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Definitions

• the present invention relates to peptides, proteins, nucleic acids and cells for use in immunotherapeutic methods.
• the present invention relates to the immunotherapy of cancer.
• the present invention furthermore relates to 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.
• MHC major histocompatibility complex
• the present invention relates to several novel peptide sequences and their variants derived from HLA class I molecules 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.
• NHLs Non-Hodgkin lymphomas
• NHL is the seventh most common type of cancer and represents 4.3% of all new cancer cases in the U.S. (SEER Stat facts, 2014). It is the most common hematological malignancy both in Europe and the U.S. (Inoges et al., 2014).
• NHL has a higher risk to develop NHL than women (23.9 cases per 100,000 males vs. 16.3 cases per 100,000 females) (SEER Stat facts, 2014).
• the 5-year relative survival of NHL patients is 70% and varies with the cancer stage at the time point of diagnosis. For localized disease, the 5-year relative survival is 82%. If NHL has spread to different parts of the body, the 5-year relative survival decreases to 73.8% for regional and 62.4% for distant stage disease (SEER Stat facts, 2014).
• Risk factors include (high) age, male gender, ethnicity (Caucasian), exposure to benzene or radiation, HIV, autoimmune diseases, infections with HTLV- 1 , EBV or HHV8, infections with Helicobacter pylori, Chlamydophila psittaci, Campylobacter jejuni or HCV, (high) body weight and breast implants (American Cancer Society, 2015).
• NHL has over 60 subtypes.
• the three most common subtypes are diffuse large B-cell lymphoma (DLBCL, the most common subtype), follicular lymphoma (FL, the second most common subtype) and small lymphocytic lymphoma/chronic lymphocytic lymphoma (SLL/CLL, the third most common subtype).
• DLBCL, FL and SLL/CLL account for about 85% of NHL (Li et al., 2015).
• DLBCL Diffuse large B-cell lymphoma
• IPI International Prognostic Index
• Follicular lymphoma FL is the second most common NHL type and comprises 20% of all NHLs and 70% of all indolent lymphomas. More than 90% of the patients exhibit rearrangement of the bcl-2 gene. Most patients are 50 years or older at the time point of diagnosis and have advanced stage disease.
• FLIPI Follicular Lymphoma International Prognostic Index
• Stage II stage II vs. stage III or IV
• Hemoglobin level (>120 g/L vs. ⁇ 120 g/L)
• Diagnosis of NHL is done on an excisional biopsy of an abnormal lymph node or an incisional biopsy of an involved organ. Besides immunohistochemistry, cytogenetics, molecular genetics and fluorescent in situ hybridization (FISH) are used to clarify the diagnosis (Armitage, 2007).
• FISH fluorescent in situ hybridization
• Staging is done after the evaluation of the patients' history, physical examination and laboratory studies including hematologic parameters, screening chemistry studies and especially a test for serum lactate dehydrogenase (LDH) level.
• Imaging studies include computed tomograms of the chest, abdomen and pelvis and a PET scan (Armitage, 2007).
• indolent NHLs Indolent NHLs progress slowly, have a good prognosis and respond in early stages to radiation therapy, chemotherapy and immunotherapy, but are not curable in advanced stages. Aggressive NHLs progress quickly, but are responsive to intensive combination chemotherapy (National Cancer Institute, 2015). Depending on the disease stage at the time point of diagnosis patients are classified into prognostic groups (National Cancer Institute, 2015) as follows:
• the Ann Arbor staging system is usually used for patients with NHL.
• stage I, stage II, stage III and stage IV are sub-classified in to the categories A and B.
• Patients with well-defined generalized symptoms receive the designation B, while patients without these symptoms belong to category A.
• Category B symptoms include unexplained loss of more than 10% of body weight in the six months before diagnosis, unexplained fever with temperatures above 38°C and drenching night sweats.
• Specialized designations are used depending on the involvement of specific organs/ sites (National Cancer Institute, 2015) as follows: Designation Specific sites
• CS clinical stage
• PS pathologic stage
• Indolent, stage I and contiguous stage II NHL Standard treatment options include radiation therapy, rituximab (anti-CD20 monoclonal antibody) ⁇ chemotherapy, watchful waiting and other therapies as designated for patients with advanced-stage disease.
• rituximab anti-CD20 monoclonal antibody
• Indolent, non-contiguous stage ll/lll/IV NHL Standard treatment options include watchful waiting for asymptomatic patients, rituximab, obinutuzumab (anti-CD20 monoclonal antibody), purine nucleoside analogs (fludarabine, 2- chlorodeoxyadenosine), alkylating agents (cyclophosphamide, chlorambucil) ⁇ steroids, bendamustine, combination chemotherapy (CVP, C-MOPP (cyclophosphamide, vincristine, procarbazine, and prednisone), CHOP, FND (fludarabine, mitoxantrone ⁇ dexamethasone)), yttrium-labeled ibritumomab tiuxetan and maintenance rituximab.
• CVP C-MOPP
• C-MOPP cyclophosphamide, vincristine, procarbazine, and prednisone
• CHOP
• Rituximab is considered first-line therapy, either alone or in combination with other agents (R-Bendamustine, R-F (fludarabine), R- CVP (cyclophosphamide, vincristine, and prednisone), R-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), R-FM (fludarabine, mitoxantrone), R-FCM (fludarabine, cyclophosphamide, and mitoxantrone)).
• BMT bone marrow transplantation
• PSCT peripheral stem cell transplantation
• idiotype vaccines and radiolabeled monoclonal antibodies
• radiolabeled monoclonal antibodies (ofatumumab: anti-CD20 monoclonal antibody).
• Indolent, recurrent NHL Standard treatment options include chemotherapy (single agent or combination), rituximab, lenalidomide, radiolabeled anti-CD20 monoclonal antibodies (yttrium-90 ibritumomab) and palliative radiation therapy. Treatment options under clinical evaluation include SCTs.
• Standard treatment options include R-CHOP ⁇ IF-XRT.
• Treatment options under clinical evaluation include R-ACVBP (rituximab + doxorubicin, cyclophosphamide, vindesine, bleomycin, prednisone).
• Standard treatment options include combination chemotherapy ⁇ local-field radiation therapy.
• Drug combinations include ACVBP, CHOP, CNOP (cyclophosphamide, mitoxantrone, vincristine, prednisone), m-BACOD (methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, dexamethasone, leucovorin), MACOP-B (methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone fixed dose, bleomycin, leucovorin), ProMACE CytaBOM (prednisone, doxorubicin, cyclophosphamide, etoposide, cytarabine, bleomycin, vincristine, methotrexate, leucovorin), R-CHOP. Under clinical evaluation are BMT and SCT
• Lymphoblastic lymphoma Standard treatment options include intensive therapy and radiation therapy.
• Standard treatment options include aggressive multidrug regimens and CNS prophylaxis.
• Aggressive, recurrent NHL Standard treatment options include BMT or SCT, re- treatment with standard agents (rituximab, radiolabeled anti-CD20 monoclonal antibodies, denileukin diftitox (a fusion protein combining diphtheria toxin and interleukin-2)) and palliative radiation therapy.
• Treatment options under clinical evaluation include SCT (National Cancer Institute, 2015). Spontaneous tumor regression can be observed in lymphoma patients. Therefore, active immunotherapy is a therapy option (Palomba, 2012).
• An important vaccination option includes Id vaccines.
• Passive immunization includes the injection of recombinant murine anti-Id monoclonal antibodies alone or in combination with IFN alpha, IL2 or chlorambucil.
• Active immunization includes the injection of recombinant protein (Id) conjugated to an adjuvant (KLH), given together with GM-CSF as an immune adjuvant.
• Id recombinant protein conjugated to an adjuvant
• KLH adjuvant
• Tumor- specific Id is produced by hybridoma cultures or using recombinant DNA technology (plasmids) by bacterial, insect or mammalian cell culture.
• Vaccines other than Id include the cancer-testis antigens MAGE, NY-ESO1 and PASD-1 , the B-cell antigen CD20 or cellular vaccines.
• the vaccines consist of DCs pulsed with apoptotic tumor cells, tumor cell lysate, DC-tumor cell fusion or DCs pulsed with tumor-derived RNA.
• In situ vaccination involves the vaccination with intra- tumoral CpG in combination with chemotherapy or irradiated tumor cells grown in the presence of GM-CSF and collection/expansion/re-infusion of T cells.
• Vaccinations with antibodies that alter immunologic checkpoints are comprised of anti-CD40, anti-OX40, anti-41 BB, anti-CD27, anti-GITR (agonist antibodies that directly enhance anti-tumor response) or anti-PD1 , anti-CTLA-4 (blocking antibodies that inhibit the checkpoint that would hinder the immune response).
• Examples are ipilimumab (anti-CTLA-4) and CT-01 1 (anti-PD1 ) (Palomba, 2012).
• 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.
• TAAs tumor associated antigens
• 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.
• CT antigens are the MAGE family members and NY-ESO-1 .
• TAAs 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 Mel an -A/MART- 1 for melanoma or PSA for prostate cancer.
• TAAs 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 ⁇ -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.
• 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.
• TAAs arising from abnormal post-translational modifications 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.
• Oncoviral proteins 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.
• 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).
• MHC major histocompatibility complex
• 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.
• MHC class I 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.
• 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.
• DRIPs defective ribosomal products
• 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.
• APCs professional antigen presenting cells
• CD8-positive T cells bearing the appropriate T-cell receptor (TCR)
• 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 .
• CD4-positive helper T cells play an important role in inducing and sustaining effective responses by CD8-positive cytotoxic T cells.
• TAA tumor associated antigens
• 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).
• CTL- cytotoxic T cell- friendly cytokine milieu
• NK natural killer cells
• macrophages macrophages
• granulocytes Hwang et al., 2007.
• MHC class II molecules 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.
• APC professional antigen-presenting cells
• monocytes e.g., monocytes, monocyte-derived cells, macrophages, dendritic cells.
• monocytes e.g., monocytes, monocyte-derived cells, macrophages, dendritic cells.
• 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.
• CD4-positive T cells are sufficient for inhibiting manifestation of tumors via inhibition of angiogenesis by secretion of interferon- gamma (IFNy) (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).
• IFNy interferon- gamma
• HLA class II molecules 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 ).
• CD8 and CD4 dependent 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.
• MHC-class-l-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.
• TCR T cell bearing specific T cell receptors
• the antigen should be expressed mainly by tumor cells and not, or in comparably small amounts, by normal healthy tissues.
• 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.
• 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.
• 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.
• 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.
• 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.
• T cell which upon stimulation with a specific antigen can be clonally expanded and is able to execute effector functions
• the immunogenicity of the underlying peptides is secondary. In these cases, the presentation is the determining factor.
• the present invention relates to a peptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 31 1 or a variant sequence thereof which is at least 77%, preferably at least 88%, homologous (preferably at least 77% or at least 88% identical) to SEQ ID NO: 1 to SEQ ID NO: 31 1 , wherein said variant binds to MHC and/or induces T cells cross-reacting with said peptide, or a pharmaceutical acceptable salt thereof, wherein said peptide is not the underlying full-length polypeptide.
• the present invention further relates to a peptide of the present invention comprising a sequence that is selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 31 1 or a variant thereof, which is at least 77%, preferably at least 88%, homologous (preferably at least 77% or at least 88% identical) to SEQ ID NO: 1 to SEQ ID NO: 31 1 , wherein said peptide or variant thereof has an overall length of between 8 and 100, preferably between 8 and 30, and most preferred of between 8 and 14 amino acids.
• the following tables show the peptides according to the present invention, 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 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 of the invention.
• the peptides in Tables 4A and B 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.
• HIST1 H2AA HIST1 H2AE
• RGPD8 RGPD6, RGPD2,
• Table 2 Additional peptides according to the present invention with no prior known cancer association.
• Table 3 Peptides useful for e.g. personalized cancer therapies.
• the present invention furthernnore generally relates to the peptides 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, renal cell cancer, brain cancer, gastric cancer, colorectal cancer, hepatocellular cancer, pancreatic cancer, leukemia, breast cancer, melanoma, ovarian cancer, urinary bladder cancer, uterine cancer, gallbladder and bile duct cancer.
• proliferative diseases such as, for example, non-small cell lung cancer, small cell lung cancer, renal cell cancer, brain cancer, gastric cancer, colorectal cancer, hepatocellular cancer, pancreatic cancer, leukemia, breast cancer, melanoma, ovarian cancer, urinary bladder cancer, uterine cancer, gallbladder and bile duct cancer.
• peptides - alone or in combination - according to the present invention selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 31 1 . More preferred are the peptides - alone or in combination - selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 217 (see Table 1 ), and their uses in the immunotherapy of NHL, non-small cell lung cancer, small cell lung cancer, renal cell cancer, brain cancer, gastric cancer, colorectal cancer, hepatocellular cancer, pancreatic cancer, leukemia, breast cancer, melanoma, ovarian cancer, urinary bladder cancer, uterine cancer, gallbladder and bile duct cancer, and preferably NHL.
• the tables show 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, eye, gallbladder, heart, kidney, liver, lung, lymph node, mononuclear white blood cells, pancreas, peripheral nerve, parathyroid gland, peritoneum, pituitary, pleura, rectum, salivary gland, skeletal muscle, skin, small intestine, spleen, stomach, thymus, thyroid gland, trachea, ureter, urinary bladder, and vein.
• Table 4A Peptides according to the present invention and their specific uses in other proliferative diseases, especially in other cancerous diseases.
• NSCLC NSCLC, SCLC, CLL, AML, BRCA,
• NSCLC NSCLC, SCLC, CRC, HCC, BRCA, Melanoma, Urinary bladder cancer,
• NSCLC NSCLC, SCLC, RCC, CLL, AML, BRCA,
• HCC HCC, CLL, BRCA, Melanoma, OC,
• HCC HCC, CLL, AML, Melanoma, Uterine
• HCC HCC
• CLL AML
• Melanoma OC
• HCC HCC, CLL, AML, Melanoma, Uterine
• NSCLC NSCLC, SCLC, CLL, Melanoma
• NSCLC NSCLC, SCLC, RCC, HCC, CLL, AML,
• NSCLC NSCLC, RCC, HCC, PC, Melanoma,
• HCC HCC, PC, CLL, AML, BRCA, Melanoma
• NSCLC NSCLC, CLL, Melanoma, Esophageal
• 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
• BRCA breast cancer
• OC ovarian cancer
• AML acute myelogenous leukemia
• CLL chronic lymphocytic leukemia.
• Table 4B Peptides according to the present invention and their specific uses in other proliferative diseases, especially in other cancerous diseases (amendment of Table 4A).
• 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.
• 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.
• 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
• BRCA breast cancer
• CLL chronic lymphocytic leukemia
• AML acute myeloid leukemia
• OC ovarian cancer
• HNSCC head and neck squamous cell carcinoma, head and neck cancer.
• another aspect of the present invention relates to the use of at least one peptide according to the present invention according to any one of SEQ ID No. 1 , 2, 3, 5, 6, 7, 8, 9, 10, 1 1 , 13, 16, 17, 19, 20, 24, 25, 27, 28, 29, 31 , 32, 33, 34, 36, 37, 39, 40, 41 , 42, 43, 44, 45, 48, 50, 53, 54, 55, 56, 57, 59, 60, 63, 64, 65, 66, 67, 68, 69, 73, 76, 77, 80, 81 , 82, 84, 85, 92, 96, 98, 101 , 102, 103, 104, 105, 107, 1 14, 1 16, 122, 124, 128, 129, 131 , 132, 138, 169, 179, 180, 182, 183, 184, 186, 188, 189, 190, 191 , 195, 200, 201 , 205, 206, 207, 208,
• another aspect of the present invention relates to the use of at least one peptide according to the present invention according to any one of SEQ ID No. 1 , 2, 3, 5, 10, 1 1 , 15, 23, 26, 27, 28, 29, 30, 31 , 34, 36, 37, 38, 39, 42, 45, 47, 53, 55, 60, 61 , 64, 65, 67, 68, 70, 73, 76, 80, 86, 87, 88, 95, 96, 103, 108, 1 10, 1 14, 1 17, 1 18, 121 , 122, 124, 125, 129, 130, 148, 161 , 163, 164, 179, 181 , 183, 188, 190, 193, 195, 207, 209, 215, 218, 219, 222, 227, 234, 235, 236, 239, 243, 244, 247, 248, 250, 253, 255, 259, 260, 265, 270, 279, 289, 290, 293, 296, 302, 303
• Another aspect of the present invention relates to the use of at least one peptide according to the present invention according to any one of SEQ ID No. 2, 20, 38, 41 , 194, 248, 253, 258, 263, 302, and 303 for the - in one preferred embodiment combined - treatment of NSCLC.
• another aspect of the present invention relates to the use of at least one peptide according to the present invention according to any one of SEQ ID No. 2, 7, 8, 1 1 , 16, 17, 31 , 37, 41 , 47, 56, 62, 69, 70, 79, 80, 92, 95, 104, 105, 1 16, 1 17, 120, 130, 132, 138, 144, 146, 148, 149, 165, 171 , 180, 183, 184, 190, 198, 207, 209, 21 1 , 212, 214, 216, 217, 226, 229, 236, 237, 239, 242, 243, 248, 254, 257, 258, 259, 274, 284, 285, 290, 299, 23, 24, 26, 30, 36, 44, 46, 48, 60, 61 , 66, 68, 88, 107, 108, 1 1 1 , 1 15, 121 , 124, 152, 166, 179, 185, 191 ,
• another aspect of the present invention relates to the use of at least one peptide according to the present invention according to any one of SEQ ID No. 2, 5, 10, 1 1 , 15, 17, 20, 23, 27, 28, 29, 36, 38, 39, 41 , 43, 48, 60, 70, 76, 93, 95, 96, 108, 122, 131 , 163, 165, 181 , 193, 197, 207, 209, 218, 222, 235, 240, 245, 247, 264, 290, 299, 305, 308, and 309 for the - in one preferred embodiment combined - treatment of BRCA.
• another aspect of the present invention relates to the use of at least one peptide according to the present invention according to any one of SEQ ID No. 2, 5, 6, 7, 12, 13, 15, 17, 20, 23, 26, 30, 31 , 33, 34, 36, 38, 40, 41 , 43, 47, 48, 53, 56, 60, 62, 69, 73, 76, 83, 85, 86, 96, 98, 108, 1 16, 1 19, 124, 125, 126, 127, 129, 131 , 132, 141 , 165, 166, 174, 179, 180, 181 , 182, 185, 188, 190, 191 , 194, 203, 204, 207, 209, 21 1 , 212, 217, 226, 227, 229, 235, 236, 237, 239, 243, 244, 246, 248, 249, 253, 254, 257, 258, 259, 260, 261 , 263, 266, 270, 271 , 273, 28
• another aspect of the present invention relates to the use of at least one peptide according to the present invention according to any one of SEQ ID No. 2, 5, 7, 27, 34, 35, 37, 38, 39, 40, 41 , 58, 60, 62, 68, 70, 77, 88, 108, 125, 126, 138, 181 , 183, 209, 218, 229, 235, 245, 248, 253, 257, 258, 260, 261 , 279, 293, 302, 306, 23, 30, 163, 214, 267, 314 and 31 1 for the - in one preferred embodiment combined - treatment of urinary bladder cancer.
• another aspect of the present invention relates to the use of at least one peptide according to the present invention according to any one of SEQ ID No. 5, 12, 16, 30, 34, 38, 41 , 44, 46, 48, 69, 78, 87, 106, 108, 128, 129, 165, 188, 194, 198, 207, 215, 216, 219, 221 , 226, 235, 249, 253, 258, 263, 266, 270, 287, 289, 290, 297, 303, and 308 for the - in one preferred embodiment combined - treatment of gallbladder cancer and/or bile duct cancer.
• another aspect of the present invention relates to the use of at least one peptide according to the present invention according to any one of SEQ ID No. 5, 12, 26, 35, 39, 43, 47, 58, 70, 77, 96, 108, 124, 128, 180, 185, 191 , 207, 213, 215, 226, 235, 245, 253, 261 , 273, 296, 308, and 31 1 for the - in one preferred embodiment combined - treatment of OC.
• another aspect of the present invention relates to the use of at least one peptide according to the present invention according to any one of SEQ ID No. 1 1 , 23, 30, 34, 38, 47, 60, 73, 97, 108, 163, 184, 209, 235, 248, 258, 290, and 299 for the - in one preferred embodiment combined - treatment of CRC.
• another aspect of the present invention relates to the use of at least one peptide according to the present invention according to any one of SEQ ID No. 12, 21 , 27, 31 , 34, 44, 47, 48, 55, 59, 61 , 77, 133, 144, 165, 191 , 215, 235, 253, 267, 296, 302, 303, 306, and 309 for the - in one preferred embodiment combined - treatment of esophageal cancer.
• another aspect of the present invention relates to the use of at least one peptide according to the present invention according to any one of SEQ ID No. 20, 41 , 47, 74, 78, 86, 93, 94, 100, 109, 122, 163, 165, 179, 181 , 197, 215, 234, 248, 258, 263, 273, 285, 304, 216, 217, 227, 236, 260, and 308 for the - in one preferred embodiment combined - treatment of RCC.
• another aspect of the present invention relates to the use of at least one peptide according to the present invention according to any one of SEQ ID No.
• Another aspect of the present invention relates to the use of at least one peptide according to the present invention according to any one of SEQ ID No. 60, 109, 263, and 290 for the - in one preferred embodiment combined - treatment of PC.
• Another aspect of the present invention relates to the use of at least one peptide according to the present invention according to any one of SEQ ID No. 47, 248, and 301 for the - in one preferred embodiment combined - treatment of brain cancer.
• another aspect of the present invention relates to the use of at least one peptide according to the present invention according to any one of SEQ ID No. 2, 3, 5, 1 1 , 12, 16, 23, 28, 30, 36, 38, 41 , 44, 47, 48, 61 , 67, 69, 70, 71 , 73, 76, 88, 95, 96, 99, 106, 108, 109, 1 10, 1 1 1 , 122, 124, 128, 146, 163, 168, 171 , 182, 183, 188, 194, 198, 213, 218, 226, 227, 228, 235, 240, 248, 251 , 253, 254, 255, 259, 263, 280, 282, 291 , 301 , 302, 303, 307, 308, and 309 for the - in one preferred embodiment combined - treatment of HNSCC.
• another aspect of the present invention relates to the use of at least one peptide according to the present invention according to any one of SEQ ID No. 2, 5, 16, 26, 28, 30, 36, 37, 38, 41 , 43, 46, 60, 70, 73, 76, 90, 108, 1 17, 164, 182, 186, 207, 227, 241 , 248, 253, 258, 259, 261 , 266, 270, 282, 301 , 31 1 , and 290 for the - in one preferred embodiment combined - treatment of SCLC.
• another aspect of the present invention relates to the use of at least one peptide according to the present invention according to any one of SEQ ID No. 60, 74 and 236 for the - in one preferred embodiment combined - treatment of GC.
• another aspect of the present invention relates to the use of the peptides according to the present invention for the - preferably combined - treatment of a proliferative disease selected from the group of NHL, non-small cell lung cancer, small cell lung cancer, renal cell cancer, brain cancer, gastric cancer, colorectal cancer, hepatocellular cancer, pancreatic cancer, leukemia, breast cancer, melanoma, ovarian cancer, urinary bladder cancer, uterine cancer, gallbladder and bile duct cancer.
• a proliferative disease selected from the group of NHL, non-small cell lung cancer, small cell lung cancer, renal cell cancer, brain cancer, gastric cancer, colorectal cancer, hepatocellular cancer, pancreatic cancer, leukemia, breast cancer, melanom
• the present invention furthermore relates to peptides according to the present invention that have the ability to bind to a molecule of the human major histocompatibility complex (MHC) class-l or - in an elongated form, such as a length- variant - MHC class -II.
• MHC human major histocompatibility complex
• the present invention further relates to the peptides according to the present invention wherein said peptides (each) consist or consist essentially of an amino acid sequence according to SEQ ID NO: 1 to SEQ ID NO: 31 1 .
• the present invention further relates to the peptides according to the present invention, wherein said peptide is modified and/or includes non-peptide bonds.
• the present invention further relates to the peptides according to the present invention, wherein said peptide is part of a fusion protein, in particular fused to the N- terminal amino acids of the HLA-DR antigen-associated invariant chain (li), or fused to (or into the sequence of) an antibody, such as, for example, an antibody that is specific for dendritic cells.
• a fusion protein in particular fused to the N- terminal amino acids of the HLA-DR antigen-associated invariant chain (li), or fused to (or into the sequence of) an antibody, such as, for example, an antibody that is specific for dendritic cells.
• the present invention further relates to a nucleic acid, encoding the peptides 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.
• the present invention further relates to an expression vector capable of expressing and/or expressing a nucleic acid according to the present invention.
• 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.
• the present invention further relates to antibodies that are specific against the peptides according to the present invention or complexes of said peptides according to the present invention with MHC, and methods of making these.
• the present invention further relates to T-cell receptors (TCRs), in particular soluble TCR (sTCRs) and in particular cloned TCRs engineered into autologous or allogeneic T cells, and methods of making these, as well as NK cells or other cells expressing and/or bearing said TCR or cross-reacting with said TCRs.
• TCRs T-cell receptors
• sTCRs soluble TCR
• the antibodies and TCRs are additional embodiments of the immunotherapeutic use of the peptides according to the invention at hand.
• 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.
• the present invention further relates to said method according to the present invention, wherein the antigen is loaded onto class I or II 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.
• the present invention further relates to the method according to the present invention, wherein the antigen-presenting cell comprises an expression vector capable of expressing or expressing said peptide containing SEQ ID No. 1 to SEQ ID No.: 31 1 , preferably containing SEQ ID No. 1 to SEQ ID No. 217, or a variant amino acid sequence.
• 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.
• the present invention further relates to 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.
• 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 or other peptide- and/or peptide-MHC- binding molecules according to the present invention as a medicament or in the manufacture of a medicament.
• said medicament is active against cancer.
• said medicament is a cellular therapy, a vaccine or a protein based on a soluble TCR or antibody.
• the present invention further relates to a use according to the present invention, wherein said cancer cells are NHL, non-small cell lung cancer, small cell lung cancer, renal cell cancer, brain cancer, gastric cancer, colorectal cancer, hepatocellular cancer, pancreatic cancer, leukemia, breast cancer, melanoma, ovarian cancer, urinary bladder cancer, uterine cancer, gallbladder and bile duct cancer, and preferably NHL cells.
• the present invention further relates to biomarkers based on the peptides according to the present invention, herein called "targets" that can be used in the diagnosis of cancer, preferably NHL.
• the marker can be over-presentation of the peptide(s) themselves, or over-expression of the corresponding gene(s).
• the markers may also be used to predict the probability of success of a treatment, preferably an immunotherapy, and most preferred an immunotherapy targeting the same target that is identified by the biomarker.
• an antibody or soluble TCR can be used to stain sections of the tumor to detect the presence of a peptide of interest in complex with MHC.
• the antibody carries a further effector function such as an immune stimulating domain or toxin.
• the present invention also relates to the use of these novel targets in the context of cancer treatment.

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