Indoleamine 2,3-dioxygenase based immunotherapy

Abstract

The present invention relates to the field of prophylaxis and therapy of cancer. In particular there is provided a protein Indoleamine 2,3-dioxygenase (IDO) or peptide fragments here of that are capable of eliciting anti-cancer immune responses. Specifically, the invention relates to the use of IDO or peptides derived here from or IDO specific T-cells for treatment of cancer. The invention thus relates to an anti-cancer vaccine which optionally may be used in combination with other immunotherapies and to IDO specific T-cells adoptively transferred or induced in vivo by vaccination as a treatment of cancer. It is an aspect of the invention that the medicaments herein provided may be used in combination with cancer chemotherapy treatment. A further aspect relates to the prophylaxis and therapy of infections by the same means as described above.The use of IDO and immunogenic peptide fragments hereof in cancer and infection treatment, diagnosis and prognosis is also provided.

1 . A vaccine composition comprising
 a) Indoleamine 2,3-dioxygenase (IDO) of SEQ ID NO: (1, 13, 14, 15 and/or 16) or a functional homologue thereof having at least 70% identity to SEQ ID NO: (1, 13, 14, 15 and/or 16) or an immunogenically active peptide fragment comprising a consecutive sequence of said IDO or said functional homologue thereof or a nucleic acid encoding said IDO or said peptide fragment; and   b) an adjuvant   
       for use as a medicament. 
     
     
         2 . The vaccine composition according to  claim 1 , wherein said Indoleamine 2,3-dioxygenase (IDO) is that of SEQ ID NO: 1. 
     
     
         3 . The vaccine composition according to any of  claim 1  or  2 , wherein said immunogenically active peptide fragment consists of a consecutive sequence of in the range of from 5 to 50 amino acids. 
     
     
         4 . The vaccine composition according to any of the preceding claims, wherein said immunogenically active peptide fragment is
 a) a consecutive sequence in the range of 8 to 11 amino acids and/or   b) a consecutive sequence in the range of 18 to 30 amino acids of said IDO of SEQ ID NO: (1, 13, 14, 15 and/or 16) or said functional homologue thereof wherein at the most two amino acid have been substituted.   
     
     
         5 . The vaccine composition of according to any of the preceding claims, wherein the vaccine composition is capable of eliciting an immune response against a cancer and/or an antigen presenting cell expressing IDO of SEQ ID NO: (1, 13, 14, 15 and/or 16) or a functional homologue thereof, when administered to an individual suffering from a clinical condition characterized by expression of IDO. 
     
     
         6 . The vaccine composition according to any of the preceding claims, wherein said vaccine composition is capable of eliciting a cellular immune response in the individual. 
     
     
         7 . The vaccine composition according to any of the preceding claims, wherein the clinical condition is cancer. 
     
     
         8 . The vaccine composition according to any of  claims 1  to  6 , wherein the clinical condition is an infection. 
     
     
         9 . The vaccine composition according to any of the preceding claims, comprising an MHC Class I-restricted peptide having at least one of the following characteristics:
 a) capable of eliciting INF-γ-producing cells in a PBL population of an individual suffering from a clinical condition at a frequency of at least 1 per 10 4  PBLs as determined by an ELISPOT assay, and/or   b) capable of in situ detection in a tumor tissue of CTLs that are reactive with the epitope peptide.   c) capable of inducing the growth of IDO specific T-cells in vitro.   
     
     
         10 . The vaccine composition according to any of the preceding claims, comprising a peptide fragment, which is restricted by a MHC Class I molecule. 
     
     
         11 . The vaccine composition according to any of the preceding claims, comprising a peptide fragment, which is restricted by a MHC Class II molecule. 
     
     
         12 . The vaccine composition according to any of the preceding claims, comprising a peptide fragment, wherein the peptide fragment consists of 8 to 10 or 18 to 25 consecutive amino acids from IDO of SEQ ID NO: (1, 13, 14, 15 and/or 16). 
     
     
         13 . The vaccine composition according to any of the preceding claims comprising a peptide fragment that is capable of eliciting INF-γ-producing cells in a PBL population of an individual suffering from a clinical condition at a frequency of at least 10 per 10 4  PBLs. 
     
     
         14 . The vaccine composition according to any of the preceding claims comprising a peptide fragment, which is capable of eliciting INF-γ-producing cells in a PBL population of an individual suffering from a clinical condition where IDO of SEQ ID NO 1 or a functional homologue thereof having at least 70% identity to SEQ ID 1 is expressed. 
     
     
         15 . The vaccine composition according to any of the preceding claims, where the cancer disease is a tumor forming cancer disease. 
     
     
         16 . The vaccine composition according to any of the preceding claims, wherein the peptide fragment consists of at the most 50 amino acid residues, for example at the most 45 amino acid residues, such as at the most 40 amino acid residues, for example at the most 35 amino acid residues, such as at the most 30 amino acid residues, for example at the most 25 amino acid residues, such as 20 to 25 amino acid residues. 
     
     
         17 . The vaccine composition according to any of the preceding claims, wherein the peptide fragment consists of at the most 20 amino acid residues, for example at the most 19 amino acid residues, such as at the most 18 amino acid residues, for example at the most 17 amino acid residues, such as at the most 16 amino acid residues, for example at the most 15 amino acid residues, such as at the most 14 amino acid residues, for example at the most 13 amino acid residues, such as at the most 12 amino acid residues, for example at the most 11 amino acid residues, such as 8 to 10 amino acid residues. 
     
     
         18 . The peptide according to any of  claims 1  to  15  and/or  17 , wherein the peptide is selected from the group of SEQ ID NO: 2, 3, 4, 5, 6, 7, 8, 9, 10 and/or 11. 
     
     
         19 . The peptide according to any of  claims 1  to  15  and/or  17  to  18 , wherein the peptide is SEQ ID NO: 3 and/or 6 (IDO2 and/or IDO5). 
     
     
         20 . The vaccine composition according to any of the preceding claims, where the vaccine elicits the production in a vaccinated individual of regulatory T-cells having a cytotoxic effect against the IDO expressing cancer cells and/or IDO expressing antigen presenting cells. 
     
     
         21 . The vaccine composition according to any of the preceding claims, wherein the vaccine composition is capable of inducing infiltration of antigen specific T-cells in tumor stroma in a subject. 
     
     
         22 . The vaccine composition according to any of the preceding claims, wherein the vaccine composition is capable of eliciting a clinical response in a subject, wherein the clinical response is characterised by a stable disease, a partial response or complete remission. 
     
     
         23 . The vaccine composition according to any of the preceding claims, further comprising an immunogenic protein or peptide fragment selected from a protein or peptide fragment, which is not IDO. 
     
     
         24 . The vaccine composition according to any of the preceding claims, wherein the adjuvant is selected from the group consisting of bacterial DNA based adjuvants, oil/surfactant based adjuvants, viral dsRNA based adjuvants and imidazochinilines. 
     
     
         25 . The vaccine composition according to any of the preceding claims, wherein the adjuvant is a Montanide ISA adjuvant. 
     
     
         26 . The vaccine composition according to  claim 25 , wherein the adjuvant is Montanide ISA 51 or Montanide ISA 720. 
     
     
         27 . The vaccine composition according to  claim 26 , wherein the adjuvant is Montanide ISA 51 
     
     
         28 . The vaccine composition according to any of  claims 1  to  24 , wherein the adjuvant is GM-CSF 
     
     
         29 . The vaccine composition according to any of the preceding claims, wherein the vaccine composition comprises antigen presenting cells comprising the immunogenically active peptide fragment or a nucleic acid encoding said immunogenically active peptide fragment. 
     
     
         30 . The vaccine composition according to  claim 29 , wherein the antigen presenting cell is a dendritic cell. 
     
     
         31 . The vaccine composition according to  claim 1 , wherein the nucleic acid encodes the peptide according to any of  claims 2  to  14 . 
     
     
         32 . The vaccine composition according to any of  claim 1  or  31 , wherein the nucleic acid is comprised within a vector. 
     
     
         33 . The vaccine composition according to  claim 32 , wherein the vector is selected from the group consisting of viral vectors and bacterial vectors. 
     
     
         34 . The vaccine composition according to any of  claim 32  or  33 , wherein the vector furthermore comprises nucleic acids encoding a T-cell stimulatory polypeptide. 
     
     
         35 . A kit-of-parts comprising the vaccine composition according to any of  claims 1  to  34 , and a second active ingredient. 
     
     
         36 . The kit-of-parts comprising the vaccine composition according to  claim 35 , wherein the second active ingredient is an immunostimulating composition. 
     
     
         37 . The kit-of-parts according to any of  claim 35  or  36 , wherein the further immunostimulating composition comprises one or more interleukins. 
     
     
         38 . The kit-of-parts according to any of  claims 35  to  37 , wherein the interleukins are selected from IL-2 and or IL-21. 
     
     
         39 . The kit-of-parts comprising the vaccine composition according to any of  claims 1  to  34 , wherein the second active ingredient is an anti-cancer agent. 
     
     
         40 . The kit-of-parts according to  claim 39 , wherein the anti-cancer agent is a chemotherapeutic agent. 
     
     
         41 . The kit-of-parts according to any of  claim 39  or  40 , wherein the chemotherapeutic agent is selected from: Actimide, Azacitidine, Azathioprine, Bleomycin, Carboplatin, Capecitabine, Cisplatin, Chlorambucil, Cyclophosphamide, Cytarabine, Daunorubicin, Docetaxel, Doxifluridine, Doxorubicin, Epirubicin, Etoposide, Fludarabine, Fluorouracil, Gemcitabine, Hydroxyurea, Idarubicin, Irinotecan, Lenalidomide, Leucovorin, Mechlorethamine, Melphalan, Mercaptopurine, Methotrexate, Mitoxantrone, Oxaliplatin, Paclitaxel, Pemetrexed, Revlimid, Temozolomide, Teniposide, Thioguanine, Valrubicin, Vinblastine, Vincristine, Vindesine and Vinorelbine. 
     
     
         42 . The kit-of-parts comprising the vaccine composition according to any of  claims 1  to  34 , wherein the second active ingredient is an antibiotic. 
     
     
         43 . The kit-of-parts comprising the vaccine composition according to any of  claims 1  to  3  and  20  to  45 , wherein the antibiotic is selected from: amoxicillin, penicillin, acyclovir and/or vidarabine. 
     
     
         44 . The kits-of-parts according to any of  claims 35  to  43 , where the provided compositions are to be administered simultaneously or sequentially. 
     
     
         45 . A composition for ex vivo or in situ diagnosis of the presence in an individual suffering from a clinical condition of T cells in PBL or in tumor tissue that is reactive with IDO, the composition comprising a peptide fragment according to any of  claims 1  to  19 . 
     
     
         46 . A diagnostic kit for ex vivo or in situ diagnosis of the presence in an individual suffering from a clinical condition of T cells in PBL or in tumor tissue that is reactive with IDO, the kit comprising a peptide fragment according to any of  claims 1  to  19 . 
     
     
         47 . A complex of a peptide fragment according to any of  claims 1  to  19  and a Class I HLA or a Class II HLA molecule or a fragment of such molecule. 
     
     
         48 . The complex of  claim 47  which is monomeric. 
     
     
         49 . The complex of  claim 47  which is multimeric. 
     
     
         50 . A method of detecting in an individual suffering from a clinical condition the presence of IDO reactive T-cells, the method comprising contacting a tumor tissue or a blood sample with a complex of  claim 47  and detecting binding of the complex to the tissue or the blood cells. 
     
     
         51 . A molecule that is capable of binding specifically to a peptide fragment according to any of  claims 1  to  19 . 
     
     
         52 . The molecule of  claim 51 , which is an antibody or a fragment hereof. 
     
     
         53 . The molecule according to any of  claim 51  or  52 , wherein the molecule is a T-cell receptor. 
     
     
         54 . A molecule that is capable of blocking the binding of the molecule of  claim 51  or  53 . 
     
     
         55 . A method of treating a clinical condition characterized by the expression of IDO, the method comprising administering to an individual suffering from said clinical condition an effective amount of the composition according to any of  claims 1  to  34 , the molecule of  claim 51  or the kit-of-parts according to any of  claims 35  to  44 . 
     
     
         56 . The method of  claim 55  wherein the clinical condition to be treated is a cancer disease where IDO is expressed. 
     
     
         57 . The method of to  claim 56 , which is combined with a further cancer treatment. 
     
     
         58 . The method of  claim 57 , wherein the further treatment is selected from the group consisting of chemotherapy, radiotherapy, treatment with immunostimulating substances, gene therapy, treatment with antibodies and treatment using dendritic cells. 
     
     
         59 . The method of  claim 55  wherein the clinical condition to be treated is an infection causing IDO expression in APCs. 
     
     
         60 . The method of  claim 59 , which is combined with a further treatment against said infection. 
     
     
         61 . The method of  claim 60 , wherein the further treatment is selected from the group consisting of chemotherapy, treatment with immunostimulating substances, gene therapy, treatment with antibodies and treatment using dendritic cells. 
     
     
         62 . Use of the peptide fragment according to any of  claims 1  to  19  or the vaccine composition according to any of  claims 1  to  34  in the manufacture of a medicament for the treatment or prevention of a clinical condition. 
     
     
         63 . The use of  claim 62  wherein the disease to be treated is a cancer disease where IDO is expressed. 
     
     
         64 . The use according to any of  claim 62  or  63 , which is combined with a further cancer treatment. 
     
     
         65 . The use of  claim 64 , wherein the further treatment is selected from the group consisting of chemotherapy, radiotherapy, treatment with immunostimulating substances, gene therapy, treatment with antibodies and treatment using dendritic cells. 
     
     
         66 . The use of  claim 62  wherein the clinical condition to be treated is an infection causing IDO expression in APCs. 
     
     
         67 . The use of  claim 66 , which is combined with a further treatment against said infection. 
     
     
         68 . The use of  claim 67 , wherein the further treatment is selected from the group consisting of chemotherapy, treatment with immunostimulating substances, gene therapy, treatment with antibodies and treatment using dendritic cells. 
     
     
         69 . A method of monitoring immunization, said method comprising the steps of
 a) providing a blood sample from an individual   b) providing IDO of SEQ ID NO: (1, 13, 14, 15 and/or 16) or a functional homologue thereof having at least 70% identity to SEQ ID NO: (1, 13, 14, 15 and/or 16) or an immunogenically active peptide fragment comprising a consecutive sequence of said IDO or said functional homologue thereof or a nucleic acid encoding said IDO or said peptide fragment.   c) determining whether said blood sample comprises antibodies or T-cells comprising T-cell receptors specifically binding the protein or peptide   d) thereby determining whether an immune response to said protein or peptide has been raised in said individual.   
     
     
         70 . The method according to  claim 69 , wherein the IDO is IDO of SEQ ID NO: 1. 
     
     
         71 . The method according to any of  claim 69  or  70 , wherein the peptide fragment is a peptide fragment according to any of  claims 1  to  19 . 
     
     
         72 . IDO of SEQ ID NO: (1, 13, 14, 15 and/or 16) or a functional homologue thereof having at least 70% identity to SEQ ID NO: (1, 13, 14, 15 and/or 16) or an immunogenically active peptide fragment comprising a consecutive sequence of said IDO or said functional homologue thereof or a nucleic acid encoding said IDO or said peptide fragment for use in the treatment or prevention of clinical conditions associated with expression of IDO, such as cancer and/or infections. 
     
     
         73 . The peptide fragment according to any of  claims 1  to  19  or the vaccine composition according to any of  claims 1  to  34  for use in the treatment or prevention of cancer.