JP2022512228A - 別の治療薬と組み合わせた免疫チェックポイント阻害剤による癌の治療方法 - Google Patents
別の治療薬と組み合わせた免疫チェックポイント阻害剤による癌の治療方法 Download PDFInfo
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Abstract
Description
本出願は、2018年12月13日に出願された非仮米国出願第16/219,203号の優先権の利益を主張する。先の出願の開示は、その一部とみなされ、参照によりその全体が本出願の開示に組み込まれる。
(i)該ICIによる治療セッション後の時点で癌患者から得られた血漿、全血、血清、または末梢血単核球から選択された血液試料に対してアッセイを実施して、ICIによる治療に応答して、宿主(「癌患者」)によって駆動される複数の宿主駆動型耐性因子のうちの1つ以上のレベルを決定する工程であって、該複数の因子のうちの1つ以上が、個別化された形態で、ICIによる治療に対する癌患者の応答性または非応答性を促進する、工程と、
(ii)ICIによる該治療セッションの前の時点で癌患者から得られた、工程(i)の血液試料と同じ種類の血液試料中の該因子のそれぞれのレベルを決定することによって、工程(i)の複数の宿主駆動型耐性因子のうちの1つ以上のそれぞれの基準レベルを得る工程と、
(iii)工程(i)の各宿主駆動型耐性因子のレベルを同じ因子について工程(ii)の基準レベルと比較することによって、工程(i)の複数の宿主駆動型耐性因子のうちの1つ以上のそれぞれについての倍率変化を確立する工程と、
(iv)工程(i)の複数の宿主駆動型耐性因子のうちの1つ以上について工程(iii)で確立された倍率変化に基づいて、癌患者が該ICIによる治療に対して好ましいか、または好ましくない応答を有することを決定する工程と、
(iva)複数の宿主駆動型耐性因子のうちの1つ以上について工程(iii)で確立された倍率変化に基づいて、癌患者が該ICIによる治療に対して好ましくない応答を有する場合、該好ましくない応答を示している倍率変化を示す1つ以上の宿主駆動型耐性因子の中で、優勢な因子を選択し、治療有効量のICIと共に、選択された優勢宿主駆動型耐性因子(本明細書では「優勢な因子」)またはその受容体の活性を遮断する治療有効量の薬剤で患者を治療する工程、あるいは
(ivb)複数の宿主駆動型耐性因子のうちの1つ以上について(iii)で確立された倍率変化に基づいて、癌患者が該ICIによる治療に対して好ましい応答を有する場合、ICI単独による癌患者の治療を継続する工程と、を含む。
(i)該ICIによる治療セッション後の時点で癌患者から得られた血漿、全血、血清、または末梢血単核球から選択された血液試料に対してアッセイを実施して、ICIによる治療に応答して、宿主(「癌患者」)によって駆動される複数の宿主駆動型耐性因子のうちの1つ以上のレベルを決定する工程であって、該複数の因子のうちの1つ以上が、個別化された形態で、ICIによる治療に対する癌患者の応答性または非応答性を促進する、工程と、
(ii)ICIによる該治療セッションの前の時点で癌患者から得られた、工程(i)の血液試料と同じ種類の血液試料中の該因子のそれぞれのレベルを決定することによって、工程(i)の複数の宿主駆動型耐性因子のうちの1つ以上のそれぞれの基準レベルを取る工程と、
(iii)工程(i)の各宿主駆動型耐性因子のレベルを同じ因子について工程(ii)の基準レベルと比較することによって、工程(i)の複数の宿主駆動型耐性因子のうちの1つ以上のそれぞれについての倍率変化を確立する工程と、
(iv)工程(i)の複数の宿主駆動型耐性因子のうちの1つ以上について工程(iii)で確立された倍率変化に基づいて、癌患者が該ICIによる治療に対して好ましいか、または好ましくない応答を有することを決定する工程と、
(iva)複数の宿主駆動型耐性因子のうちの1つ以上について工程(iii)で確立された倍率変化に基づいて、癌患者が該ICIによる治療に対して好ましくない応答を有する場合、該好ましくない応答を示している倍率変化を示す1つ以上の宿主駆動型耐性因子の中で、優勢な因子を選択し、治療有効量のICIと共に、選択された優勢宿主駆動型耐性因子(本明細書では「優勢な因子」)またはその受容体の活性を遮断する治療有効量の薬剤で患者を治療する工程、あるいは
(ivb)複数の宿主駆動型耐性因子のうちの1つ以上について(iii)で確立された倍率変化に基づいて、癌患者が倍ICIによる治療に対して好ましい応答を有する場合、ICI単独による癌患者の治療を継続する工程と、を含む。
前述のように、最近の臨床試験では、患者がICIに耐性を示す場合、またはICI療法に応答しない場合があることが報告されている(Sharma et al.,2017)。本明細書において、癌患者、すなわち宿主が、ICI療法に応答して腫瘍形成促進因子を生成し、それが次に腫瘍の再増殖、進行、および治療への耐性に寄与することを説明する。このメカニズムに寄与する因子を特定するために、非腫瘍および腫瘍担持免疫担当マウスの両方で、インビボ実験を実施する。このアプローチにより、ICIの治療的抗腫瘍活性と宿主細胞に対するこれらの薬剤の効果とを区別することが可能となる。抗PD1、抗PD-L1、抗CTL-4モノクローナル抗体を含む、診療所で広く使用されているICIに焦点を当て、特定のICIに応答または耐性があることが知られているマウス腫瘍モデルを使用する。たとえば、CT26結腸およびEMT-6乳癌細胞株は、それぞれ抗CTLA-4および抗PD-L1に応答するが(Duraiswamy et al.,2013;Swart et a.,2013)、MC38結腸および4T1乳房癌細胞株は、我々の研究室でもテストされているように、一部のICI(抗PD-1を含む)に対して耐性があるか、または中程度の応答しかない(De Henau et al.,2016;Kodumudi et al.,2016)(図示せず)。
材料
以下の抗体は、BioXCell,West Lebanon,NH,USAから購入した:InVivoMab抗マウス-CTLA-4(カタログ番号BE0131)、InVivoMab抗マウス-IL-6(カタログ番号BE0046)、InVivoMab抗マウス-PD-1(カタログ番号BEO146)、InVivoPlus抗マウス-PD-L1(カタログ番号BEO101)、およびInVivoMAbアイソタイプ対照IgG2b抗体(カタログ番号BE0090)。SB-3CT(IUPAC名:2-(((4-フェノキシフェニル)スルホニル)メチル)チイラン)は、MedKoo Biosciences Inc(カタログ番号406563)から購入した。抗アンフィレグリン(カタログ番号AF989)はR&D systemsから購入した。SB-3CTの10mMストック溶液を100%のDMSO(Sigma)中で調製した。インビボ実験では、ストック溶液を、通常の生理食塩水中10%のDMSO中で、1.25mg/mlの最終濃度に希釈した。
以前の実験は、抗PD-1療法が循環中の因子の上方制御を誘発し、それが最終的に腫瘍細胞の攻撃性を促進することを示唆している。このような影響は、他の種類の免疫チェックポイント阻害剤療法に応答して生じ得る。抗PD-1および抗PD-L1療法に応答してレベルが変化する宿主由来の循環因子を特定するために、ナイーブ(腫瘍を担持しない)マウスを使用して3つのタンパク質アレイベースのスクリーニングを実施した。ナイーブマウスを使用することで、腫瘍とは無関係に、療法に応答して宿主によって特異的に生成される因子を特定することが可能となる。
マトリックスメタロペプチダーゼ9(MMP9)は、細胞外マトリックスの分解に関与する亜鉛メタロプロテイナーゼファミリーに属する酵素である。MMP-9は、上皮間葉転換、細胞増殖、血管新生、骨形成、および創傷治癒を含む、腫瘍形成促進および組織再生の生物学的プロセスなど、様々な生物学的プロセスに関与している。MMP-9は、浸潤および転移に関与する重要な要因の1つである。MMP-9は、抗癌剤として開発された癌の様々な主要な生物学的経路に関与しているため、ICI療法に応答して誘発される主要な因子として機能し、その阻害により治療結果が改善され得る。
アンフィレグリンは、上皮成長因子受容体(EGFR)のリガンドの1つである。研究により、腫瘍形成のいくつかの態様におけるアンフィレグリンの機能的役割が実証されている。アンフィレグリンの血漿レベルが、ナイーブBALB/cおよびC57/bl/6マウスでの抗PD-L1治療に応答して、アンフィレグリンの血漿レベルが2~3倍増加し(表4)、およびBALB/cマウスでの抗PD-1治療に応答して3.7倍増加する(表5)ことを示す、上記の実施例1に記載した発見に照らして、アンフィレグリンが選択された。
IL-6は、ICI療法に応答して高度に誘発されることが上記で実証されたもう1つの優勢な因子である。提示されているように、IL-6は、BALB/cマウスでの抗PD-1治療に応答して15.6倍(表2)、ナイーブBALB/cおよびC57/bl/6での抗PD-L1治療に応答して1.7~1.8倍(表4)、ならびにSCIDマウスでの抗PD-1治療に応答して1.8倍(表5)増加した。
IL-6は、増殖、血管新生、炎症、分化、アポトーシスへの耐性など、腫瘍の発生に不可欠な多くの生物学的プロセスに関与していることが知られている。さらに、IL-6は炎症誘発性サイトカインであり、癌の予後因子として説明されている。IL-6は炎症誘発性カスケードの最上部に位置し、転移と相関することが実証されているため、腫瘍形成促進および転移促進活性を伴う主要な因子とみなされている。
抗CTLA-4治療に応答して上方制御された宿主由来IL-6の遮断(図4に示す)が治療の有効性を改善するかどうかを研究するために、BALB/cマウスにEMT6ネズミ乳癌細胞を乳腺脂肪体に同所的に注射した。腫瘍が100mm3のサイズに達した時、マウスに、抗CTLA-4、抗IL-6または抗CTLA-4と抗IL-6との組み合わせを、3日ごとに1回IP注射した(合計で4回の注射)。対照マウスを未処置のままにした。腫瘍の増殖を定期的に監視し、腫瘍のサイズが約1500mm3に達したときに、マウスを殺処分した。
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Claims (37)
- 癌患者を免疫チェックポイント阻害剤(ICI)で治療する方法であって、
(i)前記ICIによる治療セッション後の時点で前記癌患者から得られた血漿、全血、血清、または末梢血単核球から選択された血液試料に対してアッセイを実施して、前記ICIによる治療に応答して、宿主(「前記癌患者」)によって駆動される複数の宿主駆動型耐性因子のうちの1つ以上のレベルを決定する工程であって、前記複数の因子のうちの1つ以上が、個別化された形態で、前記ICIによる前記治療に対する前記癌患者の応答性または非応答性を促進する、工程と、
(ii)前記ICIによる前記治療セッションの前の時点で前記癌患者から得られた、工程(i)の前記血液試料と同じ種類の血液試料中の前記因子のそれぞれのレベルを決定することによって、工程(i)の前記複数の宿主駆動型耐性因子のうちの前記1つ以上のそれぞれの基準レベルを得る工程と、
(iii)工程(i)の各宿主駆動型耐性因子の前記レベルを同じ因子について工程(ii)の前記基準レベルと比較することによって、工程(i)の前記複数の宿主駆動型耐性因子のうちの前記1つ以上のそれぞれについての倍率変化を確立する工程と、
(iv)工程(i)の前記複数の宿主駆動型耐性因子のうちの1つ以上について工程(iii)で確立された前記倍率変化に基づいて、前記癌患者が前記ICIによる前記治療に対して好ましい、または好ましくない応答を有することを決定する工程と、
(iva)前記複数の宿主駆動型耐性因子のうちの1つ以上について工程(iii)で確立された前記倍率変化に基づいて、前記癌患者が前記ICIによる前記治療に対して好ましくない応答を有する場合、前記好ましくない応答を示している倍率変化を示す前記1つ以上の宿主駆動型耐性因子の中で、優勢な因子を選択し、治療有効量の、前記優勢な因子またはその受容体の活性を遮断する薬剤と組み合わせた、治療有効量の前記ICIで前記患者を治療する工程、あるいは、
(ivb)前記複数の宿主駆動型耐性因子のうちの1つ以上について工程(iii)で確立された前記倍率変化に基づいて、前記癌患者が前記ICIによる前記治療に対して好ましい応答を有する場合、前記ICI単独による前記癌患者の前記治療を継続する工程と、を含む、方法。 - 免疫チェックポイント阻害剤(ICI)による治療に応答しない癌患者の治療のための方法であって、前記方法が、前記癌患者に、治療有効量の前記ICIを、治療有効量の、優勢な因子、またはその受容体の活性を遮断する薬剤と組み合わせて、前記癌患者に投与することを含み、前記優勢な因子が、前記ICIによる前記癌患者の治療に応答して生成される複数の宿主駆動型耐性因子の中から選択され、前記複数の宿主駆動型耐性因子が、前記ICIによる前記治療に対する前記癌患者の好ましくない応答を予測する倍率変化を有し、前記倍率変化が、(i)前記ICIによる治療セッション後に前記癌患者から得られた、血漿、全血、血清または末梢血単核球から選択される血液試料中の各宿主駆動型耐性因子のレベルを、(ii)前記ICIによる前記治療セッション前に前記癌患者から得られた、(i)と同じ種類の血液試料からの同じ因子について得られた基準レベルと比較することによって確立される、方法。
- 工程(i)および工程(ii)の前記血液試料が、両方とも血漿である、請求項1または2に記載の方法。
- 前記ICIによる前記治療セッションが、
(a)前記ICIによる最初の治療セッションであり、工程(i)の前記血液試料が、前記最初の治療セッション後、約20、24、30、36、40、48、50、60、72時間以上(最大1週間以上、最大2週間以上または最大3週間以上を含む)の時点で前記癌患者から得られ、工程(ii)の前記基準血液試料が、前記ICIによる前記最初の治療セッション前、約72時間以下を含む時点(約60、50、48、40、36、30、24、または20時間以下を含む)、または前記ICIによる前記最初の治療セッションの直前を含む時点で前記癌患者から得られるか、
(b)前記ICIによる前記最初の治療セッションではない複数の治療セッションのうちの1つであり、血液試料が、2つの連続する治療セッションの間の任意の時点で前記癌患者から得られ、前記血液試料が、同時に、工程(i)の前記血液試料であり、工程(ii)による前記基準血液試料が、工程(i)による次のセッションアッセイのためのものであるか、あるいは
(c)2つの連続する治療セッションの間の時間が、前記ICIに応じて2週間または3週間であり、前記血液試料が、前記ICIによる前記最初の治療セッションではない前記治療セッション後、1日目、2日目、3日目、7日目、14日目、または21日目に得られる、請求項1~3のいずれか一項に記載の方法。 - 前記複数の宿主駆動型耐性因子のうちの前記1つ以上のそれぞれについての前記倍率変化は、その値が約1.5以上である場合、増加/上方制御を意味し、有意かつ前記ICIによる前記治療に対する前記癌患者の好ましくない応答を予測するとみなされ、あるいは前記倍率変化は、その値が約0.5以下である場合、減少/下方制御を意味し、有意かつ前記癌患者の前記ICIによる前記治療に対する好ましい応答を予測するとみなされる、請求項1~4のいずれか一項に記載の方法。
- 前記ICIによる前記治療に対する前記癌患者の好ましいか、または好ましくない応答の前記予測が、前記宿主駆動型耐性因子のうちの1つ以上、任意に2つ以上、3つ以上、4つ以上、5つ以上、6つ以上、7つ以上、8つ以上、9つ以上、10個以上、11個以上、12個以上、13個以上、14個以上、15個以上、20個以上、または25個以上の有意な倍率変化に基づく、請求項1~5のいずれか一項に記載の方法。
- 前記ICIが、PD-1、PD-L1、CTLA-4、A2AR、BT-H3、BT-H4、BT-H5、BTLA、IDO1、KIR、LAG-3、TDO、TIM-3、TIGIT、VISTA、またはこれらの組み合わせから選択される免疫チェックポイントに対する阻害剤である、請求項1~6のいずれか一項に記載の方法。
- 前記ICIが、ペムブロリズマブ、ニボルマブ、ピジリズマブ、セミプリマブ、AMP-224、MEDI0680、もしくはスパルタリズマブから選択される抗PD-1モノクローナル抗体、アテゾリズマブ、アベルマブ、デュルバルマブもしくはMDX-1105から選択される抗PD-L1モノクローナル抗体、イピリムマブもしくはトレメリムマブから選択される抗CTLA-4モノクローナル抗体、レラトリマブ、LAG525もしくはREGN3767から選択される抗LAG-3モノクローナル抗体、TSR022もしくはMBG453から選択される抗TIM-3モノクローナル抗体、抗KIRモノクローナル抗体リリルマブ、抗TIGITモノクローナル抗体OMP-31M32、抗VISTAモノクローナル抗体JNJ-61610588(オンバチリマブ)、またはこれらの組み合わせである、請求項7に記載の方法。
- 前記患者が、(a)2つのICIの組み合わせであって、ニボルマブ(抗PD-1)およびイピリムマブ(抗CTLA-4)、ニボルマブ(抗PD-1)およびアテゾリムマブ(抗PD-L1)、ならびにデュルバルマブ(抗PD-L1)およびトレメリムマブ(抗CTLA-4)から選択される、2つのICIの組み合わせ、(b)前記ICIと、CD40、ICOS、OX40、およびCD137(4-IBB)から選択されるT細胞共刺激分子に対するアゴニストモノクローナル抗体との組み合わせ、または(c)前記ICIと、化学療法、標的癌療法、および放射線療法を含む1つ以上の従来の癌療法との組み合わせ、により治療される、請求項1~8のいずれか一項に記載の方法。
- 前記宿主駆動型耐性因子が、サイトカイン、ケモカイン、成長因子、酵素および可溶性受容体を含む分子因子であり、前記因子が腫瘍形成促進性または転移促進性因子であり得、前記腫瘍形成促進因子が、血管新生促進、炎症誘発性/走化性、または増殖性成長因子であり得る、請求項1~9のいずれか一項に記載の方法。
- 前記宿主駆動型耐性因子が、ADAMTS1、アンフィレグリン、Axl、CCL5/RANTES、CCL17/TARC、EGF、エオタキシン-2、FGF-21、Gas6、G-CSF、GM-CSF、HGF、IFN-ガンマ、IL-1Rアルファ、IL-2、IL-6、IL-7、IL-10、IL-12p40、IL-13、IL-33、I-TAC、MadCAM-1、MCP-5、TACI、M-CSF、MMP-9、PDGF-BB、プロMMP9、またはSCFを含む、請求項10に記載の方法。
- 前記ICIが抗PD-1であり、前記抗PD-1治療に応答して上方制御される前記宿主駆動型耐性因子が、(i)G-CSF、GM-CSFおよびPDGF-BBを含む血管新生促進因子、(ii)CCL17/TARC、CCL5/RANTES、G-CSF、GM-CSF、IFN-ガンマ、IL-1Rアルファ、IL-2、IL-6、IL-7、IL-10、IL-12p40、IL-13、IL-33およびM-CSFを含む炎症誘発性および/または走化性因子、(iii)FGF-21、Gas6およびHGFを含む増殖性成長因子、ならびに(iv)前記転移促進因子MMP-9から選択される、請求項11に記載の方法。
- 前記ICIが抗PD-L1であり、抗PD-L1治療に応答して上方制御される前記宿主駆動型耐性因子が、(i)G-CSFおよびSCFを含む血管新生促進因子、(ii)エオタキシン-2、G-CSF、IL-1ra、IL-6、IL-7、IL-33、I-TAC、MadCAM-1、MCP-5、SCF、およびTACIを含む炎症誘発性および/または走化性因子、(iii)アンフィレグリン、Axl、EGF、およびHGFを含む増殖性成長因子、ならびに(iv)ADAMTS1およびプロMMP9を含む転移促進因子から選択される、請求項11に記載の方法。
- 前記選択された優勢な因子が、前記癌患者の前記ICIによる前記治療に対する好ましくない応答を示す、1.5以上の倍率変化を有し、前記優勢な因子またはその受容体を遮断する薬剤と組み合わせた前記ICIによる前記癌患者の治療を進める、請求項1または2に記載の方法。
- 前記ICIおよび前記優勢な因子または前記その受容体を遮断する前記薬剤が、いずれかの順序で同時にまたは逐次的に投与される、請求項14に記載の方法。
- 前記優勢な因子が、アンフィレグリン、EGF、EGFR、FGF、IFN-γ、IL-1β、IL-2、IL-6、MMP9、PDGF、TNF-αおよびVEGF-Aを含む、請求項14または15に記載の方法。
- 前記優勢な因子が、MMP9であり、前記ICIが、抗PD-1または抗PD-L1モノクローナル抗体であり、前記癌患者が、SB-3CTなどのMMP9阻害剤と組み合わせた前記ICIで治療される、請求項16に記載の方法。
- 前記優勢な因子が、アンフィレグリンであり、前記ICIが、抗PD-1または抗PD-L1モノクローナル抗体であり、前記癌患者が、抗アンフィレグリン抗体と組み合わせた前記ICIで治療される、請求項16に記載の方法。
- 前記優勢な因子が、IL-6であり、前記ICIが、抗CTLA-4、抗PD-1または抗PD-L1モノクローナル抗体であり、前記癌患者が、(i)シルツキシマブ、オロキズマブ、エルシリモマブ、クラザキズマブ、ゲリリムズマブ、EBI-031およびシルクマブを含む、抗IL-6モノクローナル抗体、またはそのバイオシミラー、(ii)BCD-089、トシリズマブ、LusiNEX、およびサリルマブを含む、抗IL-6Rモノクローナル抗体またはそのバイオシミラー、(iii)ナノボディボバリリズマブ、ならびに(iv)オラムキセプトを含むIL-6Rアンタゴニストから選択される抗IL-6または抗IL-6受容体(抗IL-6R)と組み合わせた前記ICIで治療される、請求項16に記載の方法。
- 前記抗PD-1モノクローナル抗体が、ペムブロリズマブ、ニボルマブ、ピジリズマブ、セミプリマブ、AMP-224、MEDI0680、もしくはスパルタリズマブであり、前記抗PD-L1モノクローナル抗体が、アテゾリズマブ、アベルマブ、デュルバルマブ、もしくはMDX-1105であり、前記抗CTLA-4モノクローナル抗体が、イピリムマブもしくはトレメリムマブ、またはこれらの組み合わせである、請求項17~19のいずれか一項に記載の方法。
- 前記癌が、膀胱癌、骨癌、乳癌、脳癌、子宮頸癌、大腸癌、大腸直腸癌、食道癌、胃癌、胃腸癌、神経膠芽細胞腫、頭頚部癌、頭頚部扁平上皮癌、肝細胞癌、腎臓癌、肝臓癌、小細胞肺癌および非小細胞肺癌(NSCLC)を含む肺癌、黒色腫、鼻咽頭癌、卵巣癌、膵臓癌、陰茎癌、前立腺癌、皮膚癌、精巣癌、胸腺癌、甲状腺癌、泌尿生殖器癌、もしくは子宮癌、白血病、リンパ腫、多発性骨髄腫ならびに肉腫を含む、原発性または転移性癌である、請求項1~20のいずれか一項に記載の方法。
- 癌の治療において、前記治療に応答しない患者で使用するための免疫チェックポイント阻害剤(ICI)であって、前記治療が、治療有効量の前記ICIを、治療有効量の、優勢な因子、またはその受容体の活性を遮断する薬剤と組み合わせて投与することを含み、前記優勢な因子が、前記ICIによる前記癌患者の治療に応答して生成される複数の宿主駆動型耐性因子の中から選択され、前記複数の宿主駆動型耐性因子が、前記ICIによる治療に対する前記癌患者の好ましくない応答を予測する倍率変化を有し、前記倍率変化が、(i)前記ICIによる治療セッション後に前記癌患者から得られた、血漿、全血、血清または末梢血単核球から選択される血液試料中の各宿主駆動型耐性因子のレベルを、(ii)前記ICIによる治療セッション前に前記癌患者から得られた、(i)と同じ種類の血液試料からの同じ因子について得られた基準レベルと比較することによって確立される、免疫チェックポイント阻害剤(ICI)。
- 前記ICIが、PD-1、PD-L1、CTLA-4、A2AR、BT-H3、BT-H4、BT-H5、BTLA、IDO1、KIR、LAG-3、TDO、TIM-3、TIGIT、VISTA、またはこれらの組み合わせから選択される免疫チェックポイントに対する阻害剤である、請求項22に記載の免疫チェックポイント阻害剤(ICI)。
- 前記ICIが、ペムブロリズマブ、ニボルマブ、ピジリズマブ、セミプリマブ、AMP-224、MEDI0680、およびスパルタリズマブから選択される抗PD-1モノクローナル抗体、アテゾリズマブ、アベルマブ、デュルバルマブおよびMDX-1105から選択される抗PD-L1モノクローナル抗体、イピリムマブおよびトレメリムマブから選択される抗CTLA-4モノクローナル抗体、レラトリマブ、LAG525およびREGN3767から選択される抗LAG-3モノクローナル抗体、TSR022およびMBG453から選択される抗TIM-3モノクローナル抗体、抗KIRモノクローナル抗体リリルマブ、抗TIGITモノクローナル抗体OMP-31M32、抗VISTAモノクローナル抗体JNJ-61610588(オンバチリマブ)、またはこれらの組み合わせである、請求項23に記載の免疫チェックポイント阻害剤(ICI)。
- (a)2つのICIの組み合わせであって、ニボルマブ(抗PD-1)およびイピリムマブ(抗CTLA-4)、ニボルマブ(抗PD-1)およびアテゾリムマブ(抗PD-L1)、またはデュルバルマブ(抗PD-L1)およびトレメリムマブ(抗CTLA-4)から選択される、2つのICIの組み合わせ、(b)前記ICIと、CD40、ICOS、OX40、およびCD137(4-IBB)から選択されるT細胞共刺激分子に対するアゴニストモノクローナル抗体との組み合わせ、あるいは(c)前記ICIと、化学療法、標的癌療法、および放射線療法を含む1つ以上の従来の癌療法様式との組み合わせから選択される、請求項23または24に記載の免疫チェックポイント阻害剤(ICI)。
- 前記宿主駆動型耐性因子が、サイトカイン、ケモカイン、成長因子、酵素および可溶性受容体を含む分子因子であり、前記因子が、腫瘍形成促進性または転移促進性因子であり得、前記腫瘍形成促進因子が、血管新生促進、炎症誘発性/走化性、または増殖性成長因子であり得る、請求項22~25のいずれか一項に記載免疫チェックポイント阻害剤(ICI)。
- 前記宿主駆動型耐性因子が、ADAMTS1、アンフィレグリン、Axl、CCL5/RANTES、CCL17/TARC、EGF、エオタキシン-2、FGF-21、Gas6、G-CSF、GM-CSF、HGF、IFN-ガンマ、IL-1Rアルファ、IL-2、IL-6、IL-7、IL-10、IL-12p40、IL-13、IL-33、I-TAC、MadCAM-1、MCP-5、TACI、M-CSF、MMP-9、PDGF-BB、プロMMP9、またはSCFを含む、請求項26に記載の免疫チェックポイント阻害剤(ICI)。
- 前記ICIが抗PD-1であり、前記抗PD-1治療に応答して上方制御される前記宿主駆動型耐性因子が、(i)G-CSF、GM-CSFおよびPDGF-BBを含む血管新生促進因子、(ii)CCL17/TARC、CCL5/RANTES、G-CSF、GM-CSF、IFN-ガンマ、IL-1Rアルファ、IL-2、IL-6、IL-7、IL-10、IL-12p40、IL-13、IL-33およびM-CSFを含む炎症誘発性および/または走化性因子、(iii)FGF-21、Gas6およびHGFを含む増殖性成長因子、および(iv)転移促進因子MMP-9から選択される、請求項27に記載の免疫チェックポイント阻害剤(ICI)。
- 前記ICIが抗PD-L1であり、前記抗PD-L1治療に応答して上方制御される前記宿主駆動型耐性因子が、(i)G-CSFおよびSCFを含む血管新生促進因子、(ii)エオタキシン-2、G-CSF、IL-1ra、IL-6、IL-7、IL-33、I-TAC、MadCAM-1、MCP-5、SCF、およびTACIを含む炎症誘発性および/または走化性因子、(iii)アンフィレグリン、Axl、EGF、およびHGFを含む増殖性成長因子、ならびに(iv)ADAMTS1およびプロMMP9を含む転移促進因子から選択される、請求項27に記載の免疫チェックポイント阻害剤(ICI)。
- 前記選択された優勢な因子が、1.5以上の倍率変化を有する、請求項22~29のいずれか一項に記載の免疫チェックポイント阻害剤(ICI)。
- 前記ICIおよび前記優勢な因子またはその受容体を遮断する前記薬剤が、いずれかの順序で同時にまたは逐次的に投与される、請求項30に記載の免疫チェックポイント阻害剤(ICI)。
- 前記優勢な因子が、アンフィレグリン、EGF、EGFR、FGF、IFN-γ、IL-1β、IL-2、IL-6、MMP9、PDGF、TNF-αおよびVEGF-Aを含む、請求項26~31のいずれか一項に記載の免疫チェックポイント阻害剤(ICI)。
- 前記優勢な因子が、MMP9であり、前記ICIが、抗PD-1または抗PD-L1モノクローナル抗体であり、前記癌患者が、SB-3CTなどのMMP9阻害剤と組み合わせた前記ICIで治療される、請求項32に記載の免疫チェックポイント阻害剤(ICI)。
- 前記優勢な因子が、アンフィレグリンであり、前記ICIが、抗PD-1または抗PD-L1モノクローナル抗体であり、前記癌患者が、抗アンフィレグリン抗体と組み合わせた前記ICIで治療される、請求項32に記載の免疫チェックポイント阻害剤(ICI)。
- 前記優勢な因子が、IL-6であり、前記ICIが、抗CTLA-4、抗PD-1または抗PD-L1モノクローナル抗体であり、前記癌患者が、(i)シルツキシマブ、オロキズマブ、エルシリモマブ、クラザキズマブ、ゲリリムズマブ、EBI-031およびシルクマブを含む、抗IL-6モノクローナル抗体、またはそのバイオシミラー、(ii)BCD-089、トシリズマブ、LusiNEX、およびサリルマブを含む、抗IL-6Rモノクローナル抗体またはそのバイオシミラー、(iii)ナノボディボバリリズマブ、ならびに(iv)オラムキセプトを含むIL-6Rアンタゴニストから選択される抗IL-6または抗IL-6受容体(抗IL-6R)と組み合わせた前記ICIで治療される、請求項32に記載の免疫チェックポイント阻害剤(ICI)。
- 前記抗CTLA-4モノクローナル抗体が、イピリムマブもしくはトレメリムマブであり、前記抗PD-1モノクローナル抗体が、ペムブロリズマブ、ニボルマブ、ピジリズマブ、セミプリマブ、AMP-224、MEDI0680、もしくはスパルタリズマブであり、および前記抗PD-L1モノクローナル抗体が、アテゾリズマブ、アベルマブ、デュルバルマブ、もしくはMDX-1105、またはこれらの組み合わせである、請求項33~35のいずれか一項に記載の免疫チェックポイント阻害剤(ICI)。
- 前記癌が、膀胱癌、骨癌、乳癌、脳癌、子宮頸癌、大腸癌、大腸直腸癌、食道癌、胃癌、胃腸癌、神経膠芽細胞腫、頭頚部癌、頭頚部扁平上皮癌、肝細胞癌、腎臓癌、肝臓癌、小細胞肺癌および非小細胞肺癌(NSCLC)を含む肺癌、黒色腫、鼻咽頭癌、卵巣癌、膵臓癌、陰茎癌、前立腺癌、皮膚癌、精巣癌、胸腺癌、甲状腺癌、泌尿生殖器癌、もしくは子宮癌、白血病、リンパ腫、多発性骨髄腫ならびに肉腫を含む、原発性または転移性癌である、請求項22~36のいずれか一項に記載の免疫チェックポイント阻害剤(ICI)。
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