JP2020535230A - 腫瘍変異負荷 - Google Patents
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- JP2020535230A JP2020535230A JP2020538768A JP2020538768A JP2020535230A JP 2020535230 A JP2020535230 A JP 2020535230A JP 2020538768 A JP2020538768 A JP 2020538768A JP 2020538768 A JP2020538768 A JP 2020538768A JP 2020535230 A JP2020535230 A JP 2020535230A
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Abstract
Description
本発明がより容易に理解されるために、ある特定の用語は、以下に定義される。当業者は、ある特定の用語の定義が、明細書の他の場所に提供され得ること、及び/または文脈から明らかになるであろうことを理解するであろう。
[発明を実施するための形態]
いくつかの実施形態では、本発明はがんの治療に関する。いくつかの実施形態では、本開示に従って治療され得るある特定の例示的ながんは、例えば、副腎皮質癌、星細胞腫、基底細胞癌、カルチノイド、心臓の、胆管細胞癌、脊索腫、慢性骨髄増殖性腫瘍、頭蓋咽頭癌、非浸潤性乳管癌、上衣腫、眼球内黒色腫、消化管カルチノイド、消化管間質腫瘍(GIST)、妊娠性絨毛性疾患、神経膠腫、組織球症、白血病(例えば、急性リンパ性白血病(ALL)、急性骨髄性白血病(AML)、慢性リンパ性白血病(CLL)、慢性骨髄性白血病(CML)、有毛細胞白血病、骨髄性白血病、及び骨髄性白血病)、リンパ腫(例えば、バーキットリンパ腫(非ホジキンリンパ腫)、皮膚T細胞リンパ腫、ホジキンリンパ腫、菌状息肉症、セザリー症候群、エイズ関連リンパ腫、濾胞性リンパ腫、びまん性大細胞型B細胞リンパ腫)、黒色腫、メルケル細胞癌腫、中皮腫、骨髄腫(例、多発性骨髄腫)、骨髄異形成症候群、乳頭腫症、傍神経節腫、褐色細胞腫、胸膜肺芽腫、網膜芽細胞腫、肉腫(例えば、ユーイング肉腫、カポジ肉腫、骨肉腫、横紋筋肉腫、子宮肉腫、脈管肉腫)、ウィルムス腫瘍、及び/または副腎皮質、肛門、虫垂、胆管、膀胱、骨、脳、乳房、気管支、中枢神経系、子宮頸部、結腸、子宮内膜、食道、目、卵管、胆嚢、消化管、生殖細胞、頭頸部、心臓、腸、腎臓(例えば、ウィルムス腫瘍)、喉頭、肝臓、肺(例えば、非小細胞肺癌、小細胞肺癌)、口、鼻腔、口腔、卵巣、膵臓、直腸、皮膚、胃、精巣、喉、甲状腺、陰茎、咽頭、腹膜、下垂体、前立腺、直腸、唾液腺、尿管、尿道、子宮、膣、または外陰のがんを含む。
免疫療法
CTLA−4
PD−1
CTLA−4またはPD−1遮断抗体での単独療法がある特定のがんを有する複数の患者の生存を有意に延長したものの、複数の患者が療法に応答しない場合が存在する。以前の研究は、イピリムマブ(CTLA−4阻害剤)及びニボルマブ(PD−1阻害剤)での組み合わせ治療がいずれか単独の治療よりも良い応答を誘導したことを示した。18、20いくつかの実施形態では、免疫療法は、本開示に従って、PD−1阻害療法及びCTLA−4阻害療法の両方を含む。ある特定の実施形態では、免疫療法(例えば、免疫チェックポイント調節因子療法)は、CTLA−4及び/またはPD−1に関与する相互作用に干渉する薬剤(例えば、抗体薬剤)での治療に関与する。いくつかの実施形態では、免疫療法(例えば、免疫チェックポイント調節因子療法)は、CTLA−4、CD80、CD86、PD−1またはPD−L1のうちの1つ以上と特異的に相互作用する薬剤(例えば、抗体薬剤)の投与に関与する。いくつかの実施形態では、かかる療法は、アテゾリズマブ、アベルマブ、デュルバルマブ、イピリムマブ、ニボルマブ、ペムブロリズマブ、及び/またはトレメリムマブのうちの1つ以上の投与に関与する。
とりわけ、本開示は、腫瘍変異負荷がある特定のがんに対する免疫療法治療の臨床的有効性を予測できることを示す。本開示は、とりわけ、ある特定の場合、より高い腫瘍変異負荷を有する個体が、有意により低い腫瘍変異負荷を有する個体よりも免疫療法に正に応答しそうであることを確立する。本開示は、とりわけ、ある特定の場合、より高い腫瘍変異負荷を有し既に免疫療法を受けた個体が、有意により低い腫瘍変異負荷を有する個体よりも免疫療法に正に応答しそうであることを確立する。
本開示は、とりわけ、意味のある制限ががん細胞の変異解析に課されることができ、そのうえ、かかる制限の使用が意外にも治療(例えば、継続した及び/または延長したまたは修正された免疫療法)に対する応答性を効果的に予測する腫瘍変異負荷閾値を定義及び/または提供するという洞察を包含する。いくつかの実施形態では、本明細書に記載の腫瘍変異負荷閾値は、免疫療法(例えば、免疫チェックポイント調節因子療法、例えば、PD−1阻害剤またはCTLA−4阻害剤)に対する応答に相関し、及び/または免疫療法(例えば、免疫チェックポイント調節因子療法、例えば、PD−1阻害剤またはCTLA−4阻害剤)に対する応答を予測する。
がんは、種々の既知の技術のうちのいずれかを使用する本明細書に記載の突然変異及び/またはネオエピトープ(例えば、腫瘍変異負荷及び/またはネオエピトープ負荷及び/またはネオ抗原同一性、及び/またはネオエピトープの性質、レベル、及び/または頻度)を検出するために選別され得る。いくつかの実施形態では、特定の突然変異またはネオエピトープ、またはそれらの発現は、核酸レベルで(例えば、DNAまたはRNAにおいて)検出される。当業者は、突然変異またはネオエピトープ、またはそれらの発現が、がん細胞からのDNAまたはRNAを含む試料において検出され得ることを認識するであろう。さらに、当業者は、がん細胞からのDNAまたはRNAを含む試料が、循環腫瘍DNA(ctDNA)、細胞遊離DNA(cfDNA)、細胞、組織、または臓器を含むがこれらに限定されないことを理解するであろう。いくつかの実施形態では、突然変異またはネオエピトープ、またはそれらの発現は、タンパク質レベルで検出される(例えば、がん細胞からのポリペプチドを含む試料におけるものであり、試料は、細胞、組織、または臓器を含むがこれらに限定されないポリペプチド複合体または他の高次構造体である)。
ヒト白血球抗原
治療
免疫チェックポイント調節因子の投与
併用療法
本実施例は、標的化シークエンシングパネルによって測定された腫瘍変異負荷と免疫チェックポイント調節因子(ICM)での治療後の全生存との関連を説明する。
実施例2:実施例1についての患者集団の選抜基準
実施例3:実施例1についての腫瘍変異負荷閾値の計算
実施例4 HLAクラスI遺伝子型は免疫チェックポイント調節因子で生存に影響を与える
材料及び方法
研究デザインと患者セットの説明
全生存及び臨床的応答データ
HLAクラスIジェノタイピングデータ
統計学的分析
変異解析パイプライン
HLAクラスI分析の異型接合性の消失
HLAクラスI構造解析及び分子動力学シミュレーション
結果
実施例5:承認されたPD−1免疫チェックポイント調節因子のための例示的投薬レジメン
本実施例は、示された免疫チェックポイント調節因子薬剤について米国食品医薬品局によって承認されたある特定の投薬レジメンを記載する。アテゾリズマブ(TECENTRIQ(商標))
アベルマブ(BAVENCIO(登録商標))
デュルバルマブ(IMFINZI(商標))
ニボルマブ(OPDIVO(登録商標))
ペムブロリズマブ(KEYTRUDA(登録商標))
実施例6:承認されたCTLA−4免疫チェックポイント調節因子のための例示的投薬レジメン
本実施例は、示された免疫チェックポイント調節因子薬剤について米国食品医薬品局によって承認されたある特定の投薬レジメンを記載する。
イピリムマブ(YERVOY(商標))
トレメリムマブ
付属書1 コホート1
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均等物
Claims (54)
- 以前の免疫療法を受けており、かつ免疫療法へ応答する統計学的に有意な確率と相関した閾値を超える腫瘍変異負荷を表示する対象に、免疫療法を投与するステップを含む、方法。
- がんが固形型腫瘍である、請求項1に記載の方法。
- がんが、膀胱癌、乳癌、食道胃癌、神経膠腫、頭頸部癌、黒色腫、非小細胞肺癌、腎細胞癌、及びそれらの組み合わせからなる群から選択される、請求項1に記載の方法。
- 前記免疫療法が、免疫チェックポイント調節因子の投与であるか、または免疫チェックポイント調節因子の投与を含む、請求項1に記載の方法。
- 前記免疫療法が、抗体薬剤の投与であるか、または抗体薬剤の投与を含む、請求項1に記載の方法。
- 前記免疫療法が、モノクローナル抗体の投与であるか、またはモノクローナル抗体の投与を含む、請求項1に記載の方法。
- 前記免疫療法が、PD−1もしくはPD−L1阻害療法のうちの1つ以上の投与であるか、またはPD−1もしくはPD−L1阻害療法のうちの1つ以上の投与を含む、請求項1に記載の方法。
- 前記免疫療法が、CTLA−4阻害療法のうちの1つ以上の投与であるか、またはCTLA−4阻害療法のうちの1つ以上の投与を含む、請求項1に記載の方法。
- 前記免疫療法が、PD−1阻害療法及びCTLA−4阻害療法のうちの1つ以上の組み合わせである、請求項1に記載の方法。
- 前記免疫療法が、アテゾリズマブ、アベルマブ、デュルバルマブ、イピリムマブ、ニボルマブ、ペムブロリズマブ、またはトレメリムマブ、及びそれらの組み合わせからなる群から選択される、請求項1に記載の方法。
- 前記表示された腫瘍変異負荷が、標的化配列パネルの使用によって決定されるか、標的化配列パネルの使用によって決定された、請求項1に記載の方法。
- 前記対象における腫瘍変異負荷を測定するステップをさらに含み、前記測定するステップが、前記投与前、前記投与中、前記投与後、及びそれらの組み合わせからなる群から選択される時点に実行される、請求項1に記載の方法。
- 前記腫瘍変異負荷が、次世代シークエンシングによって測定される、請求項1に記載の方法。
- 前記腫瘍変異負荷が、アクション可能ながん標的の変異プロファイリング(MSK−IMPACT)によって測定される、請求項1に記載の方法。
- 前記対象が以下に含まれるがんを有し、免疫チェックポイント調節因子治療後の腫瘍変異負荷閾値が以下に示されるとおりである、請求項1に記載の方法。
- 前記対象が以下に含まれるがんを有し、免疫チェックポイント調節因子治療後の腫瘍変異負荷閾値が以下に示されるとおりである、請求項1に記載の方法。
- 前記免疫療法が、前記閾値を超える前記腫瘍変異負荷を表示する集団に投与された際、全生存を改善する統計学的に有意な確率を有することが示された療法であるか、または全生存を改善する統計学的に有意な確率を有することが示された療法を含む、請求項1に記載の方法。
- 前記応答する統計学的に有意な確率が、全生存の統計学的に有意な改善を示すことによって確立されている、請求項1に記載の方法。
- HLAクラスIスーパータイプB44を表示する対象に免疫療法を投与するステップを含む、方法。
- HLAクラスIスーパータイプB62を表示する対象に免疫療法を投与するステップを含む、方法。
- HLAクラスI異型接合性を表示する対象に免疫療法を投与するステップを含む、方法。
- 前記対象が、1つ以上のHLAクラスI座位で異型接合性を表示する、請求項21に記載の方法。
- 前記対象が、HLAクラスI座位で最大の異型接合性を表示する、請求項22に記載の方法。
- 前記HLAクラスI異型接合性が、シークエンシングによって決定される、請求項21に記載の方法。
- 前記HLAクラスI異型接合性が、HLAタイピングアッセイによって決定される、請求項21に記載の方法。
- 前記免疫療法が、免疫チェックポイント調節因子の投与であるか、または免疫チェックポイント調節因子の投与を含む、請求項19〜21のいずれか一項に記載の方法。
- 前記免疫療法が、抗体薬剤の投与であるか、または抗体薬剤の投与を含む、請求項19〜21のいずれか一項に記載の方法。
- 前記免疫療法が、モノクローナル抗体の投与であるか、またはモノクローナル抗体の投与を含む、請求項19〜21のいずれか一項に記載の方法。
- 前記免疫療法が、PD−1もしくはPD−L1阻害療法のうちの1つ以上の投与であるか、またはPD−1もしくはPD−L1阻害療法のうちの1つ以上の投与を含む、請求項19〜21のいずれか一項に記載の方法。
- 前記免疫療法が、CTLA−4阻害療法のうちの1つ以上の投与であるか、またはCTLA−4阻害療法のうちの1つ以上の投与を含む、請求項19〜21のいずれか一項に記載の方法。
- 前記免疫療法が、PD−1阻害療法及びCTLA−4阻害療法のうちの1つ以上の組み合わせである、請求項19〜21のいずれか一項に記載の方法。
- 前記免疫療法が、アテゾリズマブ、アベルマブ、デュルバルマブ、イピリムマブ、ニボルマブ、ペムブロリズマブ、またはトレメリムマブ、及びそれらの組み合わせからなる群から選択される、請求項19〜21のいずれか一項に記載の方法。
- 以前の免疫療法を受けており、免疫療法へ応答する統計学的に有意な確率と相関した閾値を超える腫瘍変異負荷を表示し、かつHLAクラスI異型接合性を表示する対象に、免疫療法を投与するステップを含む、方法。
- 前記対象が、1つ以上のHLAクラスI座位で異型接合性を表示する、請求項33に記載の方法。
- 前記対象が、HLAクラスI座位で最大の異型接合性を表示する、請求項34に記載の方法。
- 前記HLAクラスI異型接合性が、シークエンシングによって決定される、請求項33に記載の方法。
- 前記HLAクラスI異型接合性が、HLAタイピングアッセイによって決定される、請求項33に記載の方法。
- がんが固形型腫瘍である、請求項33に記載の方法。
- がんが、膀胱癌、乳癌、食道胃癌、神経膠腫、頭頸部癌、黒色腫、非小細胞肺癌、腎細胞癌、及びそれらの組み合わせからなる群から選択される、請求項33に記載の方法。
- 前記免疫療法が、免疫チェックポイント調節因子の投与であるか、または免疫チェックポイント調節因子の投与を含む、請求項33に記載の方法。
- 前記免疫療法が、抗体薬剤の投与であるか、または抗体薬剤の投与を含む、請求項33に記載の方法。
- 前記免疫療法が、モノクローナル抗体の投与であるか、またはモノクローナル抗体の投与を含む、請求項33に記載の方法。
- 前記免疫療法が、PD−1もしくはPD−L1阻害療法のうちの1つ以上の投与であるか、またはPD−1もしくはPD−L1阻害療法のうちの1つ以上の投与を含む、請求項33に記載の方法。
- 前記免疫療法が、CTLA−4阻害療法のうちの1つ以上の投与であるか、またはCTLA−4阻害療法のうちの1つ以上の投与を含む、請求項33に記載の方法。
- 前記免疫療法が、PD−1阻害療法及びCTLA−4阻害療法のうちの1つ以上の組み合わせである、請求項33に記載の方法。
- 前記免疫療法が、アテゾリズマブ、アベルマブ、デュルバルマブ、イピリムマブ、ニボルマブ、ペムブロリズマブ、またはトレメリムマブ、及びそれらの組み合わせからなる群から選択される、請求項33に記載の方法。
- 前記表示された腫瘍変異負荷が、標的化配列パネルの使用によって決定されるか、標的化配列パネルの使用によって決定された、請求項33に記載の方法。
- 前記対象における腫瘍変異負荷を測定するステップをさらに含み、前記測定するステップが、前記投与前、前記投与中、前記投与後、及びそれらの組み合わせからなる群から選択される時点に実行される、請求項33に記載の方法。
- 前記腫瘍変異負荷が、次世代シークエンシングによって測定される、請求項33に記載の方法。
- 前記腫瘍変異負荷が、アクション可能ながん標的の変異プロファイリング(MSK−IMPACT)によって測定される、請求項33に記載の方法。
- 前記対象が以下に含まれるがんを有し、免疫チェックポイント調節因子治療後の腫瘍変異負荷閾値が以下に示されるとおりである、請求項33に記載の方法。
- 前記対象が以下に含まれるがんを有し、免疫チェックポイント調節因子治療後の腫瘍変異負荷閾値が以下に示されるとおりである、請求項33に記載の方法。
- 前記免疫療法が、前記閾値を超える前記腫瘍変異負荷を表示する集団に投与された際、全生存を改善する統計学的に有意な確率を有することが示された療法であるか、または全生存を改善する統計学的に有意な確率を有することが示された療法を含む、請求項33に記載の方法。
- 前記応答する統計学的に有意な確率が、全生存の統計学的に有意な改善を示すことによって確立されている、請求項33に記載の方法。
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