JP2022174309A - がんの重症度を評価するためのtim-3 - Google Patents
がんの重症度を評価するためのtim-3 Download PDFInfo
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- C12Q2600/158—Expression markers
Abstract
Description
本発明は、腫瘍試料中のTIM-3の発現レベルを測定することによって、がんの重症度を評価するための方法に関する。
処置の開発及びより正確な患者のスクリーニングを可能とする試験の開発における、多くの進展にも関わらず、がんは依然として世界中の死亡の第一原因である。
本発明者らは、TIM-3(T細胞免疫グロブリン及びムチン-ドメイン含有-3)の発現が、固形癌を患っている患者の予後に相関し得ると決定した。本発明者らは、腫瘍内の適応免疫応答のバイオマーカーの発現レベルに対する、TIM-3の発現レベルの特定の比が、患者の生存期間を極めて予測するものであることを特に実証した。
・腫瘍内のTIM-3/(適応免疫応答のバイオマーカー)の比を測定することによる、がんの予後予測
-腫瘍の中心(CT)における、適応免疫応答のバイオマーカーの発現に対する、TIM-3の発現の高い比は、良好な予後に関連し;一方
-腫瘍の浸潤周辺部分(IM)における、適応免疫応答のバイオマーカーの発現に対する、TIM-3の発現の高い比は、悪い予後に関連している
ことを特に決定した。
i)固形癌を患っている患者から得られた腫瘍組織試料中の腫瘍の中心(CT)における、TIM-3の発現レベル及び適応免疫応答のバイオマーカーの発現レベルを決定する工程;
ii)腫瘍の中心における該バイオマーカーの発現レベルに対する、TIM-3の発現レベルの比を決定する工程;
iii)前記の比を、予め決定された基準値と比較する工程;
iv)前記の比が、予め決定された基準値より高い場合に、良好な予後予測を与える工程を含む、該患者の予後を決定するための方法に関する。
i)固形癌を患っている患者から得られた腫瘍組織試料中の浸潤周辺部分(IM)における、TIM-3の発現レベル及び適応免疫応答のバイオマーカーの発現レベルを決定する工程;
ii)腫瘍の浸潤周辺部分における、該バイオマーカーの発現レベルに対する、TIM-3の発現レベルの比を決定する工程;
iii)前記の比を、予め決定された基準値と比較する工程;
iv)前記の比が、予め決定された基準値より高い場合に、悪い予後予測を与える工程
を含む、該患者の予後を決定するための方法に関する。
i)固形癌を患っている患者から得られた腫瘍組織試料中の腫瘍の中心(CT)及び腫瘍の浸潤周辺部分(IM)における、TIM-3の発現レベル及び適応免疫応答のバイオマーカーの発現レベルを決定する工程;
ii)腫瘍の中心(CT比)及び腫瘍の浸潤周辺部分(IM比)における、該バイオマーカーの発現レベルに対する、TIM-3の発現レベルの比を決定する工程;
iii)前記のCT比及びIM比を、腫瘍の中心(CT基準値)について及び腫瘍の浸潤周辺部分(IM基準値)について決定された基準値とそれぞれ比較する工程;
iv)CT比がCT基準値よりも高く、IM比がIM基準値よりも低い場合に、良好な予後予測を与える工程;
-CT比及びIM比がどちらも、CT基準値及びIM基準値よりもそれぞれ高い場合、又は、CT比及びIM比がどちらもCT基準値及びIM基準値よりもそれぞれ低い場合に、中間の予後予測を与える工程;並びに
-CT比がCT基準値よりも低く、IM比がIM基準値よりも高い場合に、悪い予後予測を与える工程
を含む、該患者の予後を決定するための方法に関する。
a)がん患者に由来する腫瘍組織試料の収集物を準備する工程;
b)工程a)で準備された各腫瘍組織試料について、対応するがん患者についての実際の予後に関連した情報(すなわち、無病生存期間(DFS)又は全生存期間(OS))を準備する工程;
c)一連の任意の定量値を準備する工程;
d)工程a)で準備された収集物に含有されている各腫瘍組織試料について腫瘍全体、又は腫瘍の浸潤周辺部分、又は腫瘍の中心における、TIM-3/(適応免疫応答のバイオマーカー)の比を決定する工程;
e)工程c)で準備された1つの特定の任意の定量値で、該腫瘍組織試料を2つの群にそれぞれ分類する工程:(i)前記の一連の定量値に含まれる前記の任意の定量値よりも低い前記の比に関する定量値を示す、組織腫瘍試料を含む第一の群;(ii)前記の一連の定量値に含まれる前記の任意の定量値よりも高い前記の比に関する定量値を示す、腫瘍組織試料を含む第二の群;それによって、前記の特定の定量値により、2つの群の腫瘍組織試料が得られ、ここでの各群の腫瘍組織試料は別々に列挙されている;
f)(i)工程e)で得られた定量値と、(ii)工程f)で定義された第一の群及び第二の群に含まれる腫瘍組織試料が由来する患者の実際の臨床転帰との間の統計学的有意性を計算する工程;
g)工程d)で得られたあらゆる任意の定量値が試験されるまで、工程f)及びg)を反復する工程;
h)最も高い統計学的有意性(最も有意)が工程g)で計算された任意の定量値からなるとして、前記の予め決定された基準値(「カットオフ値」)を設定する工程
を含む方法を実施することによって予め決定され得る。
・TIM-3のみが、固形癌の転帰の決定、及び処置に対する応答の予測を可能とする。
i)固形癌を患っている患者から得られた腫瘍組織試料中の、TIM-3の発現レベルを測定する工程;
ii)前記のTIM-3の発現レベルを、予め決定された基準値と比較する工程;
iii)TIM-3の発現レベルが、予め決定された基準値よりも高い場合に、良好な予後予測を与える工程
を含む、該患者の予後を決定するための方法に関する。
i)固形癌を患っている患者から得られた腫瘍組織試料中の、TIM-3の発現レベル及び適応免疫応答のバイオマーカーの発現レベルを測定する工程;
ii)前記TIM-3の発現レベル及び前記バイオマーカーの発現レベルを、予め決定された基準値と比較する工程;
iii)TIM-3の発現レベル及びバイオマーカーの発現レベルがどちらも、それらの予め決定された基準値よりも高い場合、良好な予後予測を与える工程
を含む、該患者の予後を決定するための方法に関する。
i)該患者から得られた腫瘍組織試料中において、TIM-3の発現レベル及び適応免疫応答のバイオマーカーの発現レベルを測定する工程;
ii)前記TIM-3発現レベル及び前記バイオマーカー発現レベルを、予め決定された基準値と比較する工程;
iii)TIM-3の発現レベル及び該バイオマーカーの発現レベルのどちらも、それらの予め決定された基準値よりも高い場合に、該患者は抗癌処置を有利に受けるであろうことを評価する工程
を含む。
実施例1:CD3、CD8、CD45RO、又はCD4の発現レベルに対する、TIM-3の発現レベルの比は、患者の予後を予測する
結腸直腸腫瘍(n=107)の中心(CT)及び浸潤周辺部分(IM)の組織マイクロアレイを構築した。浸潤周辺部分領域の評価を、標準的なパラフィン切片に対して実施し、これは組織の組織形態学的変化に基づいていた。浸潤周辺部分は、1mmの範囲で、悪性の腺から宿主組織を隔てている境界を中心とした領域として定義された。TMA切片をCD3及びTIM3に対するモノクローナル抗体と共にインキュベートした(60分間、室温)。Envision+システム(二次抗体に結合させた酵素結合ポリマー骨格)(ダコ社、グロストラップ、デンマーク)及びDAB色素原を適用した(ダコ社、グロストラップ、デンマーク)。二重染色を、リン酸にコンジュゲートさせた二次抗体及びファストブルー色素原を用いて明らかとした。単一染色では、組織切片を、ハリス・ヘマトキシリン(シグマ・アルドリッチ社、セントルイス、ミズーリ州)を用いて対比染色した。アイソタイプの一致したマウスモノクローナル抗体を、陰性対照として使用した。スライドを、画像分析ワークステーション(Spot Browser、Excilone社、エランクール、フランス)を使用して分析した。多色で高分解能の局所画像(740×540ピクセル、1.181μm/ピクセルの分解能)が得られた(200倍の拡大率)。密度は、組織表面積1単位あたりの陽性細胞の数として記録された。
1)遺伝子発現のための材料、方法(アフィメトリックスヒトゲノムU133プラス2.0アレイ)。組織試料材料(n=105)を手術後15分以内に瞬間凍結させ、液体窒素中に保存した。凍結した腫瘍標本を、RNA抽出のために無作為に選択した。全RNAを、RNeasy単離キット(キアゲン社、バレンシア、カリフォルニア州)を用いたホモジナイズによって単離した。バイオアナライザ(アジレント・テクノロジーズ社、パロアルト、カリフォルニア州)を使用して、RNAの完全性及び量を評価した。このRNAから、110個のアフィメトリックス遺伝子チップを、HG-U133A GeneChip3’ IVT Expressキットを使用してImmunomeと同じプラットフォーム(HG-U133Aプラス)上で実施した。生データを、GCRMAアルゴリズムを使用して標準化した。最後に、遺伝子発現データのlog2強度をさらなる分析のために使用した。
遺伝子発現オムニバスのレポジトリ(Subramanian A et al., 2005)を、公共的に入手可能な癌データについてスクリーニングした。大腸癌遺伝子発現データマトリックス(アフィメトリックスヒトゲノムU133プラス2.0アレイ)及びデータセットGSE40967(Marisa L et al. 2013、n=589)及びGSE31595(n=37)からの臨床情報をダウンロードした。患者を、CD8A発現レベルに基づいて選別し、高い(Hi)及び低い(Lo)発現の患者群を規定した(最適なカットオフ値)。同じように、Hi及びLo患者群を、TIM3(HAVR2)発現に基づいて規定した。補助化学療法を受けたCD8A及びTIM3の両方の遺伝子の発現が高い患者(YESHiHi)の生存期間を、これらの遺伝子の発現が高い処置を受けていない患者(NOHiHi)及び残りの集団と比較した(無病生存期間についてのカプランマイヤー(KM)曲線)。0.05より小さなログランクp値を有意と判断した。
Claims (7)
- 固形癌を患っている患者から得られた腫瘍組織試料中において、適応免疫応答のバイオマーカーの発現レベルに対するTIM-3の発現レベルの比を決定する工程を含む、該患者の予後を決定するための方法。
- 前記方法が、以下の工程:
i)前記患者から得られた腫瘍組織試料の腫瘍の中心(CT)におけるTIM-3の発現レベルと、適応免疫応答のバイオマーカーの発現レベルを決定する工程;
ii)腫瘍の中心における該バイオマーカーの発現レベルに対する、TIM-3の発現レベルの比を決定する工程;
iii)前記の比を、予め決定された基準値と比較する工程;
iv)前記の比が、予め決定された基準値よりも高い場合、良好な予後予測を与える工程
を含む、請求項1記載の方法。 - 前記方法が、以下の工程:
i)前記患者から得られた腫瘍組織試料中の浸潤周辺部分(IM)におけるTIM-3の発現レベルと、適応免疫応答のバイオマーカーの発現レベルを決定する工程;
ii)腫瘍の浸潤周辺部分における該バイオマーカーの発現レベルに対する、TIM-3の発現レベルの比を決定する工程;
iii)前記の比を、予め決定された基準値と比較する工程;
iv)前記の比が、予め決定された基準値よりも高い場合、悪い予後予測を与える工程
を含む、請求項1記載の方法。 - i)固形癌を患っている患者から得られた腫瘍組織試料中において、TIM-3の発現レベルを測定する工程;
ii)前記TIM-3発現レベルを、予め決定された基準値と比較する工程;
iii)TIM-3の発現レベルが予め決定された基準値よりも高い場合、良好な予後予測を与える工程
を含む、該患者の予後を決定するための方法。 - 工程i)において適応免疫応答のバイオマーカーの発現レベルをさらに測定し、工程ii)において前記TIM-3発現レベル及び前記バイオマーカー発現レベルを、予め決定された基準値と比較し、TIM-3の発現レベル及びバイオマーカーの発現レベルの両方が、それらの予め決定された基準値よりも高い場合に、良好な予後予測を与える、請求項4記載の方法。
- 固形癌を患っている患者が、抗癌処置を有利に受けるであろうかどうかを決定するための方法であって、該方法は、
i)該患者から得られた腫瘍組織試料中において、TIM-3の発現レベル及び適応免疫応答のバイオマーカーの発現レベルを測定する工程;
ii)前記TIM-3発現レベル及び前記バイオマーカー発現レベルを、予め決定された基準値と比較する工程;
iii)TIM-3の発現レベル及び該バイオマーカーの発現レベルの両方が、それらの予め決定された基準値よりも高い場合に、該患者が、抗癌処置を有利に受けるであろうと評価する工程
を含む、方法。 - 前記抗癌処置が免疫療法剤である、請求項6記載の方法。
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