JP2023002792A - ソマトスタチン受容体を過剰発現する神経内分泌腫瘍を処置する方法 - Google Patents
ソマトスタチン受容体を過剰発現する神経内分泌腫瘍を処置する方法 Download PDFInfo
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Abstract
Description
[該当なし]
本発明は、ソマトスタチン受容体を過剰発現するがんを処置する方法に関する。より具体的には、本発明は、ペプチド受容体放射性核種療法(PRRT)および免疫腫瘍学療法(I-O療法)の組合せが、神経内分泌腫瘍を処置するために投与される併用療法を提供する。
たが、「中腸カルチノイド」において使用されたスキームのどれも、NETの処置においていずれの活性も示さなかった。一部の良好な初期応答は、テモゾロミド+カペシタビンの組合せに関し小集団について報告されたが4、やはり、これらの早期データは、NETのために現在利用可能な療法が不十分であり、かなりの治療成果を生み出すことができる追加のロバストな療法に対する長年の切実な必要性が存在することを明らかにする。
低グレード、中グレード、または高グレード神経内分泌腫瘍であり得る。具体的な実施形態では、腫瘍は、機能性神経内分泌腫瘍である。代替として、神経内分泌腫瘍は、非機能性神経内分泌腫瘍である。
本発明は、例えば、以下の項目を提供する。
(項目1)
ソマトスタチン受容体を過剰発現するがんを有する患者を処置する方法であって、前記患者に、ペプチド受容体放射性核種療法(PRRT)および免疫腫瘍学療法の組合せを投与することを含み、前記PRRTおよび前記免疫腫瘍学療法の複合効果により、前記がんに対する治療効果が生じる、方法。
(項目2)
ソマトスタチン受容体を過剰発現するがんを有する患者を処置する方法であって、前記患者に、ペプチド受容体放射性核種療法(PRRT)およびPD-1/PD-L1/CTLA-4経路を阻害する阻害剤の組合せを投与することを含み、前記PRRTおよびPD-1/PD-L1経路の前記阻害剤の複合効果により、前記がんに対する治療効果が生じる、方法。
(項目3)
前記PRRTが、[177]ルテチウム-DOTA[O]-Tyr[3]-オクトレオテートである、項目1に記載の方法。
(項目4)
前記PD-1/PD-L1/CTLA-4経路の前記阻害剤が、PD-L1を標的とする抗体である、項目1に記載の方法。
(項目5)
前記PD-1/PD-L1経路の前記阻害剤が、PD-1を標的とする抗体である、項目1に記載の方法。
(項目6)
前記PD-1/PD-L1経路の前記阻害剤が、ニボルマブ、MK-3475、MPDL3280A、MED14736、イピリムマブ、およびトレメリムマブからなる群から選択される、項目1に記載の方法。
(項目7)
前記がんが、神経内分泌腫瘍である、項目1に記載の方法。
(項目8)
前記処置が、神経内分泌腫瘍の成長の阻害、神経内分泌腫瘍細胞の増殖の阻害、神経内分泌腫瘍転移の阻害、神経内分泌腫瘍細胞分化の誘導、神経内分泌腫瘍細胞の腫瘍形成能の低減、および神経内分泌腫瘍内のがん幹細胞または腫瘍開始細胞の頻度を低減する方法のうちの1つまたは複数を含む、項目6に記載の方法。
(項目9)
前記神経内分泌腫瘍が、胃腸膵臓神経内分泌腫瘍、カルチノイド腫瘍、褐色細胞腫、傍神経節腫、髄様甲状腺がん、肺神経内分泌腫瘍、胸腺神経内分泌腫瘍、カルチノイド腫瘍または膵神経内分泌腫瘍、下垂体腺腫、副腎腫瘍、メルケル細胞癌、乳がん、非ホジキンリンパ腫、ホジキンリンパ腫、頭頚部腫瘍、尿路上皮癌(膀胱)、腎細胞癌、肝細胞癌、GIST、神経芽細胞腫、胆管腫瘍、子宮頸腫瘍、ユーイング肉腫、骨肉腫、SCLC、前立腺がん、黒色腫、髄膜腫、神経膠腫、髄芽腫 血管芽腫、テント上原始、神経外胚葉性腫瘍、および鼻腔神経芽細胞腫からなる群から選択される、項目6に記載の方法。
(項目10)
前記神経内分泌腫瘍が、機能性カルチノイド腫瘍、膵島細胞腺腫、ガストリノーマ、血管作用性腸管ペプチド(VIP)腫瘍、グルカゴノーマ、セロトニノーマ、ヒスタミン腫瘍、ACTH腫、褐色細胞腫、およびソマトスタチノーマからなる群から選択される、項目6に記載の方法。
(項目11)
前記神経内分泌腫瘍が、低グレード、中グレード、または高グレード神経内分泌腫瘍である、項目6に記載の方法。
(項目12)
前記がんが、小細胞肺がんである、項目1に記載の方法。
(項目13)
前記がんが、進行性中腸神経内分泌腫瘍である、項目1に記載の方法。
(項目14)
前記がんが、サンドスタチン(Novartis)またはSomatuline(登録商標)(Ipsen)に応答性でない、項目12に記載の方法。
(項目15)
前記がんが、PD-1/PD-L1経路の阻害剤に非応答性であるか、または低応答を有する、項目1に記載の方法。
(項目16)
前記神経内分泌腫瘍が、機能性神経内分泌腫瘍である、項目6に記載の方法。
(項目17)
前記神経内分泌腫瘍が、非機能性神経内分泌腫瘍である、項目6に記載の方法。
ルタセラは、ガンマ線も放出するので、これは、疾患管理ツールとしても有用であり得、その理由は、この種類の放出は、SPECTカメラで捕捉することができ、よって、薬物の分布および薬物動態を判定するのに、かつまた線量推定に使用することができるためである。
示した23。CTLA-4遮断は、T細胞活性化を促進し、かつ前臨床モデルでは、腫瘍微小環境内のFcγ受容体発現マクロファージの存在に依存するプロセスにおいて腫瘍内Tregを枯渇させることが示された24、25。
本で、2014年12月にUS FDAによって承認された。2015年4月に、これは、転移性黒色腫の単剤療法としての承認についてEMAにおいて肯定的な意見を得た。これは、非小細胞肺がん(NSCLC、扁平上皮サードライン)およびホジキンリンパ腫(サードライン)において現在調査されている。
せについて、ASCO 2015で報告した。用量漸増相においてMEDI4736+トレメリムマブ併用療法で処置された102人の患者のうち、40%がグレード3またはそれ超の処置関連AEを有し、最も一般的な処置関連グレード3~4事象は、大腸炎(n=9、9%)、下痢症(n=8、8%)、間質性肺炎(n=4、4%)、AST増加(n=4、4%)、およびALT増加(n=3、3%)であった。観察された奏功率は、すべてのコホートにわたって27%であり、41%の割合が、疾患制御を呈した(少なくとも16週間のCR、PR、およびSD)28、29。
ある。
上記を考慮すると、ルタセラを、PD-1/PD-L1/CTLA-4経路を阻害する阻害剤と組み合わせると、伝統的に処置するのが困難であったNETの有効で新しい処置をもたらすことになることが予想される。
て査定された。小細胞肺がんおよび結腸直腸がん(ともに神経内分泌)からのヒト腫瘍組織試料がこの評価に使用された。sstr2発現とCTLA-4との間の関係は、あまり報告されていない。
LASソフトウェアを用いて取得した。
10HPF(高倍率視野)当たり2未満の有糸分裂および壊死なしによって特徴付けられる。一実施形態では、中グレード腫瘍は、10HPF(高倍率視野)当たり2~10有糸分裂または壊死の病巣によって特徴付けられる。一実施形態では、高グレード腫瘍は、10HPF(高倍率視野)当たり10超の有糸分裂によって特徴付けられる。
た神経内分泌腫瘍異種移植片に投与することができる。一部の実施形態では、神経内分泌腫瘍がん幹細胞が、患者試料、例えば、組織生検、胸水、または血液試料などから単離され、免疫不全マウス内に注射され、次いでそれは、神経内分泌腫瘍細胞成長を阻害するために、本発明の併用療法(すなわち、PPRTおよびPD-1/PD-L1/CTLA-4経路の阻害剤)を投与される。一部の実施形態では、PPRTおよび/またはPD-1/PD-L1/CTLA-4経路阻害剤は、神経内分泌腫瘍成長を防止するために動物内に腫瘍形成細胞を導入すると同時に、または、導入後まもなく投与される。一部の実施形態では、PPRTおよび/またはPD-1/PD-L1/CTLA-4経路の阻害剤は、腫瘍形成細胞が指定サイズまで増殖した後、治療剤として投与される。
/または追加の抗がん剤を用いた任意の処置の4、3、2、または1週間以内に投与される。一部の実施形態では、PPRTは、PD-1/PD-L1/CTLA-4阻害薬剤および/または追加の抗がん剤を用いた任意の処置の5、4、3、2、または1日以内に投与される。PPRTおよびPD-1/PD-L1/CTLA-4阻害薬剤ならびに/または追加の抗がん剤もしくは処置は、数時間または数分のうちに(すなわち、実質的に同時に)対象に投与され得ることがさらに察知されることになる。
ロモマイシン、ダクチノマイシン、ダウノルビシン、デトルビシン、6-ジアゾ-5-オキソ-L-ノルロイシン、ドキソルビシン、エピルビシン、エソルビシン、イダルビシン、マルセロマイシン、マイトマイシン、ミコフェノール酸、ノガラマイシン、オリボマイシン、ペプロマイシン、ポトフィロマイシン、ピューロマイシン、ケラマイシン、ロドルビシン、ストレプトニグリン、ストレプトゾトシン(streptozocin)、ツベルシジン、ウベニメクス、ジノスタチン、ゾルビシンなど;代謝拮抗薬、例えば、メトトレキセートおよび5-フルオロウラシル(5-FU)など;葉酸類似体、例えば、デノプテリン、メトトレキセート、プテロプテリン、トリメトレキセートなど;プリン類似体、例えば、フルダラビン、6-メルカプトプリン、チアミプリン、チオグアニンなど;ピリミジン類似体、例えば、アンシタビン、アザシチジン、6-アザウリジン、カルモフール、シタラビン、ジデオキシウリジン、ドキシフルリジン、エノシタビン、フロクスウリジン、5-FUなど;アンドロゲン、例えば、カルステロン、プロピオン酸ドロモスタノロン、エピチオスタノール、メピチオスタン、テストラクトンなど;抗副腎剤(anti-adrenal)、例えば、アミノグルテチミド、ミトタン、トリロスタンなど;フロリン酸などの葉酸補充剤;アセグラトン;アルドホスファミドグリコシド;アミノレブリン酸;アムサクリン;ベストラブシル;ビサントレン;エダトラキセート;デホファミン;デメコルシン;ジアジコン;エルフォルミチン;エリプチニウム酢酸塩;エトグルシド;硝酸ガリウム;ヒドロキシウレア;レンチナン;ロニダミン;ミトグアゾン;ミトキサントロン;モピダモール;ニトラクリン;ペントスタチン;フェナメト;ピラルビシン;ポドフィリン酸;2-エチルヒドラジド;プロカルバジン;PSK;ラゾキサン;シゾフラン(sizofuran);スピロゲルマニウム;テヌアゾン酸;トリアジコン;2,2’,2”-トリクロロトリエチルアミン;ウレタン;ビンデシン;ダカルバジン;マンノムスチン;ミトブロニトール;ミトラクトール;ピポブロマン;ガシトシン;アラビノシド(arabinoside)(「Ara-C」);シクロホスファミド;チオテパ;タキソイド、例えば、パクリタキセル(TAXOL、Bristol-Myers Squibb Oncology、Princeton、N.J.)、およびドキセタキセル(TAXOTERE、Rhone-Poulenc Rorer、Antony、フランス);クロランブシル;ゲムシタビン;6-チオグアニン;メルカプトプリン;メトトレキセート;白金類似体、例えば、シスプラチンおよびカルボプラチンなど;ビンブラスチン;白金;エトポシド(VP-16);イホスファミド;マイトマイシンC;ミトキサントロン;ビンクリスチン;ビノレルビン;ナベルビン;ノバントロン;テニポシド;ダウノマイシン;アミノプテリン;ゼローダ;イバンドロネート;CPT11;トポイソメラーゼ阻害剤RFS2000;ジフルオロメチルオルニチン(OMFO);レチノイン酸;エスペラマイシン;カペシタビン;ならびに上記のいずれかの薬学的に許容される塩、酸、または誘導体も挙げられる。化学療法剤として、腫瘍上でホルモン作用を調節または阻害するように作用する抗ホルモン剤、例えば、タモキシフェン、ラロキシフェン、アロマターゼ阻害性4(5)-イミダゾール、4-ヒドロキシタモキシフェン、トリオキシフェン、ケオキシフェン、LY117018、オナプリストン、およびトレミフェン(ファレストン)を含めた抗エストロゲン;ならびに抗アンドロゲン、例えば、フルタミド、ニルタミド、ビカルタミド、ロイプロリド、およびゴセレリンなど;ならびに上記のいずれかの薬学的に許容される塩、酸、または誘導体も挙げられる。
ス、デフォロリムス、およびエベロリムスが挙げられる。ある特定の実施形態では、第2の抗がん剤は、エベロリムスである。
持療法が頻繁に使用される。これらの投薬レジメンは、処置に対する患者の応答に従って、かつ処置臨床医の自由裁量で変動することになることが理解されるべきである。切除不能または転移性黒色腫の処置のためのイピリムマブの推奨用量は、合計4回の用量について、3週間毎に90分にわたって静脈内投与される3mg/kgである。
研究により、アミノ酸の静脈内投与は、腎臓保護効果を有することが示された。アミノ酸(リシンおよびアルギニンを含有する)の注入は、177Lu-DOTATATEを投与する30~45分前に行うことができ、3~4時間続き得る。
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