JP2021524744A - 分子遺伝子シグネチャーとその使用方法 - Google Patents
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- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
- C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
- C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
- G01N33/57484—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites
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- C—CHEMISTRY; METALLURGY
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- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
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Abstract
Description
本出願は、2018年5月21日に出願された米国仮出願第62/674,285号、及び2018年10月19日に出願された米国仮出願第62/747,853号の優先権及び利益を主張する。前述の特許出願のそれぞれの内容は、その全体が参照により本明細書に組み込まれる。
1つの態様において、本開示は、処置を必要とする癌患者の処置を選択する方法であって、任意の形態の本明細書に任意の遺伝子シグネチャーで記載された、任意の遺伝子の組合せ、又は遺伝子群の任意の組み合わせ、又は遺伝子若しくは遺伝子群の組み合わせの発現レベルを決定することを含む、上記方法に関する。
(a)MKI67、CEP55、KIF2C、MELK、CENPF、EXO1、ANLN、RRM2、UBE2C、CCNB1、及びCDC20;
(b)FAP、COL6A3、ADAM12、OLFML2B、PDGFRB、及びLRRC32;
(c)CXCL10、CXCR3、CX3CL1、PRF1、GZMK、GZMB、CD27、IL2RG、KLRK1、CTLA4、GZMH、CD3D、KLRB1、KLRD1、LCK、CD5、IRF4、CD8A、CD38、EOMES、GZMM、GNLY、IFITM1、IDO1、MS4A1、GZMA、CD2、CD3E、CD3G、CD40LG、CD6、CD7、CD79A、CD8B、CXCL11、CXCL13、CXCL9、HLA−DOB、IFNG、LAG3、LY9、PDCD1、TBX21、TIGIT、ZAP70、SLAMF7、CD96、PVR、STAT1、JAK1、JAK2、STAT2、IRF9、IGF2R、CD48、及びICOS;
(d)ITGAM、TLR4、IL1B、CSF1R、CSF3R、TLR2、TLR1、ITGAX、HCK、TLR8、SLC11A1、CD47、CD14、CLEC4E、CLEC7A、FCAR、FCN1、LILRA5、LILRB2、LYZ、NFAM1、P2RY13、S100A8、S100A9、SERPINA1、SIRPA、SIRPB2、TREM1、CLEC5A、CSF1、CYBB、FCGR1A、MARCO、NLRP3、FPR1、FPR3、CCL3、DAB2、OLR1、C5AR1、TREM2、MRC1、及びCEBPB;
(e)BCL6B、CDH5、CLEC14A、CXorf36、EMCN、FAM124B、KDR、MMRN2、MYCT1、PALMD、ROBO4、SHE、TEK、及びTIE1;
(f)B2M、TAP1、TAP2、TAPBP、HLA−A、HLA−B、及びHLA−C;
(g)HLA−DRB5、HLA−DPA1、HLA−DPB1、HLA−DQB1、HLA−DRA、HLA−DRB1、HLA−DMA、及びHLA−DOA;
(h)STAT1、CXCL9、CXCL10、及びCXCL11;
(i)GZMA、GZMB、GZMH、PRF1、及びGNLY;
(j)PSMB8、PSMB9、及びPSMB10;
(k)AXIN1、BAD、BAX、BBC3、及びBCL2L1;
(l)CCL2、CCL3、CCL4、CCL7、及びCCL8;
(m)BNIP3、SLC2A1、PGK1、BNIP3L、P4HA1、ADM、PDK1、ALDOC、PLOD2、P4HA2、及びMXI1;
(n)MAGEA3、MAGEA6、MAGEA1、MAGEA12、MAGEA4、MAGEB2、MAGEC2、及びMAGEC1;
(o)AKT1、HIF1A、SLC2A1、HK2、TPI1、ENO1、LDHA、PFKFB3、PFKM、GOT1、GOT2、GLUD1、及びHK1;
(p)IFI16、IFI27、IFI35、IFIH1、IFIT1、IFIT2、IFITM1、IFITM2、IRF1、APOL6、TMEM140、PARP9、TRIM21、GBP1、DTX3L、PSMB9、OAS1、OAS2、ISG15、MX1、IFI6、IFIT3、IRF9、及びSTAT2;
(q)CXCL1、CXCL3、CXCL2、CCL20、AREG、FOSL1、CSF3、PTGS2、IER3、及びIL6;
ここで、少なくとも1種の遺伝子シグネチャーにおける1種以上の遺伝子の発現レベルの変化は、処置のための患者を特定する。別の態様において、この方法は、処置を必要とする癌患者の処置を選択する方法を含み、患者から得られた生物学的試料中のシグネチャー(a)〜(q)で記載された、1種以上の遺伝子、又は遺伝子の群、又は遺伝子若しくは遺伝子の群の組み合わせの発現レベルを決定することを含み、ここで、遺伝子シグネチャー(a)〜(q)中の、1種以上の遺伝子、又は遺伝子の群、又は遺伝子若しくは遺伝子の群の組み合わせの発現レベルの変化は、処置のための患者を特定する。
(a)MKI67、CEP55、KIF2C、MELK、CENPF、EXO1、ANLN、RRM2、UBE2C、CCNB1、及びCDC20;
(b)FAP、COL6A3、ADAM12、OLFML2B、PDGFRB、及びLRRC32;
(c)CXCL10、CXCR3、CX3CL1、PRF1、GZMK、GZMB、CD27、IL2RG、KLRK1、CTLA4、GZMH、CD3D、KLRB1、KLRD1、LCK、CD5、IRF4、CD8A、CD38、EOMES、GZMM、GNLY、IFITM1、IDO1、MS4A1、GZMA、CD2、CD3E、CD3G、CD40LG、CD6、CD7、CD79A、CD8B、CXCL11、CXCL13、CXCL9、HLA−DOB、IFNG、LAG3、LY9、PDCD1、TBX21、TIGIT、ZAP70、SLAMF7、CD96、PVR、STAT1、JAK1、JAK2、STAT2、IRF9、IGF2R、CD48、及びICOS;
(d)ITGAM、TLR4、IL1B、CSF1R、CSF3R、TLR2、TLR1、ITGAX、HCK、TLR8、SLC11A1、CD47、CD14、CLEC4E、CLEC7A、FCAR、FCN1、LILRA5、LILRB2、LYZ、NFAM1、P2RY13、S100A8、S100A9、SERPINA1、SIRPA、SIRPB2、TREM1、CLEC5A、CSF1、CYBB、FCGR1A、MARCO、NLRP3、FPR1、FPR3、CCL3、DAB2、OLR1、C5AR1、TREM2、MRC1、及びCEBPB;
(e)BCL6B、CDH5、CLEC14A、CXorf36、EMCN、FAM124B、KDR、MMRN2、MYCT1、PALMD、ROBO4、SHE、TEK、及びTIE1;
(f)B2M、TAP1、TAP2、TAPBP、HLA−A、HLA−B、及びHLA−C;
(g)HLA−DRB5、HLA−DPA1、HLA−DPB1、HLA−DQB1、HLA−DRA、HLA−DRB1、HLA−DMA、及びHLA−DOA;
(h)STAT1、CXCL9、CXCL10、及びCXCL11;
(i)GZMA、GZMB、GZMH、PRF1、及びGNLY;
(j)PSMB8、PSMB9、及びPSMB10;
(k)AXIN1、BAD、BAX、BBC3、及びBCL2L1;
(l)CCL2、CCL3、CCL4、CCL7、及びCCL8;
(m)BNIP3、SLC2A1、PGK1、BNIP3L、P4HA1、ADM、PDK1、ALDOC、PLOD2、P4HA2、及びMXI1;
(n)MAGEA3、MAGEA6、MAGEA1、MAGEA12、MAGEA4、MAGEB2、MAGEC2、及びMAGEC1;
(o)AKT1、HIF1A、SLC2A1、HK2、TPI1、ENO1、LDHA、PFKFB3、PFKM、GOT1、GOT2、GLUD1、及びHK1;
(p)IFI16、IFI27、IFI35、IFIH1、IFIT1、IFIT2、IFITM1、IFITM2、IRF1、APOL6、TMEM140、PARP9、TRIM21、GBP1、DTX3L、PSMB9、OAS1、OAS2、ISG15、MX1、IFI6、IFIT3、IRF9、及びSTAT2;
(q)CXCL1、CXCL3、CXCL2、CCL20、AREG、FOSL1、CSF3、PTGS2、IER3、及びIL6;
ここで、遺伝子シグネチャー(a)〜(q)の少なくとも1つにおける1種以上の遺伝子の発現レベルの変化は、治療による処置のための被験体を特定する。別の態様において、この方法は、治療による処置を必要とする癌を有する被験体を選択する方法を含み、患者から得られた生物学的試料中のシグネチャー(a)〜(q)で記載された、1種以上の遺伝子、又は遺伝子の群、又は遺伝子若しくは遺伝子の群の組み合わせの発現レベルを決定することを含み、ここで、遺伝子シグネチャー(a)〜(q)中の、1種以上の遺伝子、又は遺伝子の群、又は遺伝子若しくは遺伝子の群の組み合わせの発現レベルの変化は、治療による処置のための被験体を特定する。
(a)MKI67、CEP55、KIF2C、MELK、CENPF、EXO1、ANLN、RRM2、UBE2C、CCNB1、及びCDC20;
(b)FAP、COL6A3、ADAM12、OLFML2B、PDGFRB、及びLRRC32;
(c)CXCL10、CXCR3、CX3CL1、PRF1、GZMK、GZMB、CD27、IL2RG、KLRK1、CTLA4、GZMH、CD3D、KLRB1、KLRD1、LCK、CD5、IRF4、CD8A、CD38、EOMES、GZMM、GNLY、IFITM1、IDO1、MS4A1、GZMA、CD2、CD3E、CD3G、CD40LG、CD6、CD7、CD79A、CD8B、CXCL11、CXCL13、CXCL9、HLA−DOB、IFNG、LAG3、LY9、PDCD1、TBX21、TIGIT、ZAP70、SLAMF7、CD96、PVR、STAT1、JAK1、JAK2、STAT2、IRF9、IGF2R、CD48、及びICOS;
(d)ITGAM、TLR4、IL1B、CSF1R、CSF3R、TLR2、TLR1、ITGAX、HCK、TLR8、SLC11A1、CD47、CD14、CLEC4E、CLEC7A、FCAR、FCN1、LILRA5、LILRB2、LYZ、NFAM1、P2RY13、S100A8、S100A9、SERPINA1、SIRPA、SIRPB2、TREM1、CLEC5A、CSF1、CYBB、FCGR1A、MARCO、NLRP3、FPR1、FPR3、CCL3、DAB2、OLR1、C5AR1、TREM2、MRC1、及びCEBPB;
(e)BCL6B、CDH5、CLEC14A、CXorf36、EMCN、FAM124B、KDR、MMRN2、MYCT1、PALMD、ROBO4、SHE、TEK、及びTIE1;
(f)B2M、TAP1、TAP2、TAPBP、HLA−A、HLA−B、及びHLA−C;
(g)HLA−DRB5、HLA−DPA1、HLA−DPB1、HLA−DQB1、HLA−DRA、HLA−DRB1、HLA−DMA、及びHLA−DOA;
(h)STAT1、CXCL9、CXCL10、及びCXCL11;
(i)GZMA、GZMB、GZMH、PRF1、及びGNLY;
(j)PSMB8、PSMB9、及びPSMB10;
(k)AXIN1、BAD、BAX、BBC3、及びBCL2L1;
(l)CCL2、CCL3、CCL4、CCL7、及びCCL8;
(m)BNIP3、SLC2A1、PGK1、BNIP3L、P4HA1、ADM、PDK1、ALDOC、PLOD2、P4HA2、及びMXI1;
(n)MAGEA3、MAGEA6、MAGEA1、MAGEA12、MAGEA4、MAGEB2、MAGEC2、及びMAGEC1;
(o)AKT1、HIF1A、SLC2A1、HK2、TPI1、ENO1、LDHA、PFKFB3、PFKM、GOT1、GOT2、GLUD1、及びHK1;
(p)IFI16、IFI27、IFI35、IFIH1、IFIT1、IFIT2、IFITM1、IFITM2、IRF1、APOL6、TMEM140、PARP9、TRIM21、GBP1、DTX3L、PSMB9、OAS1、OAS2、ISG15、MX1、IFI6、IFIT3、IRF9、及びSTAT2;
(q)CXCL1、CXCL3、CXCL2、CCL20、AREG、FOSL1、CSF3、PTGS2、IER3、及びIL6;
ここで、遺伝子シグネチャー(a)〜(q)の少なくとも1つにおける1種以上の遺伝子の発現レベルの変化は、治療による処置に応答する可能性が高い患者を特定する。別の態様において、この方法は、治療による処置に応答する可能性が高い癌を有する被験体を特定する方法を含み、患者から得られた生物学的試料中のシグネチャー(a)〜(q)で記載された、1種以上の遺伝子、又は遺伝子の群、又は遺伝子若しくは遺伝子の群の組み合わせの発現レベルを決定することを含み、ここで、遺伝子シグネチャー(a)〜(q)中の、1種以上の遺伝子、又は遺伝子の群、又は遺伝子若しくは遺伝子の群の組み合わせの発現レベルの変化は、治療による処置に応答する可能性が高い患者を特定する。
(i)治療で処置されている被験体から得られた生物学的試料中のシグネチャー(a)〜(q)の少なくとも1つにおける1種以上の遺伝子の発現レベルを測定すること:
(a)MKI67、CEP55、KIF2C、MELK、CENPF、EXO1、ANLN、RRM2、UBE2C、CCNB1、及びCDC20;
(b)FAP、COL6A3、ADAM12、OLFML2B、PDGFRB、及びLRRC32;
(c)CXCL10、CXCR3、CX3CL1、PRF1、GZMK、GZMB、CD27、IL2RG、KLRK1、CTLA4、GZMH、CD3D、KLRB1、KLRD1、LCK、CD5、IRF4、CD8A、CD38、EOMES、GZMM、GNLY、IFITM1、IDO1、MS4A1、GZMA、CD2、CD3E、CD3G、CD40LG、CD6、CD7、CD79A、CD8B、CXCL11、CXCL13、CXCL9、HLA−DOB、IFNG、LAG3、LY9、PDCD1、TBX21、TIGIT、ZAP70、SLAMF7、CD96、PVR、STAT1、JAK1、JAK2、STAT2、IRF9、IGF2R、CD48、及びICOS;
(d)ITGAM、TLR4、IL1B、CSF1R、CSF3R、TLR2、TLR1、ITGAX、HCK、TLR8、SLC11A1、CD47、CD14、CLEC4E、CLEC7A、FCAR、FCN1、LILRA5、LILRB2、LYZ、NFAM1、P2RY13、S100A8、S100A9、SERPINA1、SIRPA、SIRPB2、TREM1、CLEC5A、CSF1、CYBB、FCGR1A、MARCO、NLRP3、FPR1、FPR3、CCL3、DAB2、OLR1、C5AR1、TREM2、MRC1、及びCEBPB;
(e)BCL6B、CDH5、CLEC14A、CXorf36、EMCN、FAM124B、KDR、MMRN2、MYCT1、PALMD、ROBO4、SHE、TEK、及びTIE1;
(f)B2M、TAP1、TAP2、TAPBP、HLA−A、HLA−B、及びHLA−C;
(g)HLA−DRB5、HLA−DPA1、HLA−DPB1、HLA−DQB1、HLA−DRA、HLA−DRB1、HLA−DMA、及びHLA−DOA;
(h)STAT1、CXCL9、CXCL10、及びCXCL11;
(i)GZMA、GZMB、GZMH、PRF1、及びGNLY;
(j)PSMB8、PSMB9、及びPSMB10;
(k)AXIN1、BAD、BAX、BBC3、及びBCL2L1;
(l)CCL2、CCL3、CCL4、CCL7、及びCCL8;
(m)BNIP3、SLC2A1、PGK1、BNIP3L、P4HA1、ADM、PDK1、ALDOC、PLOD2、P4HA2、及びMXI1;
(n)MAGEA3、MAGEA6、MAGEA1、MAGEA12、MAGEA4、MAGEB2、MAGEC2、及びMAGEC1;
(o)AKT1、HIF1A、SLC2A1、HK2、TPI1、ENO1、LDHA、PFKFB3、PFKM、GOT1、GOT2、GLUD1、及びHK1;
(p)IFI16、IFI27、IFI35、IFIH1、IFIT1、IFIT2、IFITM1、IFITM2、IRF1、APOL6、TMEM140、PARP9、TRIM21、GBP1、DTX3L、PSMB9、OAS1、OAS2、ISG15、MX1、IFI6、IFIT3、IRF9、及びSTAT2;
(q)CXCL1、CXCL3、CXCL2、CCL20、AREG、FOSL1、CSF3、PTGS2、IER3、及びIL6;そして
(i)被験体から得られた生物学的試料中のシグネチャー(a)〜(q)の、1種以上の遺伝子、又は遺伝子の群、又は遺伝子若しくは遺伝子の群の組み合わせの発現レベルを測定することであって、ここで、被験体は治療で処置されており、そして
(ii)被験体から得られた試料中の1種以上の遺伝子、又は遺伝子の群、又は遺伝子若しくは遺伝子の群の組み合わせの発現レベルに基づいて、薬力学的活性を示すものとして処置を決定することであって、ここで、被験体から得られた試料中の1種以上の遺伝子、又は遺伝子の群、又は遺伝子若しくは遺伝子の群の組み合わせの発現レベルの上昇又は低下は、治療の薬力学的活性を示す。
特に他に定義しない限り、本明細書で使用されるすべての技術用語及び科学用語は、本開示が属する技術分野の当業者によって一般的に理解されるものと同じ意味を有する。本明細書において、文脈で特に他に明記しない限り、単数形には複数形も含まれる。例として「a」、「an」、及び「the」という用語は、単数形又は複数形であると理解され、「又は」という用語は、包括的であると理解される。例として「要素」は、1つ以上の要素を意味する。本明細書全体を通して、「含む(comprising)」という単語、又は「含む(comprises)」若しくは「含む(comprising)」などの変形は、記載された要素、整数、若しくは工程、又は要素、整数、若しくは工程の群を含むことを意味すると理解されるが、他の要素、整数、若しくは工程、又は要素の群、整数、若しくは工程の群を除外しない。約とは、記載された値の10%、9%、8%、7%、6%、5%、4%、3%、2%、1%、0.5%、0.1%、0.05%、又は0.01%以内であると理解することができる。文脈から特に明確でない限り、本明細書に提供されるすべての数値は「約」という用語によって修飾される。
多くの場合、生物学的に妥当な遺伝子のコレクションを単に平均化する遺伝子シグネチャーは、意図された生物学的プロセスをうまく測定するであろう。ただし、多くの生物学的プロセスは、mRNAの存在量の調節ではなく、タンパク質の存在量、結合、又は位置を調節することによって支配されているため、遺伝子発現でこれらのプロセスを測定しようとすると誤解を招く結果が生じる。従って、生物学的知識だけでは遺伝子シグネチャーには不適切な基礎となる。本発明は、免疫腫瘍学における遺伝子発現から生物学的解釈への架け橋を提供し、その発現が特定の生物学的プロセスをモニタリングする遺伝子を同定し、これらの遺伝子を、免疫腫瘍学の主要な生物学を測定するシグネチャーに組み込むものである。
(a)MKI67、CEP55、KIF2C、MELK、CENPF、EXO1、ANLN、RRM2、UBE2C、CCNB1、及びCDC20;
(b)FAP、COL6A3、ADAM12、OLFML2B、PDGFRB、及びLRRC32;
(c)CXCL10、CXCR3、CX3CL1、PRF1、GZMK、GZMB、CD27、IL2RG、KLRK1、CTLA4、GZMH、CD3D、KLRB1、KLRD1、LCK、CD5、IRF4、CD8A、CD38、EOMES、GZMM、GNLY、IFITM1、IDO1、MS4A1、GZMA、CD2、CD3E、CD3G、CD40LG、CD6、CD7、CD79A、CD8B、CXCL11、CXCL13、CXCL9、HLA−DOB、IFNG、LAG3、LY9、PDCD1、TBX21、TIGIT、ZAP70、SLAMF7、CD96、PVR、STAT1、JAK1、JAK2、STAT2、IRF9、IGF2R、CD48、及びICOS;
(d)ITGAM、TLR4、IL1B、CSF1R、CSF3R、TLR2、TLR1、ITGAX、HCK、TLR8、SLC11A1、CD47、CD14、CLEC4E、CLEC7A、FCAR、FCN1、LILRA5、LILRB2、LYZ、NFAM1、P2RY13、S100A8、S100A9、SERPINA1、SIRPA、SIRPB2、TREM1、CLEC5A、CSF1、CYBB、FCGR1A、MARCO、NLRP3、FPR1、FPR3、CCL3、DAB2、OLR1、C5AR1、TREM2、MRC1、及びCEBPB;
(e)BCL6B、CDH5、CLEC14A、CXorf36、EMCN、FAM124B、KDR、MMRN2、MYCT1、PALMD、ROBO4、SHE、TEK、及びTIE1;
(f)B2M、TAP1、TAP2、TAPBP、HLA−A、HLA−B、及びHLA−C;
(g)HLA−DRB5、HLA−DPA1、HLA−DPB1、HLA−DQB1、HLA−DRA、HLA−DRB1、HLA−DMA、及びHLA−DOA;
(h)STAT1、CXCL9、CXCL10、及びCXCL11;
(i)GZMA、GZMB、GZMH、PRF1、及びGNLY;
(j)PSMB8、PSMB9、及びPSMB10;
(k)AXIN1、BAD、BAX、BBC3、及びBCL2L1;
(l)CCL2、CCL3、CCL4、CCL7、及びCCL8;
(m)BNIP3、SLC2A1、PGK1、BNIP3L、P4HA1、ADM、PDK1、ALDOC、PLOD2、P4HA2、及びMXI1;
(n)MAGEA3、MAGEA6、MAGEA1、MAGEA12、MAGEA4、MAGEB2、MAGEC2、及びMAGEC1;
(o)AKT1、HIF1A、SLC2A1、HK2、TPI1、ENO1、LDHA、PFKFB3、PFKM、GOT1、GOT2、GLUD1、及びHK1;
(p)IFI16、IFI27、IFI35、IFIH1、IFIT1、IFIT2、IFITM1、IFITM2、IRF1、APOL6、TMEM140、PARP9、TRIM21、GBP1、DTX3L、PSMB9、OAS1、OAS2、ISG15、MX1、IFI6、IFIT3、IRF9、及びSTAT2;
(q)CXCL1、CXCL3、CXCL2、CCL20、AREG、FOSL1、CSF3、PTGS2、IER3、及びIL6;
ここで、少なくとも1種の遺伝子シグネチャー中の1種以上の遺伝子の発現レベルの変化は、処置のための患者を特定する。
(a)MKI67、CEP55、KIF2C、MELK、CENPF、EXO1、ANLN、RRM2、UBE2C、CCNB1、及びCDC20;
(b)FAP、COL6A3、ADAM12、OLFML2B、PDGFRB、及びLRRC32;
(c)CXCL10、CXCR3、CX3CL1、PRF1、GZMK、GZMB、CD27、IL2RG、KLRK1、CTLA4、GZMH、CD3D、KLRB1、KLRD1、LCK、CD5、IRF4、CD8A、CD38、EOMES、GZMM、GNLY、IFITM1、IDO1、MS4A1、GZMA、CD2、CD3E、CD3G、CD40LG、CD6、CD7、CD79A、CD8B、CXCL11、CXCL13、CXCL9、HLA−DOB、IFNG、LAG3、LY9、PDCD1、TBX21、TIGIT、ZAP70、SLAMF7、CD96、PVR、STAT1、JAK1、JAK2、STAT2、IRF9、IGF2R、CD48、及びICOS;
(d)ITGAM、TLR4、IL1B、CSF1R、CSF3R、TLR2、TLR1、ITGAX、HCK、TLR8、SLC11A1、CD47、CD14、CLEC4E、CLEC7A、FCAR、FCN1、LILRA5、LILRB2、LYZ、NFAM1、P2RY13、S100A8、S100A9、SERPINA1、SIRPA、SIRPB2、TREM1、CLEC5A、CSF1、CYBB、FCGR1A、MARCO、NLRP3、FPR1、FPR3、CCL3、DAB2、OLR1、C5AR1、TREM2、MRC1、及びCEBPB;
(e)BCL6B、CDH5、CLEC14A、CXorf36、EMCN、FAM124B、KDR、MMRN2、MYCT1、PALMD、ROBO4、SHE、TEK、及びTIE1;
(f)B2M、TAP1、TAP2、TAPBP、HLA−A、HLA−B、及びHLA−C;
(g)HLA−DRB5、HLA−DPA1、HLA−DPB1、HLA−DQB1、HLA−DRA、HLA−DRB1、HLA−DMA、及びHLA−DOA;
(h)STAT1、CXCL9、CXCL10、及びCXCL11;
(i)GZMA、GZMB、GZMH、PRF1、及びGNLY;
(j)PSMB8、PSMB9、及びPSMB10;
(k)AXIN1、BAD、BAX、BBC3、及びBCL2L1;
(l)CCL2、CCL3、CCL4、CCL7、及びCCL8;
(m)BNIP3、SLC2A1、PGK1、BNIP3L、P4HA1、ADM、PDK1、ALDOC、PLOD2、P4HA2、及びMXI1;
(n)MAGEA3、MAGEA6、MAGEA1、MAGEA12、MAGEA4、MAGEB2、MAGEC2、及びMAGEC1;
(o)AKT1、HIF1A、SLC2A1、HK2、TPI1、ENO1、LDHA、PFKFB3、PFKM、GOT1、GOT2、GLUD1、及びHK1;
(p)IFI16、IFI27、IFI35、IFIH1、IFIT1、IFIT2、IFITM1、IFITM2、IRF1、APOL6、TMEM140、PARP9、TRIM21、GBP1、DTX3L、PSMB9、OAS1、OAS2、ISG15、MX1、IFI6、IFIT3、IRF9、及びSTAT2;
(q)CXCL1、CXCL3、CXCL2、CCL20、AREG、FOSL1、CSF3、PTGS2、IER3、及びIL6;
ここで、遺伝子シグネチャー(a)〜(q)の少なくとも1つにおける1種以上の遺伝子の発現レベルの変化は、治療による処置のための被験体を特定する。
(a)MKI67、CEP55、KIF2C、MELK、CENPF、EXO1、ANLN、RRM2、UBE2C、CCNB1、及びCDC20;
(b)FAP、COL6A3、ADAM12、OLFML2B、PDGFRB、及びLRRC32;
(c)CXCL10、CXCR3、CX3CL1、PRF1、GZMK、GZMB、CD27、IL2RG、KLRK1、CTLA4、GZMH、CD3D、KLRB1、KLRD1、LCK、CD5、IRF4、CD8A、CD38、EOMES、GZMM、GNLY、IFITM1、IDO1、MS4A1、GZMA、CD2、CD3E、CD3G、CD40LG、CD6、CD7、CD79A、CD8B、CXCL11、CXCL13、CXCL9、HLA−DOB、IFNG、LAG3、LY9、PDCD1、TBX21、TIGIT、ZAP70、SLAMF7、CD96、PVR、STAT1、JAK1、JAK2、STAT2、IRF9、IGF2R、CD48、及びICOS;
(d)ITGAM、TLR4、IL1B、CSF1R、CSF3R、TLR2、TLR1、ITGAX、HCK、TLR8、SLC11A1、CD47、CD14、CLEC4E、CLEC7A、FCAR、FCN1、LILRA5、LILRB2、LYZ、NFAM1、P2RY13、S100A8、S100A9、SERPINA1、SIRPA、SIRPB2、TREM1、CLEC5A、CSF1、CYBB、FCGR1A、MARCO、NLRP3、FPR1、FPR3、CCL3、DAB2、OLR1、C5AR1、TREM2、MRC1、及びCEBPB;
(e)BCL6B、CDH5、CLEC14A、CXorf36、EMCN、FAM124B、KDR、MMRN2、MYCT1、PALMD、ROBO4、SHE、TEK、及びTIE1;
(f)B2M、TAP1、TAP2、TAPBP、HLA−A、HLA−B、及びHLA−C;
(g)HLA−DRB5、HLA−DPA1、HLA−DPB1、HLA−DQB1、HLA−DRA、HLA−DRB1、HLA−DMA、及びHLA−DOA;
(h)STAT1、CXCL9、CXCL10、及びCXCL11;
(i)GZMA、GZMB、GZMH、PRF1、及びGNLY;
(j)PSMB8、PSMB9、及びPSMB10;
(k)AXIN1、BAD、BAX、BBC3、及びBCL2L1;
(l)CCL2、CCL3、CCL4、CCL7、及びCCL8;
(m)BNIP3、SLC2A1、PGK1、BNIP3L、P4HA1、ADM、PDK1、ALDOC、PLOD2、P4HA2、及びMXI1;
(n)MAGEA3、MAGEA6、MAGEA1、MAGEA12、MAGEA4、MAGEB2、MAGEC2、及びMAGEC1;
(o)AKT1、HIF1A、SLC2A1、HK2、TPI1、ENO1、LDHA、PFKFB3、PFKM、GOT1、GOT2、GLUD1、及びHK1;
(p)IFI16、IFI27、IFI35、IFIH1、IFIT1、IFIT2、IFITM1、IFITM2、IRF1、APOL6、TMEM140、PARP9、TRIM21、GBP1、DTX3L、PSMB9、OAS1、OAS2、ISG15、MX1、IFI6、IFIT3、IRF9、及びSTAT2;
(q)CXCL1、CXCL3、CXCL2、CCL20、AREG、FOSL1、CSF3、PTGS2、IER3、及びIL6;
ここで、遺伝子シグネチャー(a)〜(q)の少なくとも1つにおける1種以上の遺伝子の発現レベルの変化は、治療による処置に応答する可能性が高い患者を特定する。
(i)治療で処置されている被験体から得られた生物学的試料中のシグネチャー(a)〜(q)の少なくとも1つにおける1種以上の遺伝子の発現レベルを測定すること:
(a)MKI67、CEP55、KIF2C、MELK、CENPF、EXO1、ANLN、RRM2、UBE2C、CCNB1、及びCDC20;
(b)FAP、COL6A3、ADAM12、OLFML2B、PDGFRB、及びLRRC32;
(c)CXCL10、CXCR3、CX3CL1、PRF1、GZMK、GZMB、CD27、IL2RG、KLRK1、CTLA4、GZMH、CD3D、KLRB1、KLRD1、LCK、CD5、IRF4、CD8A、CD38、EOMES、GZMM、GNLY、IFITM1、IDO1、MS4A1、GZMA、CD2、CD3E、CD3G、CD40LG、CD6、CD7、CD79A、CD8B、CXCL11、CXCL13、CXCL9、HLA−DOB、IFNG、LAG3、LY9、PDCD1、TBX21、TIGIT、ZAP70、SLAMF7、CD96、PVR、STAT1、JAK1、JAK2、STAT2、IRF9、IGF2R、CD48、及びICOS;
(d)ITGAM、TLR4、IL1B、CSF1R、CSF3R、TLR2、TLR1、ITGAX、HCK、TLR8、SLC11A1、CD47、CD14、CLEC4E、CLEC7A、FCAR、FCN1、LILRA5、LILRB2、LYZ、NFAM1、P2RY13、S100A8、S100A9、SERPINA1、SIRPA、SIRPB2、TREM1、CLEC5A、CSF1、CYBB、FCGR1A、MARCO、NLRP3、FPR1、FPR3、CCL3、DAB2、OLR1、C5AR1、TREM2、MRC1、及びCEBPB;
(e)BCL6B、CDH5、CLEC14A、CXorf36、EMCN、FAM124B、KDR、MMRN2、MYCT1、PALMD、ROBO4、SHE、TEK、及びTIE1;
(f)B2M、TAP1、TAP2、TAPBP、HLA−A、HLA−B、及びHLA−C;
(g)HLA−DRB5、HLA−DPA1、HLA−DPB1、HLA−DQB1、HLA−DRA、HLA−DRB1、HLA−DMA、及びHLA−DOA;
(h)STAT1、CXCL9、CXCL10、及びCXCL11;
(i)GZMA、GZMB、GZMH、PRF1、及びGNLY;
(j)PSMB8、PSMB9、及びPSMB10;
(k)AXIN1、BAD、BAX、BBC3、及びBCL2L1;
(l)CCL2、CCL3、CCL4、CCL7、及びCCL8;
(m)BNIP3、SLC2A1、PGK1、BNIP3L、P4HA1、ADM、PDK1、ALDOC、PLOD2、P4HA2、及びMXI1;
(n)MAGEA3、MAGEA6、MAGEA1、MAGEA12、MAGEA4、MAGEB2、MAGEC2、及びMAGEC1;
(o)AKT1、HIF1A、SLC2A1、HK2、TPI1、ENO1、LDHA、PFKFB3、PFKM、GOT1、GOT2、GLUD1、及びHK1;
(p)IFI16、IFI27、IFI35、IFIH1、IFIT1、IFIT2、IFITM1、IFITM2、IRF1、APOL6、TMEM140、PARP9、TRIM21、GBP1、DTX3L、PSMB9、OAS1、OAS2、ISG15、MX1、IFI6、IFIT3、IRF9、及びSTAT2;
(q)CXCL1、CXCL3、CXCL2、CCL20、AREG、FOSL1、CSF3、PTGS2、IER3及びIL6;そして
(ii)被験体から得られた試料中の1種以上の遺伝子の発現レベルに基づいて薬力学的活性を示すものとして処置を決定すること;
ここで、被験体から得られた試料中の1種以上の遺伝子の発現レベルの上昇又は低下は、治療の薬力学的活性を示す。
免疫腫瘍学の本質的生物学の単一シグネチャーであるかどうかのトレーニング
1.生物学的知識を使用して、潜在的な交絡シグネチャー(候補遺伝子の同時発現をもっともらしく説明できる任意のシグネチャー)を特定する。
2.各癌ゲノムアトラス(Cancer Genome Atlas)(TCGA)データセット内で、交絡シグネチャー上の各候補遺伝子を捨てて、残りを保存する。
3.各TCGAデータセット内で、シグネチャー遺伝子の残りの相関行列を計算し、遺伝子の類似性行列を、これらのデータセットに特異的な相関行列の平均として定義する。
4.まず、「活性」遺伝子セットを、セット内のすべての候補遺伝子として定義する。
5.連続する繰り返しで、活性遺伝子セット内の他の遺伝子との平均類似性が最も低い遺伝子を特定し、それを活性遺伝子セットから取り出す。各繰り返しで活性遺伝子間の平均類似性を保存する。
6.並べ替え試験:1000個のランダムな遺伝子セットについて、工程2〜5を繰り返す。各繰り返しのp値は、その繰り返しで活性遺伝子がより高い平均類似性を達成する、並べ替えられた遺伝子セットの比率である。
7.並べ替えp値が<0.01で、他の活性遺伝子との最小活性遺伝子の類似性が>0.2である最初の繰り返しを選択する。
Y=βx+ε、
最初の工程は、多数の遺伝子に影響を与える可能性が高いが、検討中の他のシグネチャー(間質の存在量及び腫瘍増殖)によって駆動される可能性が低い高レベルの生物学のシグネチャーをトレーニングすることであった。バッチ効果又はサブタイプのような強い生物学的効果によって誘発される偽の同時発現を回避するために、各TCGAデータセットの免疫関連遺伝子の主成分中のすべての我々の初期候補遺伝子の最初の3つの主成分を条件として、これらのシグネチャー遺伝子が評価される。トランスクリプトーム全体ではなく、1699個の候補遺伝子のみに対して主成分分析(PCA)を実行するという選択は恣意的であったが、免疫腫瘍学に関連する遺伝子の主成分は、より遠位の生物学に適合する主成分よりも、免疫腫瘍学遺伝子クラスターの分散を説明できる可能性が高いため、この選択は保存的である可能性があった。間質、増殖、及びこれらの交絡変数中のデータの最初の3つの主成分を含む、他のすべてのシグネチャーがトレーニングされる。
免疫療法剤に対する応答の予測
Claims (71)
- 処置を必要とする癌患者から得られた生物学的試料中のシグネチャー(a)〜(q)の少なくとも1つにおける1種以上の遺伝子の発現レベルを決定することを含む、上記患者の処置を選択する方法:
(a)MKI67、CEP55、KIF2C、MELK、CENPF、EXO1、ANLN、RRM2、UBE2C、CCNB1、及びCDC20;
(b)FAP、COL6A3、ADAM12、OLFML2B、PDGFRB、及びLRRC32;
(c)CXCL10、CXCR3、CX3CL1、PRF1、GZMK、GZMB、CD27、IL2RG、KLRK1、CTLA4、GZMH、CD3D、KLRB1、KLRD1、LCK、CD5、IRF4、CD8A、CD38、EOMES、GZMM、GNLY、IFITM1、IDO1、MS4A1、GZMA、CD2、CD3E、CD3G、CD40LG、CD6、CD7、CD79A、CD8B、CXCL11、CXCL13、CXCL9、HLA−DOB、IFNG、LAG3、LY9、PDCD1、TBX21、TIGIT、ZAP70、SLAMF7、CD96、PVR、STAT1、JAK1、JAK2、STAT2、IRF9、IGF2R、CD48、及びICOS;
(d)ITGAM、TLR4、IL1B、CSF1R、CSF3R、TLR2、TLR1、ITGAX、HCK、TLR8、SLC11A1、CD47、CD14、CLEC4E、CLEC7A、FCAR、FCN1、LILRA5、LILRB2、LYZ、NFAM1、P2RY13、S100A8、S100A9、SERPINA1、SIRPA、SIRPB2、TREM1、CLEC5A、CSF1、CYBB、FCGR1A、MARCO、NLRP3、FPR1、FPR3、CCL3、DAB2、OLR1、C5AR1、TREM2、MRC1、及びCEBPB;
(e)BCL6B、CDH5、CLEC14A、CXorf36、EMCN、FAM124B、KDR、MMRN2、MYCT1、PALMD、ROBO4、SHE、TEK、及びTIE1;
(f)B2M、TAP1、TAP2、TAPBP、HLA−A、HLA−B、及びHLA−C;
(g)HLA−DRB5、HLA−DPA1、HLA−DPB1、HLA−DQB1、HLA−DRA、HLA−DRB1、HLA−DMA、及びHLA−DOA;
(h)STAT1、CXCL9、CXCL10、及びCXCL11;
(i)GZMA、GZMB、GZMH、PRF1、及びGNLY;
(j)PSMB8、PSMB9、及びPSMB10;
(k)AXIN1、BAD、BAX、BBC3、及びBCL2L1;
(l)CCL2、CCL3、CCL4、CCL7、及びCCL8;
(m)BNIP3、SLC2A1、PGK1、BNIP3L、P4HA1、ADM、PDK1、ALDOC、PLOD2、P4HA2、及びMXI1;
(n)MAGEA3、MAGEA6、MAGEA1、MAGEA12、MAGEA4、MAGEB2、MAGEC2、及びMAGEC1;
(o)AKT1、HIF1A、SLC2A1、HK2、TPI1、ENO1、LDHA、PFKFB3、PFKM、GOT1、GOT2、GLUD1、及びHK1;
(p)IFI16、IFI27、IFI35、IFIH1、IFIT1、IFIT2、IFITM1、IFITM2、IRF1、APOL6、TMEM140、PARP9、TRIM21、GBP1、DTX3L、PSMB9、OAS1、OAS2、ISG15、MX1、IFI6、IFIT3、IRF9、及びSTAT2;
(q)CXCL1、CXCL3、CXCL2、CCL20、AREG、FOSL1、CSF3、PTGS2、IER3、及びIL6;
ここで、少なくとも1種の遺伝子シグネチャーにおける1種以上の遺伝子の発現レベルの変化は、処置のための患者を特定する。 - 前記シグネチャー(a)〜(q)の少なくとも1つにおける少なくとも2種の遺伝子の発現レベルが、患者から得られた生物学的試料において決定される、請求項1に記載の方法。
- 前記シグネチャー(a)〜(q)の少なくとも1つにおける少なくとも3種の遺伝子の発現レベルが、患者から得られた生物学的試料において決定される、請求項1に記載の方法。
- 前記シグネチャー(a)〜(q)の少なくとも1つにおける各遺伝子の発現レベルが、患者から得られた生物学的試料において決定される、請求項1に記載の方法。
- 前記シグネチャー(a)〜(q)の少なくとも2個、少なくとも3個、少なくとも4個、少なくとも5個、少なくとも6個、少なくとも7個、少なくとも8個、少なくとも9個、少なくとも10個、少なくとも11個、少なくとも12個、少なくとも13個、少なくとも14個、少なくとも15個、又は少なくとも16個における少なくとも1種の遺伝子の発現レベルが、患者から得られた生物学的試料において決定される、請求項1に記載の方法。
- 前記シグネチャー(a)〜(q)のそれぞれにおける少なくとも1種の遺伝子の発現レベルが、患者から得られた生物学的試料において決定される、請求項1に記載の方法。
- 前記シグネチャー(a)〜(q)のそれぞれにおける各遺伝子の発現レベルが、患者から得られた生物学的試料において決定される、請求項1に記載の方法。
- MKI67、CEP55、KIF2C、MELK、CENPF、EXO1、ANLN、RRM2、UBE2C、CCNB1、又はCDC20の1種以上の発現レベルが、患者から得られた生物学的試料において決定される、請求項1に記載の方法。
- FAP、COL6A3、ADAM12、OLFML2B、PDGFRB、又はLRRC32の1種以上の発現レベルが、患者から得られた生物学的試料において決定される、請求項1に記載の方法。
- CXCL10、CXCR3、CX3CL1、PRF1、GZMK、GZMB、CD27、IL2RG、KLRK1、CTLA4、GZMH、CD3D、KLRB1、KLRD1、LCK、CD5、IRF4、CD8A、CD38、EOMES、GZMM、GNLY、IFITM1、IDO1、MS4A1、GZMA、CD2、CD3E、CD3G、CD40LG、CD6、CD7、CD79A、CD8B、CXCL11、CXCL13、CXCL9、HLA−DOB、IFNG、LAG3、LY9、PDCD1、TBX21、TIGIT、ZAP70、SLAMF7、CD96、PVR、STAT1、JAK1、JAK2、STAT2、IRF9、IGF2R、CD48、又はICOSの1種以上の発現レベルが、患者から得られた生物学的試料において決定される、請求項1に記載の方法。
- ITGAM、TLR4、IL1B、CSF1R、CSF3R、TLR2、TLR1、ITGAX、HCK、TLR8、SLC11A1、CD47、CD14、CLEC4E、CLEC7A、FCAR、FCN1、LILRA5、LILRB2、LYZ、NFAM1、P2RY13、S100A8、S100A9、SERPINA1、SIRPA、SIRPB2、TREM1、CLEC5A、CSF1、CYBB、FCGR1A、MARCO、NLRP3、FPR1、FPR3、CCL3、DAB2、OLR1、C5AR1、TREM2、MRC1、又はCEBPBの1種以上の発現レベルが、患者から得られた生物学的試料において決定される、請求項1に記載の方法。
- BCL6B、CDH5、CLEC14A、CXorf36、EMCN、FAM124B、KDR、MMRN2、MYCT1、PALMD、ROBO4、SHE、TEK、又はTIE1の1種以上の発現レベルが、患者から得られた生物学的試料において決定される、請求項1に記載の方法。
- B2M、TAP1、TAP2、TAPBP、HLA−A、HLA−B、又はHLA−Cの1種以上の発現レベルが、患者から得られた生物学的試料において決定される、請求項1に記載の方法。
- HLA−DRB5、HLA−DPA1、HLA−DPB1、HLA−DQB1、HLA−DRA、HLA−DRB1、HLA−DMA、又はHLA−DOAの1種以上の発現レベルが、患者から得られた生物学的試料において決定される、請求項1に記載の方法。
- STAT1、CXCL9、CXCL10、又はCXCL11の1種以上の発現レベルが、患者から得られた生物学的試料において決定される、請求項1に記載の方法。
- GZMA、GZMB、GZMH、PRF1、又はGNLYの1種以上の発現レベルが、患者から得られた生物学的試料において決定される、請求項1に記載の方法。
- PSMB8、PSMB9、又はPSMB10の1種以上の発現レベルが、患者から得られた生物学的試料において決定される、請求項1に記載の方法。
- AXIN1、BAD、BAX、BBC3、又はBCL2L1の1種以上の発現レベルが、患者から得られた生物学的試料において決定される、請求項1に記載の方法。
- CCL2、CCL3、CCL4、CCL7、又はCCL8の1種以上の発現レベルが、患者から得られた生物学的試料において決定される、請求項1に記載の方法。
- BNIP3、SLC2A1、PGK1、BNIP3L、P4HA1、ADM、PDK1、ALDOC、PLOD2、P4HA2、又はMXI1の1種以上の発現レベルが、患者から得られた生物学的試料において決定される、請求項1に記載の方法。
- MAGEA3、MAGEA6、MAGEA1、MAGEA12、MAGEA4、MAGEB2、MAGEC2、又はMAGEC1の1種以上の発現レベルが、患者から得られた生物学的試料において決定される、請求項1に記載の方法。
- AKT1、HIF1A、SLC2A1、HK2、TPI1、ENO1、LDHA、PFKFB3、PFKM、GOT1、GOT2、GLUD1、又はHK1の1種以上の発現レベルが、患者から得られた生物学的試料において決定される、請求項1に記載の方法。
- IFI16、IFI27、IFI35、IFIH1、IFIT1、IFIT2、IFITM1、IFITM2、IRF1、APOL6、TMEM140、PARP9、TRIM21、GBP1、DTX3L、PSMB9、OAS1、OAS2、ISG15、MX1、IFI6、IFIT3、IRF9、又はSTAT2の1種以上の発現レベルが、患者から得られた生物学的試料において決定される、請求項1に記載の方法。
- CXCL1、CXCL3、CXCL2、CCL20、AREG、FOSL1、CSF3、PTGS2、IER3、又はIL6の1種以上の発現レベルが、患者から得られた生物学的試料において決定される、請求項1に記載の方法。
- 前記患者が治療に応答する可能性が高いことを患者に通知する工程をさらに含む、請求項1に記載の方法。
- 特定の治療的処置を患者に推奨する工程をさらに含む、請求項1又は25に記載の方法。
- 前記患者が治療から利益を得る可能性があると判断された場合に、患者に治療を施す工程をさらに含む、請求項1、25、又は26に記載の方法。
- 前記治療が免疫療法である、請求項1、25、26、又は27に記載の方法。
- 前記免疫療法が、チェックポイント阻害剤、キメラ抗原受容体T細胞治療、腫瘍溶解性ワクチン、サイトカインアゴニスト、若しくはサイトカインアンタゴニスト、又はこれらの組み合わせを含む、請求項28に記載の方法。
- 前記免疫療法が、PD−1阻害剤、PD−L1阻害剤、PD−L2阻害剤、GITRアゴニスト、OX40アゴニスト、TIM3アゴニスト、LAG3アゴニスト、KIRアゴニスト、CD28アゴニスト、CD137アゴニスト、CD27アゴニスト、CD40アゴニスト、CD70アゴニスト、CD276アゴニスト、ICOSアゴニスト、HVEMアゴニスト、NKG2Dアゴニスト、NKG2Aアゴニスト、MICAアゴニスト、2B4アゴニスト、41BBアゴニスト、CTLA4アンタゴニスト、PD−1軸アンタゴニスト、TIM3アンタゴニスト、BTLAアンタゴニスト、VISTAアンタゴニスト、LAG3アンタゴニスト、B7H4アンタゴニスト、CD96アンタゴニスト、TIGITアンタゴニスト、CD226アンタゴニスト、又はこれらの組み合わせを含む、請求項28に記載の方法。
- 前記サイトカインアゴニスト又はサイトカインアンタゴニストが、インターフェロン、IL−2、GMCSF、IL−17E、IL−6、IL−1a、IL−12、TFGB2、IL−15、IL−3、IL−13、IL−2R、IL−21、IL−4R、IL−7、M−CSF、MIF、ミオスタチン、Il−10、Il−24、CEA、IL−11、IL−9、IL−15、IL−2Ra、TNF、又はこれらの組み合わせのアゴニスト若しくはアンタゴニストである、請求項29に記載の方法。
- 前記癌が、副腎皮質癌、膀胱尿路上皮癌、***浸潤癌、頸部扁平上皮癌、子宮頸部腺癌、胆管癌、結腸腺癌、リンパ系新生物びまん性大型B細胞リンパ腫、食道癌、多形性神経膠芽細胞腫、頭頸部扁平上皮癌、嫌色素性腎癌、腎明細胞癌、腎乳頭細胞癌、急性骨髄性白血病、脳低悪性度神経膠腫、肝細胞癌、肺腺癌、肺扁平上皮癌、中皮腫、卵巣漿液性嚢胞腺癌、膵臓腺癌、クロム親和性細胞腫、傍神経節腫、前立腺腺癌、直腸腺癌、肉腫、皮膚黒色腫、胃腺癌、精巣生殖細胞腫瘍、甲状腺癌、胸腺腫、子宮癌肉腫、ぶどう膜黒色腫腫である、請求項1に記載の方法。
- 前記癌が、乳癌、肺癌、リンパ腫、黒色腫、肝臓癌、結腸直腸癌、卵巣癌、膀胱癌、腎臓癌、又は胃癌である、請求項1に記載の方法。
- 前記癌が、神経内分泌癌、非小細胞肺癌(NSCLC)、小細胞肺癌、甲状腺癌、子宮内膜癌、胆道癌、食道癌、肛門癌、唾液腺癌、外陰癌、又は子宮頚癌である、請求項1に記載の方法。
- 前記患者からの生物学的試料中の1種以上の遺伝子の発現が、mRNAを測定することによって決定される、請求項1に記載の方法。
- 前記患者からの生物学的試料中の1種以上の遺伝子の発現が、血漿中のmRNAを測定することによって決定される、請求項1に記載の方法。
- 前記患者からの生物学的試料中の1種以上の遺伝子の発現が、組織中のmRNAを測定することによって決定される、請求項1に記載の方法。
- 前記患者からの生物学的試料中の1種以上の遺伝子の発現が、FFPE組織中のmRNAを測定することによって決定される、請求項1に記載の方法。
- 前記患者からの生物学的試料中の1種以上の遺伝子の発現が、タンパク質レベルを測定することによって決定される、請求項1に記載の方法。
- 前記患者からの生物学的試料中の1種以上の遺伝子の発現が、血漿中のタンパク質レベルを測定することによって決定される、請求項1に記載の方法。
- 前記患者からの生物学的試料中の1種以上の遺伝子の発現が、組織中のタンパク質レベルを測定することによって決定される、請求項1に記載の方法。
- 前記患者からの生物学的試料中の1種以上の遺伝子の発現が、FFPE組織中のタンパク質レベルを測定することによって決定される、請求項1に記載の方法。
- 前記生物学的試料が腫瘍組織である、請求項1に記載の方法。
- 前記生物学的試料が血液である、請求項1に記載の方法。
- MKI67、CEP55、KIF2C、MELK、CENPF、EXO1、ANLN、RRM2、UBE2C、CCNB1、又はCDC20の1種以上の発現レベルが腫瘍増殖と相関している、請求項1に記載の方法。
- FAP、COL6A3、ADAM12、OLFML2B、PDGFRB、又はLRRC32の1種以上の発現レベルが、生物学的試料中の間質成分と相関している、請求項1に記載の方法。
- CXCL10、CXCR3、CX3CL1、PRF1、GZMK、GZMB、CD27、IL2RG、KLRK1、CTLA4、GZMH、CD3D、KLRB1、KLRD1、LCK、CD5、IRF4、CD8A、CD38、EOMES、GZMM、GNLY、IFITM1、IDO1、MS4A1、GZMA、CD2、CD3E、CD3G、CD40LG、CD6、CD7、CD79A、CD8B、CXCL11、CXCL13、CXCL9、HLA−DOB、IFNG、LAG3、LY9、PDCD1、TBX21、TIGIT、ZAP70、SLAMF7、CD96、PVR、STAT1、JAK1、JAK2、STAT2、IRF9、IGF2R、CD48、又はICOSの1種以上の発現レベルが、生物学的試料内のリンパ系の存在量及び活性と相関している、請求項1に記載の方法。
- ITGAM、TLR4、IL1B、CSF1R、CSF3R、TLR2、TLR1、ITGAX、HCK、TLR8、SLC11A1、CD47、CD14、CLEC4E、CLEC7A、FCAR、FCN1、LILRA5、LILRB2、LYZ、NFAM1、P2RY13、S100A8、S100A9、SERPINA1、SIRPA、SIRPB2、TREM1、CLEC5A、CSF1、CYBB、FCGR1A、MARCO、NLRP3、FPR1、FPR3、CCL3、DAB2、OLR1、C5AR1、TREM2、MRC1、又はCEBPBの1種以上の発現レベルが、生物学的試料中の骨髄系の存在量及び活性と相関している、請求項1に記載の方法。
- BCL6B、CDH5、CLEC14A、CXorf36、EMCN、FAM124B、KDR、MMRN2、MYCT1、PALMD、ROBO4、SHE、TEK、又はTIE1の1種以上の発現レベルが、生物学的試料中の内皮細胞の存在量と相関している、請求項1に記載の方法。
- B2M、TAP1、TAP2、TAPBP、HLA−A、HLA−B、又はHLA−Cの1種以上の発現レベルが、腫瘍中の抗原提示及び/又はプロセシングと相関している、請求項1に記載の方法。
- HLA−DRB5、HLA−DPA1、HLA−DPB1、HLA−DQB1、HLA−DRA、HLA−DRB1、HLA−DMA、又はHLA−DOAの1種以上の発現レベルが、生物学的試料中のクラスII抗原提示の量と相関している、請求項1に記載の方法。
- STAT1、CXCL9、CXCL10、又はCXCL11の1種以上の発現レベルが、生物学的試料中のインターフェロンガンマのシグナル伝達と相関している、請求項1に記載の方法。
- GZMA、GZMB、GZMH、PRF1、又はGNLYの1種以上の発現レベルが、生物学的試料中の細胞障害活性の量と相関している、請求項1に記載の方法。
- PSMB8、PSMB9、又はPSMB10の1種以上の発現レベルが、生物学的試料中のプロテアソーム活性と相関している、請求項1に記載の方法。
- AXIN1、BAD、BAX、BBC3、又はBCL2L1の1種以上の発現レベルが、生物学的試料中のアポトーシスと相関している、請求項1に記載の方法。
- CCL2、CCL3、CCL4、CCL7、又はCCL8の1種以上の発現レベルが、骨髄系及びリンパ系細胞を生物学的試料に動員するシグナル伝達と相関している、請求項1に記載の方法。
- BNIP3、SLC2A1、PGK1、BNIP3L、P4HA1、ADM、PDK1、ALDOC、PLOD2、P4HA2、又はMXI1の1種以上の発現レベルが、生物学的試料中の低酸素と相関している、請求項1に記載の方法。
- MAGEA3、MAGEA6、MAGEA1、MAGEA12、MAGEA4、MAGEB2、MAGEC2、又はMAGEC1の1種以上の発現レベルが、生物学的試料中の黒色腫関連抗原の存在と相関している、請求項1に記載の方法。
- AKT1、HIF1A、SLC2A1、HK2、TPI1、ENO1、LDHA、PFKFB3、PFKM、GOT1、GOT2、GLUD1、又はHK1の1種以上の発現レベルが、生物学的試料中の解糖と相関している、請求項1に記載の方法。
- IFI16、IFI27、IFI35、IFIH1、IFIT1、IFIT2、IFITM1、IFITM2、IRF1、APOL6、TMEM140、PARP9、TRIM21、GBP1、DTX3L、PSMB9、OAS1、OAS2、ISG15、MX1、IFI6、IFIT3、IRF9、又はSTAT2の1種以上の発現レベルが、生物学的試料中のインターフェロンに対する応答と相関している、請求項1に記載の方法。
- CXCL1、CXCL3、CXCL2、CCL20、AREG、FOSL1、CSF3、PTGS2、IER3、又はIL6の1種以上の発現レベルが、生物学的試料中の骨髄由来サイトカイン及びケモカインの存在と相関している、請求項1に記載の方法。
- 治療による処置のための癌を有する被験体から得られた生物学的試料中のシグネチャー(a)〜(q)の少なくとも1つにおける1種以上の遺伝子の発現レベルを決定することを含む、前記被験体を選択する方法:
(a)MKI67、CEP55、KIF2C、MELK、CENPF、EXO1、ANLN、RRM2、UBE2C、CCNB1、及びCDC20;
(b)FAP、COL6A3、ADAM12、OLFML2B、PDGFRB、及びLRRC32;
(c)CXCL10、CXCR3、CX3CL1、PRF1、GZMK、GZMB、CD27、IL2RG、KLRK1、CTLA4、GZMH、CD3D、KLRB1、KLRD1、LCK、CD5、IRF4、CD8A、CD38、EOMES、GZMM、GNLY、IFITM1、IDO1、MS4A1、GZMA、CD2、CD3E、CD3G、CD40LG、CD6、CD7、CD79A、CD8B、CXCL11、CXCL13、CXCL9、HLA−DOB、IFNG、LAG3、LY9、PDCD1、TBX21、TIGIT、ZAP70、SLAMF7、CD96、PVR、STAT1、JAK1、JAK2、STAT2、IRF9、IGF2R、CD48、及びICOS;
(d)ITGAM、TLR4、IL1B、CSF1R、CSF3R、TLR2、TLR1、ITGAX、HCK、TLR8、SLC11A1、CD47、CD14、CLEC4E、CLEC7A、FCAR、FCN1、LILRA5、LILRB2、LYZ、NFAM1、P2RY13、S100A8、S100A9、SERPINA1、SIRPA、SIRPB2、TREM1、CLEC5A、CSF1、CYBB、FCGR1A、MARCO、NLRP3、FPR1、FPR3、CCL3、DAB2、OLR1、C5AR1、TREM2、MRC1、及びCEBPB;
(e)BCL6B、CDH5、CLEC14A、CXorf36、EMCN、FAM124B、KDR、MMRN2、MYCT1、PALMD、ROBO4、SHE、TEK、及びTIE1;
(f)B2M、TAP1、TAP2、TAPBP、HLA−A、HLA−B、及びHLA−C;
(g)HLA−DRB5、HLA−DPA1、HLA−DPB1、HLA−DQB1、HLA−DRA、HLA−DRB1、HLA−DMA、及びHLA−DOA;
(h)STAT1、CXCL9、CXCL10、及びCXCL11;
(i)GZMA、GZMB、GZMH、PRF1、及びGNLY;
(j)PSMB8、PSMB9、及びPSMB10;
(k)AXIN1、BAD、BAX、BBC3、及びBCL2L1;
(l)CCL2、CCL3、CCL4、CCL7、及びCCL8;
(m)BNIP3、SLC2A1、PGK1、BNIP3L、P4HA1、ADM、PDK1、ALDOC、PLOD2、P4HA2、及びMXI1;
(n)MAGEA3、MAGEA6、MAGEA1、MAGEA12、MAGEA4、MAGEB2、MAGEC2、及びMAGEC1;
(o)AKT1、HIF1A、SLC2A1、HK2、TPI1、ENO1、LDHA、PFKFB3、PFKM、GOT1、GOT2、GLUD1、及びHK1;
(p)IFI16、IFI27、IFI35、IFIH1、IFIT1、IFIT2、IFITM1、IFITM2、IRF1、APOL6、TMEM140、PARP9、TRIM21、GBP1、DTX3L、PSMB9、OAS1、OAS2、ISG15、MX1、IFI6、IFIT3、IRF9、及びSTAT2;
(q)CXCL1、CXCL3、CXCL2、CCL20、AREG、FOSL1、CSF3、PTGS2、IER3、及びIL6;
ここで、遺伝子シグネチャー(a)〜(q)の少なくとも1つにおける1種以上の遺伝子の発現レベルの変化は、治療による処置のための被験体を特定する。 - 治療による処置に応答する可能性が高い癌を有する被験体から得られた生物学的試料中のシグネチャー(a)〜(q)の少なくとも1つにおける1種以上の遺伝子の発現レベルを決定することを含む、前記被験体を特定する方法:
(a)MKI67、CEP55、KIF2C、MELK、CENPF、EXO1、ANLN、RRM2、UBE2C、CCNB1、及びCDC20;
(b)FAP、COL6A3、ADAM12、OLFML2B、PDGFRB、及びLRRC32;
(c)CXCL10、CXCR3、CX3CL1、PRF1、GZMK、GZMB、CD27、IL2RG、KLRK1、CTLA4、GZMH、CD3D、KLRB1、KLRD1、LCK、CD5、IRF4、CD8A、CD38、EOMES、GZMM、GNLY、IFITM1、IDO1、MS4A1、GZMA、CD2、CD3E、CD3G、CD40LG、CD6、CD7、CD79A、CD8B、CXCL11、CXCL13、CXCL9、HLA−DOB、IFNG、LAG3、LY9、PDCD1、TBX21、TIGIT、ZAP70、SLAMF7、CD96、PVR、STAT1、JAK1、JAK2、STAT2、IRF9、IGF2R、CD48、及びICOS;
(d)ITGAM、TLR4、IL1B、CSF1R、CSF3R、TLR2、TLR1、ITGAX、HCK、TLR8、SLC11A1、CD47、CD14、CLEC4E、CLEC7A、FCAR、FCN1、LILRA5、LILRB2、LYZ、NFAM1、P2RY13、S100A8、S100A9、SERPINA1、SIRPA、SIRPB2、TREM1、CLEC5A、CSF1、CYBB、FCGR1A、MARCO、NLRP3、FPR1、FPR3、CCL3、DAB2、OLR1、C5AR1、TREM2、MRC1、及びCEBPB;
(e)BCL6B、CDH5、CLEC14A、CXorf36、EMCN、FAM124B、KDR、MMRN2、MYCT1、PALMD、ROBO4、SHE、TEK、及びTIE1;
(f)B2M、TAP1、TAP2、TAPBP、HLA−A、HLA−B、及びHLA−C;
(g)HLA−DRB5、HLA−DPA1、HLA−DPB1、HLA−DQB1、HLA−DRA、HLA−DRB1、HLA−DMA、及びHLA−DOA;
(h)STAT1、CXCL9、CXCL10、及びCXCL11;
(i)GZMA、GZMB、GZMH、PRF1、及びGNLY;
(j)PSMB8、PSMB9、及びPSMB10;
(k)AXIN1、BAD、BAX、BBC3、及びBCL2L1;
(l)CCL2、CCL3、CCL4、CCL7、及びCCL8;
(m)BNIP3、SLC2A1、PGK1、BNIP3L、P4HA1、ADM、PDK1、ALDOC、PLOD2、P4HA2、及びMXI1;
(n)MAGEA3、MAGEA6、MAGEA1、MAGEA12、MAGEA4、MAGEB2、MAGEC2、及びMAGEC1;
(o)AKT1、HIF1A、SLC2A1、HK2、TPI1、ENO1、LDHA、PFKFB3、PFKM、GOT1、GOT2、GLUD1、及びHK1;
(p)IFI16、IFI27、IFI35、IFIH1、IFIT1、IFIT2、IFITM1、IFITM2、IRF1、APOL6、TMEM140、PARP9、TRIM21、GBP1、DTX3L、PSMB9、OAS1、OAS2、ISG15、MX1、IFI6、IFIT3、IRF9、及びSTAT2;
(q)CXCL1、CXCL3、CXCL2、CCL20、AREG、FOSL1、CSF3、PTGS2、IER3、及びIL6;
ここで、遺伝子シグネチャー(a)〜(q)の少なくとも1つにおける1種以上の遺伝子の発現レベルの変化は、治療による処置に応答する可能性が高い患者を特定する。 - 以下を含む、被験体における癌治療の薬力学的活性をモニタリングするための方法:
(i)治療で処置されている被験体から得られた生物学的試料中のシグネチャー(a)〜(q)の少なくとも1つにおける1種以上の遺伝子の発現レベルを測定すること:
(a)MKI67、CEP55、KIF2C、MELK、CENPF、EXO1、ANLN、RRM2、UBE2C、CCNB1、及びCDC20;
(b)FAP、COL6A3、ADAM12、OLFML2B、PDGFRB、及びLRRC32;
(c)CXCL10、CXCR3、CX3CL1、PRF1、GZMK、GZMB、CD27、IL2RG、KLRK1、CTLA4、GZMH、CD3D、KLRB1、KLRD1、LCK、CD5、IRF4、CD8A、CD38、EOMES、GZMM、GNLY、IFITM1、IDO1、MS4A1、GZMA、CD2、CD3E、CD3G、CD40LG、CD6、CD7、CD79A、CD8B、CXCL11、CXCL13、CXCL9、HLA−DOB、IFNG、LAG3、LY9、PDCD1、TBX21、TIGIT、ZAP70、SLAMF7、CD96、PVR、STAT1、JAK1、JAK2、STAT2、IRF9、IGF2R、CD48、及びICOS;
(d)ITGAM、TLR4、IL1B、CSF1R、CSF3R、TLR2、TLR1、ITGAX、HCK、TLR8、SLC11A1、CD47、CD14、CLEC4E、CLEC7A、FCAR、FCN1、LILRA5、LILRB2、LYZ、NFAM1、P2RY13、S100A8、S100A9、SERPINA1、SIRPA、SIRPB2、TREM1、CLEC5A、CSF1、CYBB、FCGR1A、MARCO、NLRP3、FPR1、FPR3、CCL3、DAB2、OLR1、C5AR1、TREM2、MRC1、及びCEBPB;
(e)BCL6B、CDH5、CLEC14A、CXorf36、EMCN、FAM124B、KDR、MMRN2、MYCT1、PALMD、ROBO4、SHE、TEK、及びTIE1;
(f)B2M、TAP1、TAP2、TAPBP、HLA−A、HLA−B、及びHLA−C;
(g)HLA−DRB5、HLA−DPA1、HLA−DPB1、HLA−DQB1、HLA−DRA、HLA−DRB1、HLA−DMA、及びHLA−DOA;
(h)STAT1、CXCL9、CXCL10、及びCXCL11;
(i)GZMA、GZMB、GZMH、PRF1、及びGNLY;
(j)PSMB8、PSMB9、及びPSMB10;
(k)AXIN1、BAD、BAX、BBC3、及びBCL2L1;
(l)CCL2、CCL3、CCL4、CCL7、及びCCL8;
(m)BNIP3、SLC2A1、PGK1、BNIP3L、P4HA1、ADM、PDK1、ALDOC、PLOD2、P4HA2、及びMXI1;
(n)MAGEA3、MAGEA6、MAGEA1、MAGEA12、MAGEA4、MAGEB2、MAGEC2、及びMAGEC1;
(o)AKT1、HIF1A、SLC2A1、HK2、TPI1、ENO1、LDHA、PFKFB3、PFKM、GOT1、GOT2、GLUD1、及びHK1;
(p)IFI16、IFI27、IFI35、IFIH1、IFIT1、IFIT2、IFITM1、IFITM2、IRF1、APOL6、TMEM140、PARP9、TRIM21、GBP1、DTX3L、PSMB9、OAS1、OAS2、ISG15、MX1、IFI6、IFIT3、IRF9、及びSTAT2;
(q)CXCL1、CXCL3、CXCL2、CCL20、AREG、FOSL1、CSF3、PTGS2、IER3、及びIL6;そして
(ii)被験体から得られた試料中の1種以上の遺伝子の発現レベルに基づいて薬力学的活性を示すものとして治療を決定すること;
ここで、被験体から得られた試料中の1種以上の遺伝子の発現レベルの上昇又は低下は、治療の薬力学的活性を示す。 - 前記治療が被験体に施される前に、生物学的試料が被験体から得られる、請求項63又は64に記載の方法。
- 前記治療が被験体に施された後、生物学的試料が被験体から得られる、請求項63又は64に記載の方法。
- 前記被験体に少なくとも1つの治療有効量の少なくとも1つの治療を施すことをさらに含む、請求項1、62、63、又は64のいずれかに記載の方法。
- 前記少なくとも1つの治療が抗癌療法を含む、請求項67に記載の方法。
- 前記少なくとも1つの治療が免疫療法を含む、請求項67に記載の方法。
- 免疫療法が、活性化免疫療法、抑制免疫療法、又は活性化免疫療法と抑制免疫療法の組み合わせを含む、請求項69に記載の方法。
- 免疫療法が、少なくとも1つの治療有効量の少なくとも1種のチェックポイント阻害剤、少なくとも1つの治療有効量の少なくとも1つのキメラ抗原受容体T細胞療法、少なくとも1つの治療有効量の少なくとも1種の腫瘍溶解性ワクチン、少なくとも1つの治療有効量の少なくとも1種のサイトカインアゴニスト、少なくとも1つの治療有効量の少なくとも1種のサイトカインアンタゴニスト、又はこれらの任意の組み合わせの投与を含む、請求項69に記載の方法。
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AU2019275404A1 (en) | 2020-12-03 |
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