JP2018503373A - がんの予後診断及び治療のための方法及び組成物 - Google Patents
がんの予後診断及び治療のための方法及び組成物 Download PDFInfo
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Abstract
Description
腫瘍免疫微小環境は、腫瘍細胞が組織常在型T細胞を抑制し、抗腫瘍免疫を回避することを可能にする、免疫抑制因子の宿主からなる。腫瘍間質内の因子、またはT細胞が腫瘍に浸潤しないように腫瘍細胞によって分泌される因子の研究は、侵攻性腫瘍を免疫療法剤に対して応答可能である免疫原性腫瘍に変換する方法への理解のための手段を提供する。本発明では、遺伝子発現を使用して、7つの異なるがんタイプに亘り、免疫細胞サブセットを表す遺伝子シグネチャの発生率を査定した。この分析は、免疫療法剤への応答を規定する腫瘍免疫生態のドライバーを特定するために、9つの異なるがん適応症及び様々な腫瘍サブタイプへの洞察を提供する。
別途定義されない限り、本明細書で使用される専門用語及び科学用語は、本発明が属する当業者が一般に理解する意味と同じ意味を有するものとする。Singleton et al.,Dictionary of Microbiology and Molecular Biology 2nd ed.,J.Wiley & Sons(New York,N.Y.1994)、及びMarch,Advanced Organic Chemistry Reactions,Mechanisms and Structure 4th ed.,John Wiley & Sons(New York,N.Y.1992)は、本出願で使用される用語の多くへの一般的な手引きを当業者に提供する。
本発明は、がん(例えば、膀胱がん、乳がん、結腸直腸がん、胃がん、肝臓がん、黒色腫、肺がん(例えば、非小細胞肺がん)、卵巣がん、腎細胞がん腫)のバイオマーカーの特定、選択、及び使用に関し、これは、免疫細胞サブタイプ(例えば、Tエフェクター細胞、調節性T細胞、B細胞、NK細胞、骨髄細胞、Th17細胞、炎症細胞、T細胞免疫ブロッカー、及び抗原提示細胞(APC)免疫ブロッカー)と相関する。この点で、本発明は、腫瘍免疫に関与する免疫サブタイプ(例えば、Tエフェクター細胞、調節性T細胞、B細胞、NK細胞、骨髄細胞、Th17細胞、炎症細胞、T細胞免疫ブロッカー、及び抗原提示細胞(APC)免疫ブロッカー)と相関するバイオマーカー、及び免疫療法剤での治療のための患者の選択におけるこれらのバイオマーカーの使用を特定するための、がん(例えば、膀胱がん、乳がん、結腸直腸がん、胃がん、肝臓がん、黒色腫、肺がん(例えば、非小細胞肺がん)、卵巣がん、腎細胞がん腫)を有する患者からの試料における発現プロファイル(複数可)の分析に関する。本発明のバイオマーカーは、本明細書、例えば、表1に列挙される。
表1.遺伝子シグネチャセット及び免疫細胞遺伝子シグネチャセットメンバー
全ての未標識遺伝子シグネチャセットは、90−遺伝子PCRベースFLUIDIGM(商標)パネルを使用したデータ分析に由来した。
*Th17遺伝子シグネチャセットは、本明細書中で、IL17遺伝子セットとしても記載され、90−遺伝子PCRベースFLUIDIGM(商標)パネルを使用したデータ分析に由来した。Th17遺伝子セット及びIL17遺伝子セットは、本出願全体を通して互換的に使用され、同じ遺伝子セットを指す。
**尿路上皮膀胱がん(UBC)試料で、800−遺伝子カスタムNanostringパネル(90−遺伝子PCRベースFLUIDIGM(商標)パネルのの代わりに)を使用したデータ分析に由来した遺伝子シグネチャセット。
#非小細胞肺がん(NSCLC)試料で、800−遺伝子カスタムNanostringパネル(90−遺伝子PCRベースFLUIDIGM(商標)パネルのの代わりに)を使用したデータ分析に由来した遺伝子シグネチャセット。
##UBC試料中の標的RNA−Seqアクセスに由来した遺伝子シグネチャセット。
CD8A、GZMA、GZMB、IFNγ、EOMES、もしくはPRF1;または
FOXP3;または
MS4A1もしくはCD48;または
CD79A、MS4A1、CD19、STAP1、KIAA0125、POU2AF1、もしくはFCRL5;または
NCAM1もしくはNKP46;または
KLRC3、KLRK1、KLRC2、もしくはKLRD1;または
ITGAM、ITGAX、CD1C、もしくはCLEC4C;または
CD68、CD163、ITGAM、ITGAX、もしくはCD14;または
LAPTM5、LAIR1、CD4、CSF1R、CD163、ADAP2、CD68、MRC1、CD45RO、SLA、MSR1、FPR3、FCGR2A、もしくはFCGR3A;または
IL17AもしくはIL17F;または
CCL2、IL1B、IL8、IL6、もしくはPTGS2;または
CD3D、CD3E、CD2、CD3G、CD6、TRAT1、CD28、もしくはLCK;または
CTLA4、BTLA、LAG3、HAVCR2、もしくはPDCD1;または
CTLA4、BTLA、LAG3、HAVCR2、PDCD1、もしくはTIGIT;または
CD276、PDL1、PDL2、もしくはIDO1;または
CD274、PDL2、IDO1、もしくはPVR;または
CX3CL1、CXCL9、CXCL10、CXCR3、CCL21、もしくはCCL22;または
CD4、IL2RA、もしくはCD69;または
TAPBP、TAP1、TAP2、PSMB9、もしくはPSMB8;または
CD40、CD80、CD86、CD70、もしくはGITRL;または
CD27、CD28、ICOS、TNFRSF4、TNFRSF14、TNFRSF18、TNFSF14、もしくはCD226;または
GNLY、KLRK1、KLRB1、GZMH、GZMA、KLRD1、もしくはNKG7;または
FAP、FN1、MMP2、BGN、LOXL2、PDPN、PDGFRB、COL4A1、COL4A2、COL5A1、もしくはCOL8A1
が判定される。別の実施形態では、2つの特定の遺伝子シグネチャセット中の免疫細胞遺伝子シグネチャの遺伝子のうちの1つ以上の発現レベルが判定される。例えば、2つの特定の遺伝子シグネチャセットの組み合わせが、以下の表2に記載される。
表2.2つの遺伝子シグネチャセットの組み合わせ
表3.3つの遺伝子シグネチャセットの組み合わせ
表4.4つの遺伝子シグネチャセットの組み合わせ
表5.5つの遺伝子シグネチャセットの組み合わせ
表6.6つの遺伝子シグネチャセットの組み合わせ
表7.7つの遺伝子シグネチャセットの組み合わせ
表8.8つの遺伝子シグネチャセットの組み合わせ
表9.9つの遺伝子シグネチャセットの組み合わせ
CD8A、GZMA、GZMB、IFNγ、EOMES、もしくはPRF1;
FOXP3;
MS4A1もしくはCD48;
CD79A、MS4A1、CD19、STAP1、KIAA0125、POU2AF1、もしくはFCRL5;
NCAM1もしくはNKP46;
KLRC3、KLRK1、KLRC2、もしくはKLRD1;
ITGAM、ITGAX、CD1C、もしくはCLEC4C;
CD68、CD163、ITGAM、ITGAX、もしくはCD14;
LAPTM5、LAIR1、CD4、CSF1R、CD163、ADAP2、CD68、MRC1、CD45RO、SLA、MSR1、FPR3、FCGR2A、もしくはFCGR3A;
IL17AもしくはIL17F;
CCL2、IL1B、IL8、IL6、もしくはPTGS2;
CD3D、CD3E、CD2、CD3G、CD6、TRAT1、CD28、もしくはLCK;
CTLA4、BTLA、LAG3、HAVCR2、もしくはPDCD1;
CTLA4、BTLA、LAG3、HAVCR2、PDCD1、もしくはTIGIT;
CD276、PDL1、PDL2、もしくはIDO1;
CD274、PDL2、IDO1、もしくはPVR;
CX3CL1、CXCL9、CXCL10、CXCR3、CCL21、もしくはCCL22;
CD4、IL2RA、もしくはCD69;
TAPBP、TAP1、TAP2、PSMB9、もしくはPSMB8;
CD40、CD80、CD86、CD70、もしくはGITRL;
CD27、CD28、ICOS、TNFRSF4、TNFRSF14、TNFRSF18、TNFSF14、もしくはCD226;
GNLY、KLRK1、KLRB1、GZMH、GZMA、KLRD1、もしくはNKG7;及び
FAP、FN1、MMP2、BGN、LOXL2、PDPN、PDGFRB、COL4A1、COL4A2、COL5A1、COL8A1、が判定される。いくつかの実施形態では、表14の遺伝子のうちの1つ以上は、本明細書に記載される遺伝子セットのうちの1つ(例えば、Teff、B細胞、NK細胞、Treg、骨髄、T細胞走化性、等)の中の免疫細胞シグネチャ遺伝子として更に含まれる。他の実施形態では、表14の遺伝子のうちの1つ以上は、更に特定された遺伝子セット(例えば、Th1、Th2、マスト細胞、抗原提示細胞(APC)等)中の免疫細胞シグネチャ遺伝子として更に含まれる。
本発明は更に、遺伝子セットのうちのいずれかにおいて1つ以上の免疫細胞遺伝子シグネチャの発現レベルの変化を有すると判定された場合、がん(例えば、化学療法耐性、化学療法感受性、難治性、原発性、進行性、または再発性である、膀胱がん、乳がん、結腸直腸がん、胃がん、肝臓がん、黒色腫、肺がん(例えば、非小細胞肺がん)、卵巣がん、または腎細胞がん腫)を有する患者に活性化または抑制免疫療法剤を投与する方法を提供する。一実施形態では、Teff遺伝子セット(すなわち、CD8A、GZMA、GZMB、IFNγ、EOMES、またはPRF1のうちの1つ以上)において1つ以上の免疫細胞遺伝子シグネチャの発現レベルの増加がある場合、またはTreg遺伝子セットにおいて1つ以上の免疫細胞遺伝子シグネチャの発現レベルの減少がある場合、患者に活性化免疫療法剤を投与する。他の実施形態では、Treg遺伝子セット(すなわち、FOXP3)において1つ以上の免疫細胞遺伝子シグネチャの発現レベルの増加がある場合、またはTeff遺伝子セット(すなわち、CD8A、GZMA、GZMB、IFNγ、EOMES、またはPRF1のうちの1つ以上)において1つ以上の免疫細胞遺伝子シグネチャの発現レベルの減少がある場合、患者に抑制免疫療法剤を投与する。他の実施形態では、Teff及び/またはTreg遺伝子セットにおける1つ以上の免疫細胞遺伝子シグネチャの発現レベルを判定することに加えて、表2〜8に記載される遺伝子セットのいずれか1つと組み合わせた1つ以上の免疫細胞遺伝子シグネチャの発現レベルを、患者に特定の免疫療法剤レジメン(例えば、活性化免疫療法剤レジメンまたは抑制免疫療法剤レジメン)を投与する前に判定することができる。
統計分析
R統計ソフトウェアを使用して統計分析を行った。FLUIDIGM(商標)及びNanostringデータを、ハウスキーピング遺伝子アプローチを使用して正規化した。具体的には、5つのハウスキーピング遺伝子(SP2、GUSB、TMEM55B、VPS33B、及びSDHA)の遺伝子発現の中央値を予測し、各試料から減算した。遺伝子セットの発現を、メンバー遺伝子の発現の中央値で表した。各遺伝子シグネチャにおける適応症間及び適応症内の変動性を査定するために、適応症を変量効果として線形混合効果モデルを使用した。全体の分散に対する適応症間の分散の比率であるICC(級内相関係数)を、各遺伝子シグネチャについて算出した。ウィルコクソン順位和検定を使用して、臨床反応群間の発現差異分析を実施した。複数の補正について、P値は調整されなかった。ウィルコクソン符号順位検定を使用して原発性及び転移性CRC対の間の発現差異を評価し、得られたp値は、ボンフェローニ法を使用して複数の試験エラーについて調整された。
異なる腫瘍の腫瘍微小環境中の免疫環境の特性を評価するために、PCRに基づく遺伝子発現シグネチャを用いて、尿路上皮膀胱がん(UBC)、乳がん(BC)、非小細胞肺がん(NSCLC)、黒色腫、腎細胞がん腫(RCC)、卵巣がん(OvCa)、胃がん、肝臓がん、及び結腸直腸がん(CRC)を含む7つのがんタイプに亘る免疫細胞サブセットの分布を分析した。表1は、CD8 T細胞(Teff)、調節性T細胞(Treg)、T細胞(全て)、活性化CD4 T細胞、T細胞走化性、骨髄細胞、マクロファージ(全て)、M2マクロファージ、B細胞、Th17細胞、NK細胞、及び先天性炎症シグネチャを含む免疫細胞サブセット中の遺伝子の排他的発現に基づいて生成された免疫遺伝子シグネチャを示す。T細胞中に存在する免疫ブロッカー(IB T細胞)及び抗原提示細胞または腫瘍細胞中に存在する免疫ブロッカー(IB APC/腫瘍)の発現もまた分析した(表1)。表1はまた、抗原プロセシング、共刺激リガンド、共刺激受容体、細胞溶解性、血管新生、及び活性化線維芽細胞シグネチャの免疫遺伝子シグネチャセットも示す。表1に示されるように、アーカイブの腫瘍標本から抽出されたRNAを使用し、90−遺伝子FLUIDIGM(商標)パネルまたは800−遺伝子カスタムNanostringパネルを使用して、遺伝子シグネチャセットを分析した。一般に、METHODOLOGYによる所定の遺伝子セット中の遺伝子において高度の相関性が認められた(図1〜11):Teff、0.72;B細胞、0.8;骨髄、0.54;炎症、0.59;T細胞 IB、0.49;IB APC/腫瘍、0.5。唯一の例外は、IL17シグネチャ(R=0.3)であった。
表10.
がんタイプに亘る、Teff遺伝子セット中のシグネチャ遺伝子の発現プロファイル(上記の表1を参照されたい)が判定された。がんタイプに亘るTeffシグネチャの調査は、がんの間だけではなく、所定の適応症内のサブタイプ間における発現の中央値の差異を示した。ほとんどの適応症がTeff遺伝子の同等の発現を示した一方、NSCLC、黒色腫、RCC、及びHer2+またはTN BCが最も高いレベルのTeffを有し、CRC及びOvCaは最も低いレベルを有し、ホルモン受容体陽性(HR+)BCがそれに続いた(図13)。がんタイプ内で幅広い発現パターンが認められ、これは、CRCまたはOvCa内のサブ集団が、黒色腫またはRCC等のがんの種類と類似するTeff発現レベルを有し得ることを示唆する。
腫瘍は、抗腫瘍Teff応答を阻害するために免疫抑制細胞を補充する。Foxp3発現によって特徴づけられる調節性T細胞(Treg)は、Teff活性をアンタゴナイズする。その場での免疫抑制の潜在能力を試験するため、腫瘍適応症間のFoxp3の発生率を査定した。Tregの存在は、BCサブタイプ(トリプルネガティブ(TN)と類似のHer2+は、どちらもホルモン受容体陽性(HR+)よりも高い)において最も高く、NSCLC、UBC、CRC、OvCa、RCC、及び黒色腫が続き、著しく減少した数を有した(図14)。有効なTreg依存性免疫抑制は、Teff:Tregの特定の割合を必要とするため、よって、Tregに対するTeffの割合を評価した。Teff:Tregの比率は、黒色腫で最も高く、RCC、NSCLC、及びUBCが続いた(図15)。独立したTeff及びTregの値の差異にかかわらず、BC(HR+、Her2+、及びTN)、CRC、及び卵巣は、同様に低減したTeff:Tregの比率を有した(図15)。これらの結果は、低いTeff:Tregを有する腫瘍は、Tregを標的とする療法剤から利益を得られる可能性があることを示唆する。
前臨床モデルにおいて、B細胞は、抗炎症マクロファージを補充し、作動させることで、腫瘍内免疫抑制を促進することが示された。一方、NK細胞は、腫瘍によって発現されたストレス分子を認識し、腫瘍拒絶を指示することが示された。B細胞の存在は、適応症に亘ってTeffと類似の分布を伴い(図16)、一方、NK細胞は、OvCa中で最も高く、全ての他の適応症がそれに続いた(図17)。マクロファージ及び樹状細胞の両方を包含する骨髄シグネチャは、CRC及びOvCaにおける低減されたレベルを除いて適応症間で類似し(図18)、これはおそらく、それらの適応症での低い免疫浸潤性を表す。更なる区別は、骨髄遺伝子セットの発現の中央値が、扁平上皮NSCLCと比較して非扁平上皮NSCLCにおいてより高かったことである。
細胞浸潤性リンパ球は、いくつかのがん適応症においてより良い予後と関連することが示された一方、Th17細胞によるIL−17A及びIL−17Fの産生は、CRC、TN BC(Couchad,20123 Scientific Reports)、及び卵巣がん等のいくつかの腫瘍においてより悪い予後に関連付けられた。いくつかの場合では、IL−17A及びIL−17Fの産生は、食道扁平上皮がん等の適応症においてより良い予後と関連付けられた。適応症に亘るIL−17A及びIL−17Fの分析は、複雑な分布を示した:IL−17A単独、IL−17F単独、IL−17A+/IL−17F+、及びIL−17A−/IL−17F−を発現する腫瘍(図20)。単一の集団の存在は、遺伝子シグネチャ指数0.3をもたらした(図2A)。結腸直腸がんが、IL−17遺伝子の最も高いレベルを有する適応症であり、扁平上皮NSCLC、膀胱がん、及び非扁平上皮NSCLCがそれに続く(図19)。Her2+BC、HR+BC、及びOvCaは、IL−17遺伝子の最も低い発生率を有する適応症であった。
腫瘍微小環境中の免疫環境は、器官の内因性免疫応答特性または腫瘍細胞による特異的な補充のいずれかを反映し得る。よって、腫瘍が転移したときに腫瘍免疫微小環境が維持されるかどうかはまだ判定されない。この可能性を試験するために、47対の非同調性の適合する原発性及び転移性CRC腫瘍間で免疫遺伝子シグネチャを比較した。転移のほとんどは、肝臓または肺(それぞれ、36個及び5個)に位置し、残りは他の器官に位置した。
表12.
腫瘍関連炎症は、腫瘍成長、血管新生、及び骨髄抑制細胞の補充を促進し得、それは次いでT細胞媒介抗腫瘍応答を止める。インフラマソーム産物(IL−1β及びIL−18)、ケモカイン(CCL2、CCL22)、及びサイトカイン(IL−6、IL−8)は、異なる適応症においてこのプロセスの一部であることが記載された。炎症遺伝子シグネチャを使用することで、適応症に亘り総体的な炎症が変化することが認められた(図21)。最も炎症の多い腫瘍は、NSCLC、UBC、及びRCCであり、一方、最も炎症の少ない適応症は、HR+BC、肝臓、Her2+BC、及びOvCaであった。これらの結果は、ホルモンによって制御される腫瘍は、低減された局所炎症を発揮することを示唆する。
制御されないTeff活性を防止するために、T細胞活性に際し、阻害性受容体(IB)は、免疫細胞及び/または腫瘍細胞上で上方制御される。腫瘍逃避の機構は、T細胞IBへのリガンドの誘導であり、それにより、有効な抗腫瘍応答を遮断する。これらの受容体:リガンド相互作用の考えられる影響を判定するために、IB T細胞シグネチャ及びIB APC/腫瘍シグネチャの発生率を分析した。T細胞免疫ブロッカーの存在は、適応症に亘りTeff分布を追跡した(図22)。全ての適応症において、CTLA4がIB T細胞の最も低い発生率を提示し、一方、Tim3(HVACR2)が最も高い発生率を有した(図26)。PD−1及びLag3は、IB T細胞シグネチャを2番目に豊富に有した。BTLAの発現は、OvCa及びCRC中で低減されるか、または黒色腫、RCC、UBC、BC、及びNSCLC中でのPD1及びLag3と同様に発現された。これらのデータは、腫瘍タイプにかかわらず、浸潤性Teffは同様に阻害性受容体を備えることを示唆する。
適応症に亘る免疫遺伝子セットの階層的クラスタリングを行い、腫瘍タイプ間の免疫環境を分析した。がん適応症に亘り免疫シグネチャ遺伝子セット中に高度の異種性が認められ、いくつかの腫瘍は注目すべき免疫の存在を示し、一方、他のものは「免疫砂漠」であった(図28)。
HCCの4つの病因群間の遺伝子セット発現の差異を、クラスカルワリス検定を使用して査定し、ボッフェローニ法を使用して試験の多重性を調整した。表13は、各病因群における発現の中央値と、クラスカルワリス検定p値を共に示す。HCCの病因と著しく関連する免疫サブセットは発見されなかったが、Teffサブセットは、数の上ではウイルスダブルポジティブ群中でより高かった(図34及び35)。免疫遺伝子発現の差異を、ラスカルワリス検定を使用して表14に示される96個の免疫遺伝子のそれぞれについて査定し、多重性の補正は適用しなかった。これらのデータは、異種の腫瘍の病因にもかかわらず、肝臓腫瘍は、類似の免疫微小環境を共通して有することを示唆する。
Claims (67)
- 免疫療法剤での治療のためのがんを有する患者を選択する方法であって、前記患者から取得した生体試料中の免疫細胞遺伝子シグネチャの発現レベルを判定することを含み、前記免疫細胞遺伝子シグネチャは、以下の遺伝子:
CD8A、GZMA、GZMB、IFNγ、EOMES、もしくはPRF1;
FOXP3;
MS4A1もしくはCD48;
CD79A、MS4A1、CD19、STAP1、KIAA0125、POU2AF1、もしくはFCRL5;
NCAM1もしくはNKP46;
KLRC3、KLRK1、KLRC2、もしくはKLRD1;
ITGAM、ITGAX、CD1C、もしくはCLEC4C;
CD68、CD163、ITGAM、ITGAX、もしくはCD14;
LAPTM5、LAIR1、CD4、CSF1R、CD163、ADAP2、CD68、MRC1、CD45RO、SLA、MSR1、FPR3、FCGR2A、もしくはFCGR3A;
IL17AもしくはIL17F
CCL2、IL1B、IL8、IL6、もしくはPTGS2;
CD3D、CD3E、CD2、CD3G、CD6、TRAT1、CD28、もしくはLCK;
CTLA4、BTLA、LAG3、HAVCR2、もしくはPDCD1;
CTLA4、BTLA、LAG3、HAVCR2、PDCD1、もしくはTIGIT;
CD276、PDL1、PDL2、もしくはIDO1;
CD274、PDL2、IDO1、もしくはPVR;
CX3CL1、CXCL9、CXCL10、CXCR3、CCL21、もしくはCCL22;
CD4、IL2RA、もしくはCD69;
TAPBP、TAP1、TAP2、PSMB9、もしくはPSMB8;
CD40、CD80、CD86、CD70、もしくはGITRL;
CD27、CD28、ICOS、TNFRSF4、TNFRSF14、TNFRSF18、TNFSF14、もしくはCD226;
GNLY、KLRK1、KLRB1、GZMH、GZMA、KLRD1、もしくはNKG7;または
FAP、FN1、MMP2、BGN、LOXL2、PDPN、PDGFRB、COL4A1、COL4A2、COL5A1、もしくはCOL8A1、のうちの1つ以上を含み、
中央値レベルと比べた、前記免疫細胞遺伝子シグネチャ中の前記1つ以上の遺伝子の発現レベルの変化は、免疫療法剤での治療のための患者を特定する、前記方法。 - 前記患者に、彼らが前記免疫療法剤に対して応答性である高い見込みを有していることを伝えるステップを更に含む、請求項1に記載の方法。
- 前記患者に特定の免疫療法剤の推奨を提供するステップを更に含む、請求項1または2に記載の方法。
- 前記患者が免疫療法剤から利益を得られると判定された場合、前記患者に免疫療法剤を投与するステップを更に含む、請求項1〜3のいずれか1項に記載の方法。
- 前記免疫療法剤が、活性化免疫療法剤または抑制免疫療法剤である、請求項1〜4のいずれか1項に記載の方法。
- CD8A、GZMA、GZMB、IFNγ、EOMES、またはPRF1のうちの1つ以上の発現レベルが、腫瘍微小環境中のTエフェクター(Teff)細胞の存在と相関する、請求項1〜5のいずれか1項に記載の方法。
- CD8A、GZMA、GZMB、IFNγ、EOMES、またはPRF1のうちの1つ以上の発現レベルの増加は、前記患者が活性化免疫療法剤から利益を得られる見込みがあることを示す、請求項6に記載の方法。
- 前記活性化免疫療法剤が、CD28、OX40、GITR、CD137、CD27、ICOS、HVEM、NKG2D、MICA、または2B4アゴニストを含む、請求項7に記載の方法。
- FOXP3の発現レベルが、前記腫瘍微小環境中の調節性T(Treg)細胞の存在と相関する、請求項1〜5のいずれか1項に記載の方法。
- FOXP3の発現レベルの増加は、前記患者が抑制免疫療法剤から利益を得られる見込みがあることを示す、請求項9に記載の方法。
- 前記抑制免疫療法剤が、CTLA−4、PD−1軸、TIM−3、BTLA、VISTA、LAG−3、B7H4、CD96、TIGIT、またはCD226アンタゴニストを含む、請求項10に記載の方法。
- (a)MS3A1もしくはCD48のうちの1つ以上、及び/または(b)CD79A、MS4A1、CD19、STAP1、KIAA0125、POU2AF1、もしくはFCRL5のうちの1つ以上の発現レベルが、前記腫瘍微小環境中のB細胞の存在と相関する、請求項1〜5のいずれか1項に記載の方法。
- (a)NCAM1もしくはNKP46のうちの1つ以上、及び/または(b)KLRC3、KLRK1、KLRC2、もしくはKLRD1の発現レベルが、前記腫瘍微小環境中のNK細胞の存在と相関する、請求項1〜5のいずれか1項に記載の方法。
- (a)ITGAM、ITGAX、CD1C、もしくはCLEC4Cのうちの1つ以上の発現レベルが、前記腫瘍微小環境中の骨髄細胞の存在と相関し、
(b)CD68、CD163、ITGAM、ITGAX、もしくはCD14のうちの1つ以上の発現レベルが、前記腫瘍微小環境中のマクロファージ細胞の存在と相関し、かつ/または
(c)LAPTM5、LAIR1、CD4、CSF1R、CD163、ADAP2、CD68、MRC1、CD45RO、SLA、MSR1、FPR3、FCGR2A、もしくはFCGR3Aのうちの1つ以上の発現レベルが、前記腫瘍微小環境中のM2マクロファージ細胞の存在と相関する、請求項1〜5のいずれか1項に記載の方法。 - IL17AまたはIL17Fのうちの1つ以上の発現レベルが、前記腫瘍微小環境中のTh17細胞の存在と相関する、請求項1〜5のいずれか1項に記載の方法。
- CCL2、IL1B、IL8、IL6、またはPTGS2のうちの1つ以上の発現レベルが、前記腫瘍微小環境中の炎症細胞の存在と相関する、請求項1〜5のいずれか1項に記載の方法。
- (a)CTLA4、BTLA、LAG3、HAVCR2、もしくはPDCD1のうちの1つ以上、及び/または(b)CTLA4、BTLA、LAG3、HAVCR2、PDCD1、もしくはTIGITのうちの1つ以上の発現レベルが、前記腫瘍微小環境中のT細胞免疫ブロッカーの存在と相関する、請求項1〜5に記載の方法。
- (a)CD276、PDL1、PDL2、もしくはIDO1のうちの1つ以上、及び/または(b)CD274、PDL2、IDO1、もしくはPVRのうちの1つ以上の発現レベルが、前記腫瘍微小環境中の抗原提供細胞(APC)免疫ブロッカーの存在と相関する、請求項1〜5のいずれか1項に記載の方法。
- CX3CL1、CXCL9、CXCL10、CXCR3、CCL21、またはCCL22のうちの1つ以上の発現レベルが、T細胞走化性と相関する、請求項1〜5のいずれか1項に記載の方法。
- CD4、IL2RA、またはCD69のうちの1つ以上の発現レベルが、前記腫瘍微小環境中の活性化CD4 T細胞の存在と相関する、請求項1〜5のいずれか1項に記載の方法。
- TAPBP、TAP1、TAP2、PSMB9、またはPSMB8のうちの1つ以上の発現レベルが、前記腫瘍微小環境中の抗原プロセシングの存在と相関する、請求項1〜5のいずれか1項に記載の方法。
- CD40、CD80、CD86、CD70、またはGITRLのうちの1つ以上の発現レベルが、前記腫瘍微小環境中の共刺激リガンドの存在と相関する、請求項1〜5のいずれか1項に記載の方法。
- CD27、CD28、ICOS、TNFRSF4、TNFRSF14、TNFRSF18、TNFSF14、またはCD226のうちの1つ以上の発現レベルが、前記腫瘍微小環境中の共刺激受容体の存在と相関する、請求項1〜5のいずれか1項に記載の方法。
- GNLY、KLRK1、KLRB1、GZMH、GZMA、KLRD1、またはNKG7のうちの1つ以上の発現レベルが、前記腫瘍微小環境中の細胞溶解反応及び/または細胞溶解性細胞の存在と相関する、請求項1〜5のいずれか1項に記載の方法。
- FAP、FN1、MMP2、BGN、LOXL2、PDPN、PDGFRB、COL4A1、COL4A2、COL5A1、またはCOL8A1のうちの1つ以上の発現レベルが、前記腫瘍微小環境中の活性化線維芽細胞の存在と相関する、請求項1〜5のいずれか1項に記載の方法。
- CD3D、CD3E、CD2、CD3G、CD6、TRAT1、CD28、またはLCKのうちの1つ以上の発現レベルが、前記腫瘍微小環境中のT細胞の存在と相関する、請求項1〜5のいずれか1項に記載の方法。
- CD8A、GZMA、GZMB、IFNγ、EOMES、またはPRF1のうちの1つ以上の発現レベルが判定される、請求項1〜26のいずれか1項に記載の方法。
- FOXP3の発現レベルが判定される、請求項1〜26のいずれか1項に記載の方法。
- (a)
MS4A1もしくはCD48のうちの1つ以上、及び/または(b)CD79A、MS4A1、CD19、STAP1、KIAA0125、POU2AF1、もしくはFCRL5のうちの1つ以上の発現レベルが判定される、請求項1〜26のいずれか1項に記載の方法。 - (a)
NCAM1及びNKP46のうちの1つ以上、ならびに/または(b)KLRC3、KLRK1、KLRC2、もしくはKLRD1の発現レベルが判定される、請求項1〜26のいずれか1項に記載の方法。 - (a)
ITGAM、ITGAX、CD1C、もしくはCLEC4Cのうちの1つ以上、(b)CD68、CD163、ITGAM、ITGAX、もしくはCD14のうちの1つ以上、及び/または(c)LAPTM5、LAIR1、CD4、CSF1R、CD163、ADAP2、CD68、MRC1、CD45RO、SLA、MSR1、FPR3、FCGR2A、もしくはFCGR3Aのうちの1つ以上の発現レベルが判定される、請求項1〜26のいずれか1項に記載の方法。 - IL17AまたはIL17Bのうちの1つ以上の発現レベルが判定される、請求項1〜26のいずれか1項に記載の方法。
- CD3D、CD3E、CD2、CD3G、CD6、TRAT1、CD28、またはLCKのうちの1つ以上の発現レベルが判定される、請求項1〜26のいずれか1項に記載の方法。
- CCL2、IL1B、IL8、IL6、またはPTGS2のうちの1つ以上の発現レベルが判定される、請求項1〜26のいずれか1項に記載の方法。
- (a)
CTLA4、BTLA、LAG3、HAVCR2、もしくはPDCD1のうちの1つ以上、及び/または(b)CTLA4、BTLA、LAG3、HAVCR2、PDCD1、もしくはTIGITのうちの1つ以上の発現レベルが判定される、請求項1〜26のいずれか1項に記載の方法。 - (a)
CD276、PDL1、PDL2、もしくはIDO1のうちの1つ以上、及び/または(b)CD274、PDL2、IDO1、もしくはPVRのうちの1つ以上の発現レベルが判定される、請求項1〜26のいずれか1項に記載の方法。 - CX3CL1、CXCL9、CXCL10、CXCR3、CCL21、またはCCL22のうちの1つ以上の発現レベルが判定される、請求項1〜26のいずれか1項に記載の方法。
- CD4、IL2RA、またはCD69のうちの1つ以上の発現レベルが判定される、請求項1〜26のいずれか1項に記載の方法。
- TAPBP、TAP1、TAP2、PSMB9、またはPSMB8のうちの1つ以上の発現レベルが判定される、請求項1〜26のいずれか1項に記載の方法。
- CD40、CD80、CD86、CD70、またはGITRLのうちの1つ以上の発現レベルが判定される、請求項1〜26のいずれか1項に記載の方法。
- CD27、CD28、ICOS、TNFRSF4、TNFRSF14、TNFRSF18、TNFSF14、またはCD226のうちの1つ以上の発現レベルが判定される、請求項1〜26のいずれか1項に記載の方法。
- GNLY、KLRK1、KLRB1、GZMH、GZMA、KLRD1、またはNKG7のうちの1つ以上の発現レベルが判定される、請求項1〜26のいずれか1項に記載の方法。
- FAP、FN1、MMP2、BGN、LOXL2、PDPN、PDGFRB、COL4A1、COL4A2、COL5A1、またはCOL8A1のうちの1つ以上の発現レベルが判定される、請求項1〜26のいずれか1項に記載の方法。
- 表2の遺伝子のうちの1つ以上の発現レベルが判定される、請求項1〜26のいずれか1項に記載の方法。
- 表3の遺伝子のうちの1つ以上の発現レベルが判定される、請求項1〜26のいずれか1項に記載の方法。
- 表4の遺伝子のうちの1つ以上の発現レベルが判定される、請求項1〜26のいずれか1項に記載の方法。
- 表5の遺伝子のうちの1つ以上の発現レベルが判定される、請求項1〜26のいずれか1項に記載の方法。
- 表6の遺伝子のうちの1つ以上の発現レベルが判定される、請求項1〜26のいずれか1項に記載の方法。
- 表7の遺伝子のうちの1つ以上の発現レベルが判定される、請求項1〜26のいずれか1項に記載の方法。
- 表8の遺伝子のうちの1つ以上の発現レベルが判定される、請求項1〜26のいずれか1項に記載の方法。
- 表9の遺伝子のうちの1つ以上の発現レベルが判定される、請求項1〜26のいずれか1項に記載の方法。
- 以下の遺伝子シグネチャ
CD8A、GZMA、GZMB、IFNγ、EOMES、もしくはPRF1;
FOXP3;
MS4A1もしくはCD48;
CD79A、MS4A1、CD19、STAP1、KIAA0125、POU2AF1、もしくはFCRL5;
NCAM1もしくはNKP46;
KLRC3、KLRK1、KLRC2、もしくはKLRD1;
ITGAM、ITGAX、CD1C、もしくはCLEC4C;
CD68、CD163、ITGAM、ITGAX、もしくはCD14;
LAPTM5、LAIR1、CD4、CSF1R、CD163、ADAP2、CD68、MRC1、CD45RO、SLA、MSR1、FPR3、FCGR2A、もしくはFCGR3A;
IL17AもしくはIL17F;
CCL2、IL1B、IL8、IL6、もしくはPTGS2;
CD3D、CD3E、CD2、CD3G、CD6、TRAT1、CD28、もしくはLCK;
CTLA4、BTLA、LAG3、HAVCR2、もしくはPDCD1;
CTLA4、BTLA、LAG3、HAVCR2、PDCD1、もしくはTIGIT;
CD276、PDL1、PDL2、もしくはIDO1;
CD274、PDL2、IDO1、もしくはPVR;
CX3CL1、CXCL9、CXCL10、CXCR3、CCL21、もしくはCCL22;
CD4、IL2RA、もしくはCD69;
TAPBP、TAP1、TAP2、PSMB9、もしくはPSMB8;
CD40、CD80、CD86、CD70、もしくはGITRL;
CD27、CD28、ICOS、TNFRSF4、TNFRSF14、TNFRSF18、TNFSF14、もしくはCD226;
GNLY、KLRK1、KLRB1、GZMH、GZMA、KLRD1、もしくはNKG7;及び
FAP、FN1、MMP2、BGN、LOXL2、PDPN、PDGFRB、COL4A1、COL4A2、COL5A1、またはCOL8A1のそれぞれの遺伝子のうちの1つ以上の発現レベルが判定される、請求項1〜26のいずれか1項に記載の方法。 - CD8A、GZMA、GZMB、IFNγ、EOMES、またはPRF1のうちの1つ以上の発現レベル対FOXP3の発現レベルの比率を判定することを更に含む、請求項1〜52のいずれか1項に記載の方法。
- CD8A、GZMA、GZMB、IFNγ、EOMES、またはPRF1のうちの1つ以上の発現レベル対FOXP3の発現レベルの比率が高い場合、前記患者は活性化免疫療法剤から利益を得られる見込みがある、請求項53に記載の方法。
- CD8A、GZMA、GZMB、IFNγ、EOMES、またはPRF1のうちの1つ以上の発現レベル対FOXP3の発現レベルの比率が低い場合、前記患者は抑制免疫療法剤から利益を得られる見込みがある、請求項53に記載の方法。
- Teff細胞対Treg細胞の比率を判定することを更に含む、請求項1〜55のいずれか1項に記載の方法。
- Teff対Tregの比率が高い場合、前記患者は活性化免疫療法剤から利益を得られる見込みがある、請求項56に記載の方法。
- Teff対Tregの比率が低い場合、前記患者は抑制免疫療法剤から利益を得られる見込みがある、請求項56に記載の方法。
- 前記活性化免疫療法剤が、CD28、OX40、GITR、CD137、CD27、ICOS、HVEM、NKG2D、MICA、または2B4アゴニストを含む、請求項54または57に記載の方法。
- 前記抑制免疫療法剤が、CTLA−4、PD−1軸、TIM−3、BTLA、VISTA、LAG−3、B7H4、CD96、TIGIT、またはCD226アンタゴニストを含む、請求項55または58に記載の方法。
- 前記方法が、応答に関する投与前予後診断を患者に提供するために、免疫療法剤の投与の前に実施される、請求項1〜60のいずれか1項に記載の方法。
- 前記がんが、乳がん、黒色腫、非小細胞肺がん(NSCLC)、膀胱がん、腎細胞がん腫、結腸直腸がん、卵巣がん、胃がん、または肝臓がんである、請求項1〜61のいずれか1項に記載の方法。
- 前記がんが、原発がん、進行がん、難治性がん、または再発がんである、請求項62に記載の方法。
- 前記乳がんが、ホルモン受容体+(HR+)、HER2+、またはトリプルネガティブ(TN)乳がんである、請求項62に記載の方法。
- 前記NSCLCが、非扁平上皮NSCLCまたは扁平上皮NSCLCである、請求項62に記載の方法。
- 前記患者から取得した前記生体試料中の前記免疫細胞遺伝子シグネチャの発現が、mRNAを測定することによって検出される、請求項1〜65のいずれか1項に記載の方法。
- 前記患者から取得した前記生体試料中の前記免疫細胞遺伝子シグネチャの発現が、血漿タンパク質レベルを測定することによって検出される、請求項1〜65のいずれか1項に記載の方法。
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US20170260594A1 (en) | 2017-09-14 |
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