T cell receptors and peptides derived by mutations for the treatment of cancer

Abstract

The present invention relates to a method for treating cancer in a subject, comprising the step of administering to a subject in need thereof administering a therapeutically effective dose of a T cell capable of binding a neopeptide that is expressed by a tumor suppressor gene, wherein said neopeptide is derived from a frameshift product of a tumor suppressor gene and wherein the T cell binds to the neopeptide-MHC complex with a half-life (T1/2) of at least 50 s.

What is claimed is: 
     
         1 . A method of treating cancer in a subject, comprising the step of administering to a subject in need thereof administering a therapeutically effective dose of a T cell capable of binding a neopeptide that is expressed by a tumor suppressor gene, wherein said neopeptide is derived from a frameshift product of a tumor suppressor gene and wherein the T cell binds to the neopeptide-MHC complex with a half-life (T 1/2 ) of at least 50 s, wherein the T cell is obtained by a method of providing a neopeptide-specific T cell, wherein the neopeptide-specific T cell forms a complex having a half-life (T 1/2 ) of at least 50 s with a neopeptide-MHC monomer, wherein said neopeptide is derived from a frameshift product of a tumor suppressor gene, wherein the method of providing the neopeptide-specific T cell comprises:
 a) contacting a population of T cells obtained from a human subject with a detectably labeled neopeptide-MHC complex;   b) isolating a T-cell from the population of step (a) which comprises a T cell receptor (TCR) that specifically binds to the neopeptide-MHC complex or wherein the T cell is activated via binding to the neopeptide-MHC complex to obtain neopeptide-specific T cells;   c) determining the T 1/2  of the neopeptide-MHC complex formed by the neopeptide-specific T cells by measuring the signal of the detectable label comprised in the MHC monomer over a period of time; and   d) selecting neopeptide-specific T cells in which the T 1/2  is at least 50 s.   
     
     
         2 . The method of  claim 1 , wherein the cancer is selected from the group consisting adrenal cancer, anal cancer, bile duct cancer, bladder cancer, bone cancer, brain and spinal cord tumors, breast cancer, Castleman disease, cervical cancer, colon cancer, endometrial cancer, esophagus cancer, Ewing family of tumors, eye cancer, gallbladder cancer, gastrointestinal cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumor (GIST), gestational trophoblastic disease, Hodgkin disease, Kaposi sarcoma, kidney cancer, laryngeal and hypopharyngeal cancer, leukemia, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), liver cancer, lung cancer, non-small cell lung cancer, small cell lung cancer, lung carcinoid tumor, lymphoma, lymphoma of the skin, malignant mesothelioma, multiple myeloma, myelodysplastic syndrome, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, oral cavity and oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, penile cancer, pituitary tumors, prostate cancer, rectum cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, skin cancer, basal and squamous cell cancer, melanoma, merkel cell cancer, small intestine cancer, stomach cancer, testicular cancer, thymus cancer, thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom macroglobulinemia, and Wilms tumor. 
     
     
         3 . The method of  claim 2 , wherein the cancer is gastrointestinal cancer 
     
     
         4 . The method of  claim 3 , wherein the gastrointestinal cancer is selected from the group consisting of colon cancer, liver cancer, and pancreatic cancer. 
     
     
         5 . The method of  claim 1 , wherein the T cell is administered to the subject by infusion. 
     
     
         6 . The method of  claim 1 , wherein the T cell is administered to the subject in a dosage of about 1.46×10 5  to about 1.60×10 7  T cells cells/kg body weight of the subject. 
     
     
         7 . The method of  claim 1 , wherein the T cell is administered to the subject in a dosage of 1×10 8 /m 2  to 3.3×10 9 )/m 2  skin surface of the subject. 
     
     
         8 . The method of  claim 1 , wherein the subject is a human. 
     
     
         9 . The method of  claim 1 , wherein the neopeptide is expressed by a tumor suppressor gene comprising a point mutation or a frameshift mutation. 
     
     
         10 . The method of  claim 1 , wherein the neopeptide is selected from the group consisting of SEQ ID NO: 1-SEQ ID NO: 45 and SEQ ID NO: 58-SEQ ID NO: 62. 
     
     
         11 . The method of  claim 1 , wherein the neopeptide is HLA class I restricted. 
     
     
         12 . The method of  claim 1 , wherein the neopeptide is MHC class I presentable. 
     
     
         13 . The method of  claim 1 , wherein the T cell is a cytotoxic T cell, a regulatory T cell, a T helper cell or a NK T cell. 
     
     
         14 . The method of  claim 1 , wherein the tumor suppressor gene comprises a high frameshift mutation rate. 
     
     
         15 . The method of  claim 1 , wherein the tumor suppressor gene is one of RNF43, APC, WT1, ARID1A, GATA3, NOTCH1, NPM1, ACVR2A, PTEN, SMAD4, CDKN2A, SLC16A4, CDC27, MYO6, MLL3, TAF1, MAP2K4, TGFBR2, ACVR1B, PREX2, ARID1B, PBRM1, SMARCA2, SMARCA4, MLL2, KDM6A, SF3B1, PALB2, RPA1, ATM, STK11, MLH1, MSH2, ROBO1, ROBO2, SLIT2, MYC, GATA6, CDK6, NOV, MET, SOX9, ERBB2, PIK3CA, PIK3R3 or FGFR2, 
     
     
         16 . The method of  claim 15 , wherein the tumor suppressor gene is RNF43 or APC. 
     
     
         17 . The method of  claim 1 , wherein the T cell has been obtained from a healthy donor or a non-healthy donor. 
     
     
         18 . The method of  claim 17 , wherein the non-healthy donor is a cancer patient.