Patent for “Peptides and combinations of peptides to be used in immunotherapy against small-cell lung cancer and other types of cancer”

Biopharmaceuticals – Andrea MAHR, Toni Weinschenk, Valentina GOLDFINGER, Oliver Schoor, Jens FRITSCHE, Harpreet Singh, Immatics Biotechnologies GmbH

Search Patent for “Peptides and combinations of peptides to be used in immunotherapy against small-cell lung cancer and other types of cancer”

Abstract for “Peptides and combinations of peptides to be used in immunotherapy against small-cell lung cancer and other types of cancer”

“The invention concerns peptides and proteins as well as cells that can be used in immunotherapeutic procedures. The present invention is particularly relevant to immunotherapy for cancer. The invention also relates to tumor-associated T cell peptide epitopes. These can be used alone or in combination, to stimulate immune responses or T cells ex-vivo for transplantation into patients. Antibodies, soluble T cell receptors and other binding molecules can target peptides bound to the major histocompatibility complicated (MHC) or peptides in general.

Background for “Peptides and combinations of peptides to be used in immunotherapy against small-cell lung cancer and other types of cancer”

“Small Cell Lung Cancer, (SCLC).”

“Small-cell lung cancer (SCLC), is named based on the size of the tumor cells under a microscope. It must be distinguished from non-small-cell lung cancer (NSCLC). According to the American Cancer Society (2015)a, SCLC is responsible for 10% to 15% of all lung cancers.

Both lung cancers (SCLC or NSCLC), are the second most prevalent cancer in men and women. About 25% of all cancer deaths are caused by lung cancer. Lung cancer is the leading cause of death from all cancers, accounting for about 25%. Lung cancers make up about 13% (more that 1.8 million) percent of all new cancers. Lung cancer is most common in the elderly. About 70 years is the average age of diagnosis. Only 2% of cases are found in patients under 45. SCLC treatment and prognosis depend heavily on the stage of cancer. SCLC staging based on clinical findings is more common than pathologic staging. Clinical staging is based on the results of the physical exam, imaging tests and biopsies. American Cancer Society data shows that the 5-year relative survival rate is 31% for stage I, 19% in stage II, 8% in stage III, and 2% in stage IV.

“The standard SCLC chemo treatment consists of either etoposide, irinotecan or both cisplatin and carboplatin. Each cycle lasts between 4 and 6 cycles. Each cycle starts with a chemo treatment lasting 1 to 3 days, followed by a recovery period lasting 3 to 4 weeks.

External beam radiation therapy (EBRT), is the standard treatment for SCLC. It’s usually administered once to twice daily, five days a week for three to seven weeks. The new radiation techniques were developed in the past few years. Three-dimensional conformal radiation treatment (3D-CRT), and intensity modulated radiotherapy (IMRT) are the new radiation techniques. They allow for more precise targeting of radiation dose towards tumors by reducing radiation exposure to healthy tissue surrounding them.

“At stage I, where SCLC has been diagnosed as a small tumor that is not spreading to lymph nodes or other organs (less than 1 in 20 patients), then a combination chemo-radiation therapy and surgery is recommended. Patients in good health are not eligible for this treatment. Most often, SCLC has spread by the time it is diagnosed. It is therefore unlikely that surgery can be used to treat SCLC (American Cancer Society 2015a; S3 Leitlinie Lungenkarzinom 2011,).

“Concurrent chemoradiation, which combines chemo-and radiation therapy (also known as concurrent chemoradiation) is an option for patients with limited SCLC. This happens when the SCLC has spread to one side of their chest or near the lymph nodes. Surgery is not an option at this stage. Etoposide (VP-16), along with cisplatin and carboplatin, are the standard chemo drugs. Although concurrent chemo-radiation therapy has therapeutic benefits, it can also cause severe side effects that are not as severe as the radiation or chemo alone. Chemotherapy is recommended for patients who cannot tolerate concurrent radiation therapy. Radiation therapy can also be used as an option to chemotherapy (American Cancer Society 2015a; S3 Leitlinie Lungenkarzinom 2011, 2011).

“At an advanced stage, where SCLC has spread extensively throughout the lung, nearby lymphodes (like bone marrow), the systematic chemotherapy mostly consisting of etoposide, carboplatin optionally, and radiation treatment to the chest is the applicable treatment (American Cancer Society 2015a; S3 Leitlinie Lungenkarzinom 2011).

“Since SCLC can spread to the brain, patients with SCLC will receive the prophylactic radiation treatment to the head (or PCI) because it is well-known that they do.”

The treatment will likely result in significant shrinkage of the cancer at the early stages, but the majority of cases will see the cancer return. Consider the case where cancer grows despite being treated with chemotherapy. The length of the cancer remission period will determine which chemotherapy is best for you.

“Innovations were made in the detection, diagnosis, and treatment of SCLC. The risk of dying from lung cancer was lower when CT scans were used instead of xrays. The diagnosis of SCLC can now be supported by fluorescence and virtual bronchoscopy. Radiation treatment can also be used to real-time tumor imaging. American Cancer Society (2015)a showed that the treatment of SCLC can be supported by novel anti-angiogenesis drugs such as bevacizumab, sunitinib and nintedanib.

The immune therapy is a highly researched field in cancer treatment. There are many options for treating SCLC. One approach is to block CTLA-4, which is a natural human immune suppression. Inhibiting CTLA-4 will increase the immune system’s ability to fight cancer. Recent developments in immuno check point inhibitors have been promising for the treatment of SCLC. Another option is to use anti-cancer vaccines, which are currently being tested in clinical trials for SCLC treatment (American Cancer Society (2015b) and National Cancer Institute (NCI) 2011).

“Considering the serious side effects and high cost of treating cancer, it is important to identify the factors that can be used to treat the disease. It is important to identify biomarkers of cancer in order to improve diagnosis, prognosis and treatment success.

“Immunotherapy for cancer” is a way to target specific cancer cells and minimize side effects. Cancer immunotherapy uses tumor-associated antigens.

“The current classification for tumor-associated antigens (TAAs), includes 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. These antigens are immunologically specific for testis cells because they do not contain class I or II HLA molecules. The MAGE family members, NY-ESO-1 and NY-ESO-2 are two well-known CT antigens. Melanomas and normal melanocytes contain most of the well-known differentiation antigens. These melanocyte-related proteins play an important role in the biosynthesis of melanin. Although not specific to cancer, they are often used for immunotherapy. These include, but not limited to, tyrosinase, Melan-A/MART-1, for melanoma, and PSA, for prostate cancer. Many epitopes that are processed in normal tissues and could be presented to T-cells may not reach the threshold for recognition. However, their overexpression in tumor cells can cause an anticancer response. This is due to the loss of previously established tolerance. The most prominent examples of this class of TAAs include Her-2/neu and survivin. Telomerase and WT1 are also important. These molecular modifications can lead to neoplastic progression and/or transformation. The majority of tumor-specific antigens can induce strong immune responses, without triggering autoimmune reactions against normal tissue. These TAAs, however, are often only applicable to the specific tumor they were identified in and are not shared among other tumors. If a peptide is derived from a tumor-specific exon, or -association of tumor-specific exons in proteins with tumor-specific isoforms, tumor-specific TAAs can also occur. This class includes altered glycosylation patterns that lead to novel epitopes or events such as protein splicing in degradation, which can trigger a T-cell response. The E6 and 7 human papilloma 16 virus proteins proteins are examples of such proteins. They are found in cervical carcinoma.

T-cell-based immunotherapy targets epitopes of peptides derived form tumor-associated proteins or tumor-specific protein molecules. These epitopes are presented by molecules in the major histocompatibility complicated (MHC). The tumor-specific T lymphocytes recognize antigens. These epitopes can be molecules from all protein classes such as enzymes and transcription factors. These antigens are usually expressed in tumor cells and up-regulated when compared to cells unaltered of the same origin.

There are two types of MHC-molecules: MHC class I or MHC class 2. 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. The binding groove is formed by their three-dimensional conformation, which allows for non-covalent interaction of peptides.

Most nucleated cells contain “MHC class 1 molecules.” These peptides are the result of proteolytic cleavage primarily endogenous proteins, defective Ribosomal Products (DRIPs), and larger peptides. MHC class I molecules can also contain peptides that are derived from exogenous or endosomal sources. Cross-presentation is a non-classical method of class I presentation. (Brossart et al. 1997; Rock et. al. 1990). MHC class II molecules are found primarily on professional antigen-presenting cells (APCs). They mainly contain peptides from exogenous or crossmembrane protein peptides that are taken up and processed by APCs, e.g. They are then processed by the endocytosis.

“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 and the peptide are present in a stoichiometric ratio of 1:1.

“CD4-positive helper cells are crucial in inducing and maintaining effective responses by CD8+ cytotoxic T cell cells. It is crucial to identify CD4-positive T cell epitopes from tumor-associated antigens (TAA), in order to develop pharmaceutical products that can trigger anti-tumor immune reactions (Gnjatic and al., 2003). T helper cells are present at the tumor site and support a cytotoxic-T cell-friendly cytokine milieu. (Mortara, et al. 2006) They also attract effector cells such as. CTLs, natural killing (NK) cells and macrophages are all present at the tumor site (Hwang et. al., 2007).

In the absence of inflammation expression of MHC class 2 molecules is mainly restricted only to immune system cells, particularly professional antigen-presenting cell (APC) cells. These include monocytes, monocyte derived cells, macrophages and dendritics cells. MHC class II molecules have been identified in cancer patients’ tumor cells (Dengjel and colleagues, 2006; Dengjel and co-authors, 2006). The invention’s elongated (longer) proteins can be used as MHC class 2 active epitopes.

MHC class II epitopes activate T-helper cells and play an important role in the orchestration of CTLs’ anti-tumor immunity effector function. The T-helper cells that activate a T-helper response of the type TH1 support effector functions for CD8-positive killer cells. These functions include cytotoxic functions directed at tumor cells with tumor-associated protein/MHC complexes. This allows tumor-associated Thelper cell peptide epitopes to be used as active pharmaceutical ingredients in vaccine compositions that stimulate antitumor immune responses.

“It was demonstrated in mammalian animal models (e.g. mice) that CD4-positive cells can inhibit the manifestation of tumors via inhibition o giogenesis by secretion interferon-gamma. Mumberg et. al. 1999; Beatty and Paterson 2001. Evidence supports the direct anti-tumor effects of CD4 T cells (Braumuller and Paterson, 2013; Tran and al. 2014).

“HLA class II constitutive expression is typically limited to immune cells so the possibility of isolating class 2 peptides directly in primary tumors was not previously considered. However, Dengjel et al. Dengjel et al.

“Both CD8- and CD4-dependent responses contribute together and synergistically in the anti-tumor effect. It is crucial to identify and characterize tumor-associated antigens by either CD8+ T cell (ligand : MHC Class I molecule+peptide Epitope) or CD4-positive T-helper (ligand : MHC Class II molecule+peptide Epitope) for the development of vaccines against tumors.

An MHC class I peptide must also bind to an MHC molecule in order to trigger or elicit a cellular immune reaction. This depends on the MHC-molecule allele and the specific polymorphisms in the amino acid sequence. MHC-class-1-binding Peptides are typically 8-12 amino acids long and often contain two conserved residues. They interact with the MHC-molecule’s binding groove. Each MHC-molecule allele is assigned a “binding motif”. This allows you to determine which peptides will bind to the specific binding groove.

“In order to activate the MHC Class I dependent immune reaction, peptides must not only be able to bind certain MHC class I molecules produced by tumor cells but also need to be recognized by T cells that have specific T cell receptors (TCR).

Certain prerequisites are required in order for proteins to be recognized as antigens by T-lymphocytes and used in therapy. The antigen must be expressed predominantly by tumor cells, and not in comparable amounts by healthy tissue. Preferably, the antigen should be more abundant in tumor cells than normal healthy tissue. The antigen should be present in tumor cells in high levels (i.e. It is also desirable that the antigen be present in high concentrations (i.e., more than one copy per cell) Many tumor-specific and tumor-associated antibodies are derived from proteins that directly affect the transformation of normal cells to tumor cells. In cell cycle control and suppression of apoptosis. Indirectly, tumor-associated proteins may also be linked to downstream targets of directly responsible for the transformation. These indirect tumor-associated antigens could also be targets for a vaccination strategy (Singh Jasuja and al., 2004). To ensure that an immunogenic peptide is produced, it is important that epitopes be present in the antigen’s amino acid sequence. The peptide (derived from tumor-associated antigen) can be used to induce an in vitro and in vivo response in T-cells.

“Basically, any peptide that can bind to an MHC molecule could function as a T cell epitope. Induction of an in vitro and in vivo T cell-response requires that there is a T cells with corresponding TCRs, as well as the absence of immunological tolerance to this epitope.

TAAs can be used as a starting point to develop a T-cell-based therapy, including vaccines. T-cells can usually be isolated from patients or healthy individuals to identify and characterize TAAs. They also allow for the generation of differential transcription profiles and differential peptide expression patterns. The identification of genes that are over-expressed or selectively expressed within tumor tissues or human cell lines does not give precise information about the use of antigens transcribed from these genes in immune therapy. Because only a subset of antigens can be used in this manner, a T cell must have a TCR and an immunological tolerance must be minimal or absent. It is important that only those peptides are over- or selectively present in a preferred embodiment of the invention. A functional T cell can be defined as a cell that, upon stimulation with a particular antigen, can be clonally grown and capable of performing effector functions (?effector cell ).

Targeting peptide-MHC with specific TCRs (e.g. “In the case of targeting peptide-MHC by specific TCRs (e.g. The presentation of the underlying peptides is in these cases the determining factor.

“A first aspect of the invention is a peptide consisting of an amino acid sequence chosen from the group consisting SEQID NO: 1 through SEQID NO: 126 or a variant thereof that is at minimum 77%, preferably 88%, homologous to SEQID NO: 1 and SEQID NO: 126. Said variant binds or induces T cells to cross-react with said peptide or a pharmaceutically acceptable salt thereof. The underlying full-length peptide

“The present invention also relates to a protein of the invention consisting of a sequence selected from the group consisting SEQID NO: 1 through SEQID NO: 126 or a variation thereof. The sequence is homologous (preferably at minimum 77% or at most 88% identical) with SEQID NO: 1 through SEQID NO: 126. SEQID NO: 126 is a group that includes SEQID NO: 1 through SEQID NO: 126. SEQID NO: peptide/variant thereof is between 8 to 100, preferably between 1 and 30 amino acids.

“The following tables list the peptides as per the present invention, their respective SEQ ID NOs and the potential source (underlying) genes. All peptides listed in Table 1 and 2 bind to HLAA*02. Although the peptides listed in Table 2 were previously disclosed in large listing, they have never been linked to cancer. The peptides listed in Table 3 may be used in combination with other peptides. These peptides can also be used to diagnose and/or treat other malignancies that are caused by an over-expression of or over-presentation the respective underlying polypeptide.

“TABLE?1\nPeptides?according?to?the?present?invention.\nSEQ\nID Official\nNo Sequence Gene?ID(s) Gene?Symbol(s)\n1 AMLEEVNYI 9134 CCNE2\n2 VMFNFPDQATV 26960 NBEA\n3 VLAEIDPKQLV 28981 IFT81\n4 GLLDPGMLVNI 7182 NR2C2\n5 SLQSLIISV 7398 USP1\n6 SIMDYVVFV 8884 SLC5A6\n7 GLLGDIAIHL 84059 GPR98\n8 VLIDDSQSIIFI 57380 MRS2\n9 AAAPGEALHTA 153572 IRX2\n10 ILAAGFDGM 149175 MANEAL\n11 KLFAIPILL 2328 FMO3\n12 MLFEGLDLVSA 56603 CYP26B1\n13 FLTAFLVQI 392 ARHGAP1\n14 ILIETKLVL 3708 ITPR1\n15 SLLTAISEV 55086 CXorf57\n16 VILDLPLVI 101060503,?10628 TXNIP\n17 SLMLVTVEL 8546 AP3B1\n18 ALGEISVSV 23113 CUL9\n19 VLLTTAVEV 23677 SH3BP4\n20 MLDEILLQL 5425 POLD2\n21 TMEEMIFEV 2140 EYA3\n22 LLPEKSWEI 6898 TAT\n23 YQIDTVINL 50808 AK3\n24 FLMEEVHMI 10057 ABCC5\n25 GLSETILAV 9631 NUP155\n26 KMLDEAVFQV 89796 NAV1\n27 SLDIITITV 79572 ATP13A3\n28 ILVSQLEQL 10844 TUBGCP2\n29 NLISQLTTV 22979 EFR3B\n30 KMLGLTVSL 51651 PTRH2\n31 RLLQDPVGV 6002 RGS12\n32 ALTSLELEL 163732 CITED4\n33 GLYSKTSQSV 27032 ATP2C1\n34 LVFEGIMEV 11215 AKAP11\n35 FMGDVFINV 23491 CES3\n36 RMDGAVTSV 8648 NCOA1\n37 SLFYNELHYV 114793 FMNL2\n38 GLISSLNEI 6578 SLCO2A1\n39 GLDPTQFRV 5422 POLA1\n40 GLLEVQVEV 84171 LOXL4\n41 KAYQELLATV 8914 TIMELESS\n42 GLLEDERALQL 92312 MEX3A\n43 YLWSEVFSM 57486 NLN\n44 ALIVGIPSV 7976 FZD3\n45 SLSGEIILHSV 121441 NEDD1\n46 ALWVAVPKA 93109 TMEM44\n47 GLLEALLKI 57187 THOC2\n48 SLIGLDLSSV 9765 ZFYVE16\n49 RLALNTPKV 23094 SIPA1L3\n50 FLLSQIVAL 347051 SLC10A5\n51 ILDEAGVKYFL 113828 FAM83F\n52 ILASFMLTGV 9931 HELZ\n53 LLSEEHITL 9969 MED13\n54 HLFDIILTSV 79659 DYNC2H1\n55 LLIADNPQL 7404 UTY\n56 SLFSQMGSQYEL 79192 IRX1\n57 VLIGDVLVAV 27152 INTU\n58 VLLNINGIDL 222484 LNX2\n59 VLLSGLTEV 9498 SLC4A8\n60 VVSGATETL 23547 LILRA4\n61 YQAPYFLTV 9890 LPPR4\n62 VMLPIGAVVMV 151258 SLC38A11\n63 LLMSTENEL 4602 MYB\n64 VLFHQLQEI 25821 MTO1\n65 VMYDLITEL 3782 KCNN3\n66 YLNLISTSV 55757 UGGT2\n67 MLYDIVPVV 151963 MB21D2\n68 FLFPVYPLI 79796,?91893 ALG9,?FDXACB1\n69 KLFDRSVDL 55957 LIN37\n70 TLLWKLVEV 54901 CDKAL1\n71 FIFEQVQNV 83852 SETDB2\n72 KAIGSLKEV 1894 ECT2\n73 SLSSYTPDV 29843 SENP1\n74 FLDSLSPSV 65250 C5orf42\n75 SLDLHVPSL 51750,?8771 RTEL1,\nTNFRSF6B\n76 VLTTVMITV 166929 SGMS2”

“TABLE?2\nAdditional?peptides?according?to?the?present\ninvention?with?no?prior?known?cancer?association.\nSEQ\nID Official\nNo Sequence Gene?ID(s) Gene?Symbol(s)\n77 AIIDGKIFCV 5531 PPP4C\n78 RIIDPEDLKALL 29994 BAZ2B\n79 RLLEPAQVQQL 152002 XXYLT1\n80 ILMDPSPEYA 1786 DNMT1\n81 LLAEIGAVTLV 79042 TSEN34\n82 ALSSVIKEL 440145 MZT1\n83 KLLEIDIDGV 5422 POLA1\n84 KMFENEFLL 29 ABR\n85 FAYDGKDYLTL 3133 HLA-E\n86 KVIDYVPGI 25976 TIPARP\n87 LLQNNLPAV 22948 CCT5\n88 TLHRETFYL 9134 CCNE2\n89 IQHDLIFSL 3091 HIF1A\n90 TLVDNISTMAL 55856 ACOT13\n91 KLQDGVHII 51118 UTP11L\n92 YLQDYTDRV 10946 SF3A3\n93 ALRETVVEV 7415 VCP\n94 ALFPVAEDISL 84164 ASCC2\n95 ALYSKGILL 9631 NUP155\n96 NLLKLIAEV 57405 SPC25\n97 ALLDGTVFEI 8214,?85359 DGCR6,?DGCR6L\n98 ALVDHLNVGV 2647 BLOC1S1\n99 QMLEAIKALEV 7690 ZNF131\n100 VADPETRTV 11284 PNKP\n101 AMNSQILEV 23036 ZNF292\n102 ALFARPDLLLL 55324 ABCF3\n103 SLLEYQMLV 23511 NUP188\n104 TLIQFTVKL 6775 STAT4\n105 SMYDKVLML 9328 GTF3C5\n106 KMPDDVWLV 8567 MADD\n107 AMYGTKLETI 8573 CASK\n108 ILLDDQFQPKL 11213 IRAK3\n109 SLFERLVVL 5976 UPF1\n110 GLTETGLYRI 29127,?83956 RACGAP1,\nRACGAP1P\n111 FLPEAPAEL 4171 MCM2\n112 LLLPGVIKTV 3980 LIG3\n113 LTDPDIHVL 23335 WDR7\n114 ALLEPGGVLTI 23195 MDN1\n115 ALLPSDCLQEA 64410 KLHL25\n116 ALLVRLQEV 3695 ITGB7\n117 FLLDSAPLNV 134430 WDR36\n118 KLPSFLANV 2585 GALK2\n119 SLIDDNNEINL 65975 STK33\n120 SLAADIPRL 171425 CLYBL\n121 YMLEHVITL 9735 KNTC1\n122 SMMPDELLTSL 9994 CASP8AP2\n123 KLDKNPNQV 9994 CASP8AP2\n124 SLITDLQTI 26005 C2CD3\n125 LLSEPSLLRTV 91442 C19orf40\n126 AAASLIRLV 3064 HTT”

“TABLE?3\nPeptides?useful?for?e.g. ?personalized?cancer\ntherapies.\nSEQ\nID Official\nNo Sequence Gene?ID(s) Gene?Symbol(s)\n127 SQAPVLDAI 1293 COL6A3\n128 SLAPAGVIRV 30012 TLX3\n129 RVADYIVKV 201780 SLC10A4\n130 SLYDNQITTV 6585,?9353 SLIT1,?SLIT2\n131 ILMGTELTQV 10439 OLFM1\n132 NLLAEIHGV 10570 DPYSL4\n133 IMEDIILTL 1656 DDX6\n134 FMIDASVHPTL 221960,?51622 CCZ1,?CCZ1B\n135 SLMMTIINL 7153 TOP2A\n136 FLPPEHTIVYI 9896 FIG4\n137 NLLELFVQL 5297 PI4KA\n138 RLLDFPEAMVL 23113 CUL9\n139 FLSSVTYNL 23312 DMXL2\n140 GLLEVMVNL 23001 WDFY3\n141 NLPEYLPFV 55832,?91689 C22orf32,?CAND1”

“The invention also generally refers to peptides according the present invention for treatment of proliferative disorders such as non-small cell lung carcinoma, small cell lung carcinoma, kidney cancers, brain cancers, colorectal and prostate cancers, leukemias, breast cancers, Merkel cell carcinomas, leukemias, prostate cancers, pancreatic cancers, liver cancers, pancreatic cancers, colorectal and colorectal cancers, leukemias, lung cancers, gallbladder and duct cancers and bile ducts.

“Particularly preferred are the peptides?alone or in combination?according to the present invention selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 126. The peptides that are used in immunotherapy of small-cell lung cancer, nonsmall-cell lung cancers, small cell carcinomas, lung cancers, lung cancers, kidney cancers, bladder cancers, lung cancers, lung cancers, lung cancers, lung cancers, lung cancers, lung cancers, lung cancers, lung cancer cells, lung cancers, lung cancers, lung cancers, lung cancers, lung cancers, gallbladder, bile duct, and esophesulen, but not preferably, small-cell lung cancer

The peptide of SEQ ID No: 72 is the most preferred. The peptide SEQ ID No: 72 is most preferred.

“As can be seen in the following Tables 4, A and B, many peptides of the present invention can also be found on other types of tumors and can therefore also be used for immunotherapy of other indications. Refer to FIGS. FIGS. 1A-1P, and Example 1.

“TABLE?4A\nPeptides?according?to?the?present?invention?and?their?specific?uses?in?other\nproliferative?diseases?than?SCLC,?especially?in?other?cancerous?diseases.\nThe?table?shows?for?selected?peptides?on?which?additional?tumor?types?they?were\nfound?and?either?over-presented?on?more?than?5%?of?the?measured?tumor?samples,\nor?presented?on?more?than?5%?of?the?measured?tumor?samples?with?a?ratio?of\ngeometric?means?tumor?vs?normal?tissues?being?larger?than?3.?Over-presentation\nis?defined?as?higher?presentation?on?the?tumor?sample?as?compared?to?the?normal\nsample?with?highest?presentation. ?Normal?tissues?against?which?over-presentation\nwas?tested?were:?adipose?tissue,?adrenal?gland,?blood?cells,?blood?vessel,?bone\nmarrow,?brain,?esophagus,?eye,?gallbladder,?heart,?kidney,?large?intestine,?liver,\nlung,?lymph?node,?nerve,?pancreas,?parathyroid?gland,?peritoneum,?pituitary,\npleura,?salivary?gland,?skeletal?muscle,?skin,?small?intestine,?spleen,?stomach,\nthymus,?thyroid?gland,?trachea,?ureter,?urinary?bladder.\nSEQ?ID\nNO: Sequence Other?relevant?organs/diseases\n1 AMLEEVNYI PC,?Leukemia\n2 VMFNFPDQATV PrC\n3 VLAEIDPKQLV HCC,?OC\n4 GLLDPGMLVNI Uterine?Cancer\n6 SIMDYVVFV GC,?CRC,?HCC,?BRCA,?Urinary?bladder?cancer,\nGallbladder?Cancer,?Bile?Duct?Cancer\n7 GLLGDIAIHL Brain?Cancer,?BRCA,?Uterine?Cancer\n8 VLIDDSQSIIFI Leukemia,?OC\n9 AAAPGEALHTA NSCLC,?BRCA,?MCC,?Esophageal?Cancer,?Urinary\nbladder?cancer\n11 KLFAIPILL HCC,?Gallbladder?Cancer,?Bile?Duct?Cancer\n12 MLFEGLDLVSA PrC\n13 FLTAFLVQI Leukemia,?Urinary?bladder?cancer\n14 ILIETKLVL Leukemia\n15 SLLTAISEV Brain?Cancer,?HCC,?PC,?Urinary?bladder?cancer,\nGallbladder?Cancer,?Bile?Duct?Cancer\n16 VILDLPLVI PC,?Leukemia\n17 SLMLVTVEL PC,?Leukemia,?BRCA,?Urinary?bladder?cancer\n18 ALGEISVSV Leukemia\n19 VLLTTAVEV BRCA,?Uterine?Cancer\n20 MLDEILLQL RCC,?GC,?CRC,?Leukemia,?Urinary?bladder?cancer\n21 TMEEMIFEV CRC,?Leukemia,?Urinary?bladder?cancer,?Gallbladder\nCancer,?Bile?Duct?Cancer\n22 LLPEKSWEI HCC\n23 YQIDTVINL PrC,?Urinary?bladder?cancer\n24 FLMEEVHMI NSCLC,?CRC,?Melanoma,?Gallbladder?Cancer,?Bile\nDuct?Cancer\n25 GLSETILAV NSCLC,?Brain?Cancer,?CRC,?HCC,?PC,?PrC,\nLeukemia,?BRCA,?Melanoma,?Esophageal?Cancer,\nOC,?Urinary?bladder?cancer,?Uterine?Cancer,\nGallbladder?Cancer,?Bile?Duct?Cancer\n26 KMLDEAVFQV NSCLC,?Brain?Cancer,?CRC,?BRCA,?Melanoma,\nUrinary?bladder?cancer\n27 SLDIITITV NSCLC,?RCC,?Brain?Cancer,?GC,?HCC,?PC,?BRCA,\nMelanoma,?Urinary?bladder?cancer,?Gallbladder\nCancer,?Bile?Duct?Cancer\n28 ILVSQLEQL Gallbladder?Cancer,?Bile?Duct?Cancer\n29 NLISQLTTV Brain?Cancer\n30 KMLGLTVSL CRC,?BRCA,?OC,?Gallbladder?Cancer,?Bile?Duct\nCancer\n31 RLLQDPVGV Brain?Cancer,?HCC,?PrC,?BRCA,?Uterine?Cancer\n32 ALTSLELEL HCC,?PrC,?BRCA,?OC,?Uterine?Cancer,?Gallbladder\nCancer,?Bile?Duct?Cancer\n33 GLYSKTSQSV NSCLC,?HCC,?Esophageal?Cancer\n34 LVFEGIMEV Leukemia,?Urinary?bladder?cancer,?Uterine?Cancer\n37 SLFYNELHYV Melanoma\n38 GLISSLNEI Leukemia\n39 GLDPTQFRV Urinary?bladder?cancer\n43 YLWSEVFSM Leukemia\n45 SLSGEIILHSV NSCLC,?CRC,?Melanoma,?Urinary?bladder?cancer\n47 GLLEALLKI Leukemia\n49 RLALNTPKV HCC,?Leukemia\n52 ILASFMLTGV Leukemia\n53 LLSEEHITL Leukemia,?Urinary?bladder?cancer\n57 VLIGDVLVAV OC\n58 VLLNINGIDL Urinary?bladder?cancer\n59 VLLSGLTEV Brain?Cancer,?Leukemia\n61 YQAPYFLTV Brain?Cancer,?OC,?Urinary?bladder?cancer,?Uterine\nCancer\n64 VLFHQLQEI Leukemia,?Melanoma\n65 VMYDLITEL NSCLC,?PC,?BRCA,?Uterine?Cancer,?Gallbladder\nCancer,?Bile?Duct?Cancer\n66 YLNLISTSV Urinary?bladder?cancer,?Gallbladder?Cancer,?Bile\nDuct?Cancer\n67 MLYDIVPVV NSCLC,?PC,?OC,?Urinary?bladder?cancer\n68 FLFPVYPLI Brain?Cancer,?CRC,?Melanoma,?Urinary?bladder\ncancer\n69 KLFDRSVDL NSCLC,?RCC,?Brain?Cancer,?CRC,?HCC,?PC,?BRCA,\nOC,?Urinary?bladder?cancer\n72 KAIGSLKEV OC\n73 SLSSYTPDV Leukemia\n76 VLTTVMITV PC,?OC\n77 AIIDGKIFCV GC,?Urinary?bladder?cancer\n78 RIIDPEDLKALL NSCLC,?CRC,?HCC,?Urinary?bladder?cancer,?Uterine\nCancer\n79 RLLEPAQVQQL NSCLC,?Brain?Cancer,?HCC,?BRCA,?Esophageal\nCancer\n80 ILMDPSPEYA Brain?Cancer,?BRCA,?MCC,?Melanoma,?Urinary\nbladder?cancer\n81 LLAEIGAVTLV NSCLC,?HCC,?Melanoma,?OC,?Urinary?bladder\ncancer\n82 ALSSVIKEL CRC,?Esophageal?Cancer,?Urinary?bladder?cancer,\nUterine?Cancer\n83 KLLEIDIDGV Brain?Cancer,?CRC,?Leukemia,?BRCA,?MCC,?OC,\nUrinary?bladder?cancer,?Uterine?Cancer\n84 KMFENEFLL CRC,?Leukemia,?Urinary?bladder?cancer,?Gallbladder\nCancer,?Bile?Duct?Cancer\n85 FAYDGKDYLTL RCC,?Leukemia,?BRCA,?Esophageal?Cancer\n86 KVIDYVPGI NSCLC,?Brain?Cancer,?HCC,?BRCA,?Esophageal\nCancer,?OC,?Gallbladder?Cancer,?Bile?Duct?Cancer\n87 LLQNNLPAV Leukemia,?Melanoma,?OC,?Urinary?bladder?cancer\n88 TLHRETFYL OC,?Urinary?bladder?cancer,?Gallbladder?Cancer,\nBile?Duct?Cancer\n89 IQHDLIFSL GC\n90 TLVDNISTMAL CRC,?OC\n91 KLQDGVHII NSCLC,?Gallbladder?Cancer,?Bile?Duct?Cancer\n92 YLQDYTDRV Leukemia,?OC\n93 ALRETVVEV NSCLC,?Brain?Cancer,?Leukemia,?BRCA,\nEsophageal?Cancer,?OC,?Urinary?bladder?cancer,\nGallbladder?Cancer,?Bile?Duct?Cancer\n94 ALFPVAEDISL NSCLC,?Leukemia,?Urinary?bladder?cancer\n95 ALYSKG ILL?NSCLC,?RCC,?CRC,?HCC,?MCC,?Esophageal\nCancer,?OC,?Urinary?bladder?cancer\n96 NLLKLIAEV RCC,?Brain?Cancer,?CRC,?HCC,?Melanoma,?Uterine\nCancer,?Gallbladder?Cancer,?Bile?Duct?Cancer\n97 ALLDGTVFEI Brain?Cancer,?HCC,?MCC,?OC,?Urinary?bladder\ncancer\n98 ALVDHLNVGV Brain?Cancer,?HCC,?PrC,?Leukemia,?OC,?Uterine\nCancer,?Gallbladder?Cancer,?Bile?Duct?Cancer\n99 QMLEAIKALEV CRC,?Leukemia,?Melanoma,?Urinary?bladder?cancer\n101 AMNSQILEV Brain?Cancer,?CRC,?Leukemia,?BRCA,?Uterine\nCancer\n102 ALFARPDLLLL Leukemia,?Melanoma,?OC,?Urinary?bladder?cancer\n103 SLLEYQMLV BRCA,?Urinary?bladder?cancer,?Gallbladder?Cancer,\nBile?Duct?Cancer\n105 SMYDKVLML MCC,?OC\n106 KMPDDVWLV BRCA,?Uterine?Cancer\n107 AMYGTKLETI CRC,?HCC,?PC,?OC\n108 ILLDDQFQPKL Melanoma\n109 SLFERLVVL HCC,?MCC,?Urinary?bladder?cancer\n110 GLTETGLYRI NSCLC,?CRC,?PC,?Leukemia,?Esophageal?Cancer,\nOC,?Gallbladder?Cancer,?Bile?Duct?Cancer\n111 FLPEAPAEL Leukemia,?Gallbladder?Cancer,?Bile?Duct?Cancer\n112 LLLPGVIKTV Leukemia\n116 ALLVRLQEV Leukemia\n118 KLPSFLANV HCC,?Uterine?Cancer,?Gallbladder?Cancer,?Bile?Duct\nCancer\n119 SLIDDNNEINL OC,?Uterine?Cancer\n121 YMLEHVITL CRC,?Leukemia,?MCC,?Melanoma,?OC,?Urinary\nbladder?cancer,?Gallbladder?Cancer,?Bile?Duct\nCancer\n123 KLDKNPNQV Leukemia,?Urinary?bladder?cancer\n124 SLITDLQTI NSCLC,?Brain?Cancer,?CRC,?BRCA,?OC,?Urinary\nbladder?cancer,?Uterine?Cancer\n126 AAASLIRLV Leukemia,?BRCA\nNSCLC = non-small cell lung cancer, RCC = kidney cancer, CRC = colon or rectum cancer, GC = stomach cancer, HCC = liver cancer, PC = pancreatic cancer, PrC = prostate cancer, leukemia, BrCa = breast cancer, MCC = Merkel cell carcinoma, OC = ovarian cancer”

“TABLE?4B\nPeptides?according?to?the?present?invention?and?their?specific?uses?in?other\nproliferative?diseases,?especially?in?other?cancerous?diseases?(amendment?of?Table\n4).?This?table?shows,?like?Table?4A,?for?selected?peptides?on?which?additional\ntumor?types?they?were?found?showing?over-presentation?(including?specific\npresentation)?on?more?than?5%?of?the?measured?tumor?samples,?or?presentation?on\nmore?than?5%?of?the?measured?tumor?samples?with?a?ratio?of?geometric?means?tumor\nvs?normal?tissues?being?larger?than?3.?Over-presentation?is?defined?as?higher\npresentation?on?the?tumor?sample?as?compared?to?the?normal?sample?with?highest\npresentation. ?Normal?tissues?against?which?over-presentation?was?tested?were:\nadipose?tissue,?adrenal?gland,?artery,?bone?marrow,?brain,?central?nerve,?colon,\nduodenum,?esophagus,?eye,?gallbladder,?heart,?kidney,?liver,?lung,?lymph?node,\nmononuclear?white?blood?cells,?pancreas,?parathyroid?gland,?peripheral?nerve,\nperitoneum,?pituitary,?pleura,?rectum,?salivary?gland,?skeletal?muscle,?skin,\nsmall?intestine,?spleen,?stomach,?thyroid?gland,?trachea,?ureter,?urinary?bladder,\nvein.\nSEQ\nID?No Sequence Additional?Entities\n4 GLLDPGMLVNI Brain?Cancer\n13 FLTAFLVQI RCC\n14 ILIETKLVL CLL,?NHL\n16 VILDLPLVI CLL,?HNSCC\n17 SLMLVTVEL CLL,?Melanoma,?NHL\n20 MLDEILLQL CLL,?AML,?NHL,?HNSCC\n21 TMEEMIFEV CLL,?Esophageal?Cancer,?Uterine?Cancer,?HNSCC\n24 FLMEEVHMI HNSCC\n25 GLSETILAV CLL,?AML,?NHL,?HNSCC\n26 KMLDEAVFQV HNSCC\n27 SLDIITITV NHL\n28 ILVSQLEQL CLL,?BRCA,?NHL\n30 KMLGLTVSL RCC,?Melanoma,?AML,?NHL\n32 ALTSLELEL HNSCC\n34 LVFEGIMEV CLL\n49 RLALNTPKV CLL,?NHL\n58 VLLNINGIDL RCC,?Melanoma,?Uterine?Cancer,?NHL,?HNSCC\n64 VLFHQLQEI CRC,?CLL,?AML,?NHL\n68 FLFPVYPLI Uterine?Cancer,?AML,?NHL,?HNSCC\n69 KLFDRSVDL Uterine?Cancer,?AML\n72 KAIGSLKEV CRC,?Esophageal?Cancer,?Uterine?Cancer\n77 AIIDGKIFCV Uterine?Cancer\n82 ALSSVIKEL NSCLC,?CLL,?BRCA,?Melanoma,?OC,?Gallbladder?Cancer,\nBile?Duct?Cancer,?AML,?NHL,?HNSCC\n83 KLLEIDIDGV Melanoma,?AML,?NHL,?HNSCC\n84 KMFENEFLL CLL,?NHL,?HNSCC\n85 FAYDGKDYLTL CLL,?Melanoma,?Gallbladder?Cancer,?Bile?Duct?Cancer,\nAML\n86 KVIDYVPGI Melanoma,?HNSCC\n87 LLQNNLPAV HNSCC\n89 IQHDLIFSL CLL,?Melanoma,?Urinary?bladder?cancer,?AML\n91 KLQDGVHII CLL,?Melanoma,?AML,?NHL\n92 YLQDYTDRV CLL,?NHL\n93 ALRETVVEV Melanoma,?Uterine?Cancer,?AML,?HNSCC\n94 ALFPVAEDISL RCC,?CLL,?BRCA,?Melanoma,?AML,?NHL\n95 ALYSKGILL Gallbladder?Cancer,?Bile?Duct?Cancer,?NHL\n96 NLLKLIAEV PC,?AML,?NHL\n97 ALLDGTVFEI BRCA,?Uterine?Cancer\n98 ALVDHLNVGV CLL\n99 QMLEAIKALEV Brain?Cancer,?CLL,?NHL,?HNSCC\n100 VADPETRTV Melanoma\n101 AMNSQILEV AML\n102 ALFARPDLLLL CLL\n105 SMYDKVLML Gallbladder?Cancer,?Bile?Duct?Cancer,?AML,?HNSCC\n107 AMYGTKLETI RCC,?Esophageal?Cancer,?Gallbladder?Cancer,?Bile?Duct\nCancer,?NHL\n108 ILLDDQFQPKL AML\n109 SLFERLVVL Uterine?Cancer\n113 LTDPDIHVL RCC,?CLL,?BRCA,?Melanoma,?AML\n121 YMLEHVITL NSCLC,?HCC,?CLL,?BRCA,?Uterine?Cancer,?AML,?NHL,\nHNSCC\n122 SMMPDELLTSL NHL\n124 SLITDLQTI AML,?NHL\nNSCLC = non-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, OC = ovarian cancer, NHL = non-Hodgkin lymphoma, AML = acute myeloid leukemia, CLL = chronic lymphocytic leukemia, HNSCC = head and neck squamous cell carcinoma.”

“Thus, another aspect to the invention is the use of at minimum one peptide according the present invention according any one of SEQ ID No: 1, 15, 16, 17, 25, 26, 65, 67.69.69.76, 96.107 and 110 for the?in a preferred embodiment combined?treatments of pancreatic carcinoma.”

“Thus, another aspect to the invention is the use of at minimum one peptide according the present invention according any one of SEQ ID No: 1, 8, 13, 16, 17, 18, 20, 21, 24, 28, 30, 34, 43, 47. 49. 53. 64. 73. 82. 83. 84. 85. 87. 89. 91. 92. 94. 96. 97. 101. 102. 105. 108. 111. 113. 112, 116. 124, and 126 for?in the?in the?in the?in the?in the?in the?in the?in the?in the?in the?in combination?treatment of?treatment of?in the?treatment of?in the?in the?in the?in the?in the?in the?for the?in the?in the?the?in the?in the treatment of the?in the?in the?in the?in the?for the?in the?for the? in the?in the?the?for the?in the?treatment of the?in the?for the?in the?treatment of the?treatment of the?in the?in the?treatment of the?treatment of the?the?for the?treatment of the?treatment of the?for the?treatment of the?treatment of the?in the?treatment of the?treatment of the?for the?in the?in the?in the?the?for the?in the?for the?in the?d?for the?in the?in the?for the?in the?in the?in the?in the?d?in the?in the?in the? in the?in the? in the?in the?in the?in the?d?the?the?in the apparently darin

“Thus, another aspect to the invention is the use of at minimum one peptide according the present invention according any one of SEQ ID No: 2, 12, 23, 25, 31 32, or 98 for the?in a preferred embodiment combined?treatment prostate cancer.”

“Another aspect of the invention is the use of at minimum one peptide according the present invention according any one of SEQ ID No: 3, 6, 11, 25, 27, 31, 32 and 33, 49, 70, 779, 869, 969, 597, 96, 95, or 97, to treat liver cancer.

“Another aspect of the invention is the use of at minimum one peptide according the present invention according any one of SEQ ID No: 3, 8, 25, 32, 56, 70, 72,,, 69, 72 and 76, respectively, of any one of SEQID NO: 9, 23, 57, 669, 769,,,72, 77,, 68,,, 79, 72, 75,76,, 81,82,83,86,87,88, 90.92, 95, 97., 98, 102 for the?in the?in the?treatment of ovarian carcinoma treatment of?in the combination?treatment of a?in the?in the?treatment of?in the?of the?in the?in the?in the?in the?in the?treatment of?in the?in the? in the?in the?treatment of the?in the?the? in the?in the?in the?in the?in the?for the?in the?in the?in the? the?in the?for the?in the?treatment of the?treatment of the?in the?

“Thus, another aspect to the invention is the use of at minimum one peptide according the present invention according any one of SEQ ID No: 4, 7, 19, 25, 31, 32 or 34, and 58, 65, 64, 65,, 669, 69, 72.77.78.78.77.78.82.83.78.77.78.78.82.83.93.97.98.101,106.109.118.119.121.124 for the?in one preferred embodiment combined treatment of a combination?treatment of adis the?treatment of a preferred?treatment of uterine carcinoma of the treatment of?treatment of?treatment of?treatment of?a combination?treatment of?for the?the?for the?in the?treatment of?for the?in the?for the?in the?treatment of?for the?for the?for the?in the?treatment of?treatment of?for the?for the?in the?treatment of?treatment of?treatment of?treatment of?treatment of?treatment of?treatment of?treatment of the?

“Thus, another aspect to the invention is the use of at minimum one peptide according the present invention according any one of SEQ ID No: 6, 20, 27,, 77, 89 and 89 for treatment of stomach cancer in one preferred embodiment.”

“Thus, another aspect to the invention is the use of at minimum one peptide according the present invention according any one of SEQ ID No: 6, 20, 21, 25, 26, 30, 45 and 72, respectively, 72, 68, 70, 72, 78, 80, 82. 83. 84. 90, 95. 96. 99. 101. 107. 121. 124 for treatment of colon or rectal cancer in one preferred embodiment.”

“Thus, another aspect to the invention is the use of at minimum one peptide according the present invention according any one of SEQ ID No: 6, 7, 19, 25, 26, 27, 30, 31, 32, 65 and 69, as well as the use of any one of SEQID NO: 6, 9, 17, 19, 25, 26, 27, 27, 28, 31, 32, 65, 70,, 79, 82, 80, 84,5, 85,86, 93.94.101, 103.106. 121.124.126 for the?in the?in the?treatment of breast?in the?in the treatment of?in the combination?treatment of?treatment of?treatment of?treatment of?treatment of?treatment of?as of?treatment of?treatment of?treatment of?treatment of?treatment of?treatment of?treatment of?treatment of?treatment of?treatment of?for the?treatment of?a preferred?treatment of?treatment of?for the?treatment of?the?treatment of?the?treatment of the?s?treatment of the?treatment of the? treatment of?treatment of the?in the

“Thus, another aspect to the invention is the use of at minimum one peptide according the present invention according any one of SEQ ID No: 6, 9, 13, 20, 21, 23, 25, 26, 27, 39, 45, 53. 57, 66.1, 76.7, 68. 69. 77.78. 79. 78. 78. 80. 81. 82. 83. 84. 87. 88. 89. 93. 94. 95. 97. 99. 103, 123 and 124 for?in the?in the?in the?treatment of bladder cancer?treatment?in the?in the?in the?in the?treatment of?treatment of?in the?in the?treatment of the?in the?in the?in the?in the?treatment of the?in the?treatment of the?in the?in the?in the?in the?in the treatment of the?in the?in the?in the?in the?the? in the treatment of the?the?in the?

“Thus, another aspect to the invention is the use of at minimum one peptide according the present invention according any one of SEQ ID No: 6, 11, 25, 27, 27, 28, 32, 65 and 66, respectively.

“Another aspect of the invention is the use of at minimum one peptide according the present invention according SEQ ID NO. 6, 11, 25, 27, 28, 32, 32, 65 and 66, respectively.

“Thus, another aspect to the invention is the use of at minimum one peptide according the present invention according any one of SEQ ID No: 4, 7, 25, 26, 27, 29, 31, 31, 59, 70, and 69, respectively.

“Another aspect of the invention is the use of at minimum one peptide according the present invention according any one of SEQ ID No: 9, 25, 26, 27, 33 or 45, 65, 70,, 69, 75, 78, 779, 85, 81, 886, 991, 95, 110, 120, 121 and 124 for?in one preferred embodiment combined?treatment NSCLC.”

“Another aspect of the invention is the use of at minimum one peptide according the present invention according any one of SEQ ID No: 9, 80 or 83, 95,97, 105 and 109, and/or 121 for the?in one preferred?treatment of Merkel cell carcinoma.”

“The present invention also relates to the use at least one peptide according SEQ ID NO. 9, 21, 25, 33 or 72, 79, 80, 82, 79, 82, 86, 93 or 95, 107 and 110 for treatment of esophageal carcinoma in one preferred embodiment.”

“There is another aspect to the invention that relates to the use at least one peptide according the present invention according SEQ ID NO. 17, 25, 26, 27, 30, 37. 58. 64. 68. 80. 81. 82. 83. 85. 87. 89. 91. 93. 94. 99. 100. 101. 102. 113. 121 for the?in a preferred embodiment combined?treatment?of melanoma.

“Thus, another aspect to the invention is the use of at minimum one peptide according the present invention according any one of SEQ ID No: 16, 20, 21, 24, 25, 32, 58 and 68, respectively.

“Thus, another aspect to the invention is the use of at minimum one peptide according the present invention according any one of SEQ ID No: 14, 17, 20, 27, 28, 29, 49, 58.64, 668. 82,83,84, 92.1, 95. 96. 99. 107. 121. 122 and 124 for treatment of NHL?in one preferred embodiment.

“Another aspect of the invention is the use of the peptides according the present invention to treat a proliferative disorder selected from the group: small cell lung carcinoma, non-small cell lung carcinoma, small cell kidney cancers, small cell lung tumors, small cell lung and small cell lung cancers, lung cancers, liver cancers, pancreatic cancers, prostate cancers, lung cancers, lung cancers, lung cancers, lung cancers, lung cancers, lung cancers, lung cancers and bile duct and bile duct and bile d sophageal cancersophageal cancer.

“The invention also relates to peptides according the present invention that can bind to a human major histocompatibility complicated (MHC) class I or an elongated form such as a length-variant MHC class II.”

“The invention further refers to peptides according the present invention, wherein each peptide consists or essentially of an amino acids sequence according to SEQID NO: 1 through SEQ ID No: 126.”

“The invention further refers to peptides according the present invention wherein said peptides are modified and/or include non-peptide bonding.”

“The invention also relates to peptides according the present invention wherein said peptide is part a fusion protein in particular fused with the N-terminal amino acid chains (Ii) of the HLA?DR antigen-associated invariant system (Ii), or fused (or into the sequence thereof) an antibody such as, for instance, an antibody that is specifically for dendritic cell.”

“The present invention also relates to a nucleic acids, which encode the peptides according the invention.” Further, the present invention relates to the nucleic acids according to the invention, which can be DNA, cDNA or PNA, RNA, or combinations thereof.

“The invention also relates to an expression vector capable to express and/or expressing nucleic acids according to the invention.”

“The invention further refers to a peptide according the present invention, an nucleic acid according the present invention or an expression Vector according to this invention for use in treatment of diseases and medicine, in particular, the treatment of cancer.”

“The invention also relates to antibodies that are specific for the peptides described in the present invention, or complexes thereof with MHC. There are also methods of making these.”

“The invention also relates to T cell receptors (TCRs), specifically soluble TCRs (sTCRs), and cloned TCRs engineered in autologous and allogeneic T cell lines, and methods for making them, as well as NK and other cells bearing said TCRs or cross-reacting.

“The immunotherapeutic use and TCRs of the peptides according the invention are further embodiments.”

“The present invention also relates to a host cells comprising a nucleic acids according to the invention or an expression vector, as described above. Further, the present invention relates to a host cell that is an antigen-presenting cell and preferably a dendritic cells.

“The present invention also relates to a method of producing a protein according to its invention. This method comprises culturing the host cells according to the invention and isolating said peptide from said culture medium or said host cell.”

“The present invention further refers to said method according the invention wherein the antigen can be loaded onto class I or 2 MHC molecules on the surface of an appropriate antigen-presenting cells or artificial antigen presenting cells by contacting sufficient amounts of the antigen with the antigen present cell.”

“The present invention also relates to the method according the present invention wherein the antigen present cell includes an expression vector capable to express or expressing said propeptide containing SEQID NO: 1 through SEQID NO: 126, preferentially containing SEQID NO: 1 through SEQID NO: 76 or a variant amino acids sequence.”

“The invention also relates to activated cells, which are produced according to the method of the present invention. In this case, said T cell recognizes selectively a cell that expresses a polypeptide containing an amino acid sequence according the present invention.”

“The invention also relates to a method for killing target cells in a patient that target cells aberrantly expression a polypeptide consisting of any amino acid sequence according the present invention. The method involves administering to the patient an effectual number of T cells produced according the present invention.

“The invention also relates to the use any peptide described, the nucleic acids according to present invention, expression vector according the present invention and the cell according the present embodiment, activated T lymphocytes, T cell receptors or antibody or other peptide/peptide-MHC binding molecules according the invention as medicaments or in the manufacturing of medicaments. Preferably, the medicament is active against cancer.

“Preferably said medicament is a cell therapy, a vaccination or a protein based upon a TCR or antibody.

The present invention also relates to a method of using said cancer cells. These include small cell lung carcinoma, non-small cell lung carcinoma, small cell kidney cancer and brain cancer.

The present invention also relates to biomarkers that are based on peptides according the invention, herein referred to as?targets?. These biomarkers can be used to diagnose small-cell lung cancer. Over-presentation or over-expression can be used as a marker. These markers can also be used to predict whether a treatment will succeed, most preferably an immunotherapy. The biomarker is preferred because it targets the same target as the immunotherapy. To detect a peptide of particular interest, a TCR or antibody can be used to stain tumor sections.

“Optionally, the antibody may have an additional effector function such a immune stimulating domain or xin.”

“The invention also addresses the use of novel targets in cancer treatment. The following detailed description of the polypeptides (underlying expression products) is provided to help you understand the therapeutic and diagnostic purposes of these peptides.

“ABCC5 is upregulated in various cancer entities, such as pancreatic cancer, breast cancer metastasis and esophageal carcinoma with an amplified region on chromosome 3. ABCC5 is further frequently mutated in microsatellite instable (MSI) colorectal cancer (Mohelnikova-Duchonova et al., 2013; Chen et al., 2008; Alhopuro et al., 2012; Mourskaia et al., 2012). The estrogen metabolism and elevated levels of HES1, DELTEX1 or c-Myc influence ABCC5’s expression (Larson, et. al. 2009; Vendrell, et. al. 2004).

“ABCF3 gene locus has frequent chromosomal gains that are related to cervical cancer. ABCF3 also increases the proliferation of human liver cancer cell lines (Choi and Zhou, 2007; Zhou and al. (2013)b). ABCF3 binds with the tumor protein D52L2 and positively regulates cell growth (Zhou et. al., 2013b).

“Deletion mapping of medulloblastoma tumours reveals loss distal chromosome (17p13.3) sequences also in ABR gene (McDonald and al., 1994).

“AK3 is downregulated in hepatocellular cancers and overexpressed in B cell chronic lymphocyticleukemia (Carlucci, et. al. 2009; Melle, et. al. 2007).

“AKAP11 is often altered and over-expressed within oral tumors, and is further associated with the progression of cancer (Garnis et. al. 2005). AKAP11 promotes cell movement in cancer cells by suppressing GSK-3beta, and interfacing with cytoskeletal scaffolding protein. AKAP11 influences the Rb pathway, which can alter cell cycle regulation (Logue et. al., 2011).

“The expression of ALG9 during TGFbeta-induced epithelial-to-mesenchymal transition (EMT) is significantly changed and influences the N-glycan profile of cancer cells (Tan et al., 2014).”

“AP3B1 is downregulated in cervical cancers in comparison to normal tissue of the uterine cervix” (Petrenko et. al. 2006). “AP3B1 is a target for the microRNA miR-9 which is deregulated in many types of cancer, including breast and hepatocellular.

“The expression of ARHGAP1 can be altered in various cancer types, including prostate and metastatic head cancer (Davalieva, et. al. 2015; Zohrabian, et. al. 2007, 2007). ARHGAP1 is repressed by TGF-beta-induced tumour cell invasion through miR-34a. ARHGAP1 is associated with epithelial-to-mesenchymal transition (EMT) by restricting Rho activation which is necessary for detachment (Ahn et al., 2012; Clay and Halloran, 2013).”

“ATP13A3 expression is affected in cervical cancer (Bierkens et. al., 2013).

Through a common chromosomal loss of the locus, ATP2C1 is high-expressed in cervical carcinoma. In mice, ATP2C1 loss causes increased apoptosis, and a genetic predisposition for squamous cells carcinomas of skin and esophagus in heterozygotes (Wilting et. al. 2008; Okunade et. al. 2007, 2007). Grice et. al. (2010). ATP2C1 inhibition causes a marked alteration in IGF1R processing, which is critical for tumor progression.

“BLOC1S1 is lower in malignant prostate tissue than in normal prostate tissue” (Asmann and al. 2002). BLOC1S1 is essential for proper EGFR lysosomal transport (Zhang et. al., 2014). C19orf40, also known as FAAP24, encodes a component in the Fanconi anemia core complex that plays a critical role in DNA damage response. (RefSeq 2002). C19orf40 and FANCM form a complex that is important for DNA damage recognition and suppression of sister-chromatid exchange. ATR-mediated checkpoint activation, DNA damage repair, replication, and maintenance of chromosomal stability can also be achieved by C19orf40. C19orf40 mutations are linked to cancer-prone Fanconianemia (Valeri and al. (2011); Wang et. al. (2013)d; Ciccia, et. al. (2007)).

“C2CD3 was associated with oropharyngeal carcinomas of the squamous cells (Wang and al., 2013b).

“CAND1 is linked to prostate cancer and lung cancer (Zhai, et. al., 2014; Salon, et. al. 2007,).

CASK is overexpressed in many types of cancer, including colorectal and gastric cancers as well as leukemia. CASK is also associated with cancer progression (Wei et. al. 2014; Zhou and al. 2014c; Al Lamki et. al. 2005). Exendin-4 stimulates beta-cell insulin secretion, and Necl-2, together with E-cadherin, increases CASK (Giangreco, Zhu, and al., 2009).

Summary for “Peptides and combinations of peptides to be used in immunotherapy against small-cell lung cancer and other types of cancer”