the TCR or the antibody from the host cell or its culture medium.

9. An in vitro method for producing activated T lymphocytes, the method comprising contacting in vitro T cells with antigen loaded human class I MHC molecules expressed on the surface of a suitable antigen-presenting cell or an artificial construct mimicking an antigen-presenting cell for a period of time sufficient to activate said T cells in an antigen specific manner, wherein said antigen is a peptide according to claim 1.

10. An activated T lymphocyte, produced by the method according to claim 9 that selectively recognizes a cell which presents a peptide comprising the amino acid sequence given in claim 1.

11. A pharmaceutical composition comprising at least one active ingredient selected from the group consisting of the peptide according to any one of claims 1 to 3, the nucleic acid or the expression vector according to claim 4, the cell according to claim 7, the activated T lymphocyte according to claim 10 or the antibody according to claim 5 or T-cell receptor according to claim 4, and a pharmaceutically acceptable carrier, and optionally additional pharmaceutically acceptable excipients and / or stabilizers.

12. The peptide according to any one of claims 1 to 3, the nucleic acid or the expression vector according to claim 4, the cell according to claim 7, the activated T lymphocyte according to claim 10 or the antibody according to claim 5 or T-cell receptor according to claim 4 for use in medicine, preferably for use in the diagnosis and / or treatment of cancer, or for use in the manufacture of a medicament against cancer.

13. The peptide according to any one of claims 1 to 3, the nucleic acid or the expression vector according to claim 4, the cell according to claim 7, the activated T lymphocyte according to claim 10 or the antibody according to claim 5 or T-cell receptor according to claim 4 for use in the diagnosis and / or treatment of cancer, or for use in the manufacture of a medicament against cancer according to claim 13, wherein said cancer is selected from the group of ovarian cancer, non-small cell lung cancer, small cell lung cancer, kidney cancer, brain cancer, colon or rectum cancer, stomach cancer, liver cancer, pancreatic cancer, prostate cancer, leukemia, breast cancer, Merkel cell carcinoma, melanoma, esophageal cancer, urinary bladder cancer, uterine cancer, gallbladder cancer, bile duct cancer and other tumors that show an overexpression of a protein from which a peptide according to SEQ ID No. 11 is derived from.

14. A kit comprising: a) a container comprising a pharmaceutical composition containing the peptide according to any one of claims 1 to 3, the nucleic acid or the expression vector according to claim 4, the cell according to claim 7, the activated T lymphocyte according to claim 10 or the antibody according to claim 5 or T-cell receptor according to claim 4, in solution or in lyophilized form; b) optionally, a second container containing a diluent or reconstituting solution for the lyophilized formulation; c) optionally, at least one more peptide selected from the group consisting of SEQ ID No. 1 to 10, and 12 to 640, and d) optionally, instructions for (i) use of the solution or (ii) reconstitution and / or use of the lyophilized formulation, and e) optionally further comprising one or more of (iii) a buffer, (iv) a diluent, (v) a filter, (vi) a needle, or (v) a syringe.