Method for assessing a prognosis and predicting the response of patients with malignant diseases to immunotherapy

Abstract

The invention relates to, among others, a method for assessing a prognosis of a patient with a malignant disease and/or for predicting the response of a patient with a malignant disease to immunotherapy. For this purpose, a DNA methylation analysis is carried out on at least one immunoregulatory gene of cells of the malignant disease and/or T lymphocytes which interact with the cells of the malignant disease, said gene coding for an immune checkpoint selected from B7 proteins and the receptors thereof, MHC-peptide complex-binding co-receptors, the members of the tumor necrosis factor receptor superfamily TNFRSF9, CD40, TNFRSF4, TNFRSF18, and CD27, the members of the immunoglobulin superfamily TIGIT, BTLA, HAVCR2, BTNL2 and CD48, and the andenosine-binding adenosine 2A receptor.

1 .- 15 . (canceled) 
     
     
         16 . A method for assessing prognosis of a patient with a malignant disease and/or predicting response of a patient with a malignant disease to immunotherapy, the method comprising
 performing a DNA methylation analysis of at least one immunoregulatory gene of cells of the malignant disease and/or T lymphocytes interacting with said cells of the malignant disease,   wherein said immunoregulatory gene encodes an immune checkpoint selected from B7 proteins and their receptors, MHC:peptide complex binding co-receptors, members of the tumor necrosis factor receptor superfamily TNFRSF9, CD40, TNTRSF4, TNTRSF18 and CD27, members of the immunoglobulin superfamily TIGIT, BTLA, HAVCR2 BTNL2 and CD48, and the adenosine-binding adenosine 2A receptor, and   assessing the prognosis and/or predicting the response to immunotherapy on the basis of the result of said DNA methylation analysis.   
     
     
         17 . The method according to  claim 16 , wherein the malignant disease comprises a carcinoma, in particular a squamous cell carcinoma or an adenocarcinoma, a melanoma, a leukemia, a glioma, a sarcoma and/or a lymphoma. 
     
     
         18 . The method according to  claim 16 , wherein said immunoregulatory gene is selected from the genes encoding the B7 proteins and their receptors CD274, PDCD1LG2 and/or PDCD1. 
     
     
         19 . The method according to  claim 16 , wherein said immunoregulatory gene is selected from the genes encoding the B7 protein and its receptor CD80 and/or CTLA4. 
     
     
         20 . The method according to  claim 16 , wherein said immunoregulatory gene is the gene ICOS encoding the receptor of a B7 protein. 
     
     
         21 . The method according to  claim 16 , wherein said immunoregulatory gene is selected from the genes encoding the B7 proteins CD276, C10orf54 and/or HHLA2. 
     
     
         22 . The method according to  claim 16 , wherein said immunoregulatory gene is selected from the genes encoding the MHC:peptide complex binding co-receptors LAG3, CD160, KIR2DL4 and/or KIR3DL1. 
     
     
         23 . The method according to  claim 16 , wherein the prognosis is assessed before, during or after immunotherapeutic treatment of the patient with at least one pharmaceutical compound which is designed to alter an immunoregulatory effect of said immune checkpoint. 
     
     
         24 . The method according to  claim 16 , wherein predicting response comprises the response of the malignant disease of the patient to immunotherapy with at least one pharmaceutical compound which is designed to alter an immunoregulatory effect of said immune checkpoint. 
     
     
         25 . The method according to  claim 23 , wherein said immune checkpoint comprises CD274 and/or PDCD1LG2 and said pharmaceutical compound is designed to alter, in particular inhibit, an immunoregulatory effect of CD274 and/or PDCD1LG2 by interaction with PDCD1. 
     
     
         26 . The method according to  claim 24 , wherein said immune checkpoint comprises CD274 and/or PDCD1LG2 and said pharmaceutical compound is designed to alter, in particular inhibit, an immunoregulatory effect of CD274 and/or PDCD1LG2 by interaction with PDCD1. 
     
     
         27 . The method according to  claim 16 , wherein the DNA methylation analysis comprises determining the presence, absence or level of methylation of at least one CpG dinucleotide contained in said immunoregulatory gene. 
     
     
         28 . The method according to  claim 26 , wherein the methylation of at least one CpG dinucleotide from each of at least two different immunoregulatory genes is determined. 
     
     
         29 . The method according to  claim 26 , wherein the DNA methylation analysis is performed under conditions which allow for a quantitative determination of said methylation of the at least one CpG dinucleotide. 
     
     
         30 . The method according to  claim 16 , the method further comprising performing an mRNA expression analysis of said immunoregulatory gene. 
     
     
         31 . A method for individualized selection of a pharmaceutical compound for immunotherapeutic treatment of a patient with a malignant disease, the method comprising
 performing a DNA methylation analysis of at least one immunoregulatory gene of cells of the malignant disease and/or T lymphocytes interacting with said cells of the malignant disease,   wherein said immunoregulatory gene encodes an immune checkpoint selected from 137 proteins and their receptors, MHC:peptide complex binding co-receptors, members of the tumor necrosis factor receptor superfamily TNFRSF9, CD40, TNFRSF4, TNFRSF18 and CD27, members of the immunoglobulin superfamily TIGIT, BTLA, HAVCR2, BTNL2 and CD48, and the adenosine-binding adenosine 2A receptor, and   selecting the pharmaceutical compound on the basis of the result of said DNA methylation analysis.   
     
     
         32 . The method according to  claim 31 , wherein the pharmaceutical compound is selected to be capable of altering an immunoregulatory effect of said immune checkpoint. 
     
     
         33 . The method according to  claim 31 , wherein the pharmaceutical compound is selected when the DNA methylation analysis indicates expression of said immune checkpoint in said cells of the malignant disease and/or in said T lymphocytes. 
     
     
         34 . A kit for carrying out the method according to  claim 16 , the kit comprising
 at least one pair of oligonucleotides for said DNA methylation analysis, said oligonucleotide pair being designed to hybridize to a sequence of the immunoregulatory gene in DNA from said cells of the malignant disease and/or from said T lymphocytes after cytosines contained in said DNA have been converted into uracil or another base having a base pairing behaviour and/or molecular weight distinguishable from that of cytosine in order to amplify and/or detect said sequence.   
     
     
         35 . A kit for carrying out the method according to  claim 31 , the kit comprising
 at least one pair of oligonucleotides for said DNA methylation analysis, said oligonucleotide pair being designed to hybridize to a sequence of the immunoregulatory gene in DNA from said cells of the malignant disease and/or from said T lymphocytes after cytosines contained in said DNA have been converted into uracil or another base having a base pairing behaviour and/or molecular weight distinguishable from that of cytosine in order to amplify and/or detect said sequence.   
     
     
         36 . A method for identifying a patient with a malignant disease who is more likely to respond to immunotherapeutic treatment, the method comprising
 performing a DNA methylation analysis of at least one immunoregulatory gene of cells of the malignant disease and/or T lymphocytes interacting with said cells of the malignant disease,   wherein said immunoregulatory gene encodes an immune checkpoint selected from B7 proteins and their receptors, MHC:peptide complex binding co-receptors, members of the tumor necrosis factor receptor superfamily TNFRSF9, CD40, TNFRSF4, TNFRSF18 and CD27, members of the immunoglobulin superfamily TIGIT, 1311A, HAVCR2 BTNL2 and CD48, and the adenosine-binding adenosine 2A receptor, and   identifying the patient on the basis of the result of said DNA methylation analysis.   
     
     
         37 . A method of treating a patient with a malignant disease with an immunotherapy, the method comprising
 performing a DNA methylation analysis of at least one immunoregulatory gene of cells of the malignant disease and/or T lymphocytes interacting with said cells of the malignant disease,   wherein said immunoregulatory gene encodes an immune checkpoint selected from B7 proteins and their receptors, MHC:peptide complex binding co-receptors, members of the tumor necrosis factor receptor superfamily TNFRSF9, CD40, TNFRSF4, TNFRSF18 and CD27, members of the immunoglobulin superfamily TIGIT, BTLA, HAVCR2, BTNL2 and CD48, and the adenosine-binding adenosine 2A receptor,   selecting a pharmaceutical compound for immunotherapeutic treatment of said patient on the basis of the result of said DNA methylation analysis, and   administering said pharmaceutical compound to said patient.   
     
     
         38 . A method of treating a patient with a malignant disease with an immunotherapy, the method comprising
 determining presence, absence or level of methylation of at least one CCG dinucleotide of an immunoregulatory gene of cells of the malignant disease and/or of T lymphocytes interacting with said cells of the malignant disease,   wherein said immunoregulatory gene encodes an immune checkpoint selected from B7 proteins and their receptors, MHC:peptide complex binding co-receptors, members of the tumor necrosis factor receptor superfamily TNFRSF9, CD40, TNFRSF4, TNFRSF18 and CD27, members of the immunoglobulin superfamily TIGIT, BTLA, HAVCR2 BTNL2 and CD48, and the adenosine-binding adenosine 2A receptor,   selecting a pharmaceutical compound for immunotherapeutic treatment of said patient on the basis of the result of said DNA methylation analysis, and   administering said pharmaceutical compound to said patient.   
     
     
         39 . The method of  claim 37 , wherein the pharmaceutical compound is selected to be capable of altering an immunoregulatory effect of said immune checkpoint. 
     
     
         40 . The method of  claim 38 , wherein the pharmaceutical compound is selected to be capable of altering an immunoregulatory effect of said immune checkpoint.