JP6819012B2 - 癌と転移を処置するための低密度焦点式超音波 - Google Patents
癌と転移を処置するための低密度焦点式超音波 Download PDFInfo
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Description
本発明は、国立衛生研究所によって与えられた認可番号EB009040とAI059738で政府の支援を受けて作られた。政府は本発明において一定の権利を有している。
マスタードガス誘発体(例えばメクロレタミン、シクロホスファミド、クロラムブシル、メルファラン、及びイホスファミド);
エチレンイミン(例えば、チオテパ及びヘキサメチルメラミン);
スルホン酸アルキル(例えばブスルファン);
ヒドラジン及びトリアジン(例えばアルトレタミン、プロカルバジン、ダカルバジン、及びテモゾロミド);
ニトロソ尿素(nitrosureas)(例えばカルムスチン、ロムスチン、及びストレプトゾシン);
金属塩(例えばカルボプラチン、シスプラチン、及びオキサリプラチン);
植物アルカロイド(例えばビンクリスチン、ビンブラスチン、及びビノレルビンなどのビンカアルカロイド、パクリタキセル及びドセタキセルなどのタキサン、エトポシド及びテニポシドなどのポドフィロトキシン、イリノテカン及びトポテカンなどのカンプトテカン類似体(トポイソメラーゼ阻害剤));
抗腫瘍抗生物質(例えばアントラサイクリン:ドキソルビシン、ダウノルビシン、エピルビシン、ミトキサントロン、及びイダルビシン;クロモマイシン:ダクチノマイシン及びプリカマイシン;マイトマイシン及びブレオマイシンなどの様々なもの);
代謝拮抗薬(例えば葉酸桔抗体:メトトレキサート;ピリミジンアンタゴニスト:5−フルオロウラシル、フロクスウリジン(foxuridine)、シタラビン、カペシタビン、及びゲムシタビン;プリンアンタゴニスト:6−メルカプトプリン及び6−チオグアニン;アデノシンデアミナーゼ阻害剤:クラドリビン、フルダラビン、ネララビン、及びペントスタチン);
トポイソメラーゼ阻害剤(例えばイリノテカン(ironotecan)、トポテカン;アムサクリン、エトポシド、リン酸エトポシド、テニポシド);
プロテアソーム(protesomal)阻害剤;
化学療法用のNSAID;及び
様々な抗悪性腫瘍薬(例えばリボヌクレオチドリダクターゼ阻害剤:ヒドロキシ尿素;副腎皮質ステロイド阻害剤:ミトタン;酵素:アスパラギナーゼ及びペガスパルガーゼ;微小管阻害薬:エストラムスチン;レチノイド:ベキサロテン、イソトレチノイン、トレチノイン(ATRA))。
超音波刺激療法装置であって:
周波数波形を生成する制御システムと、
処置ゾーンで1〜1000W/cm2の空間ピークの一時的な平均の音響出力強度(Ispta)の周波数波形に基づいて超音波を生成するように構成された1以上のトランスデューサーであって、ここで、超音波は0.5〜5秒の範囲の時間にわたり連続的に適用され、超音波周波数は0.01〜10MHzの範囲である、トランスデューサーと
を含む音響刺激装置;
放射線療法機械;及び
第1の量の超音波及び第2の量の放射線療法が被験体に施されるよう、超音波刺激療法装置及び放射線療法機械を制御するように動作可能に構成された制御システムであって、ここで、第1及び第2の量は共に、被験体の腫瘍を処置するのに十分なものである、制御システム
を含む、システムも提供される。
該超音波刺激療法装置は:
周波数波形を生成する制御システムと、
処置ゾーンで1〜1000W/cm2の空間ピークの一時的な平均の音響出力強度(Ispta)の周波数波形に基づいて超音波を生成するように構成された1以上のトランスデューサーであって、ここで、超音波は0.5〜5秒の範囲の時間にわたり連続的に適用され、超音波周波数は0.01〜10MHzの範囲である、トランスデューサーと
を含み、
超音波刺激療法装置は、第1の量の超音波及び第2の量の化学療法が被験体に施されるよう、化学療法と組み合わせて使用され、ここで、第1及び第2の量は共に、被験体の腫瘍を処置するのに十分なものである。
該超音波刺激療法装置は:
周波数波形を生成する制御システムと
処置ゾーンで1〜1000W/cm2の空間ピークの一時的な平均の音響出力強度(Ispta)の周波数波形に基づいて超音波を生成するように構成された1以上のトランスデューサーであって、ここで、超音波は0.5〜5秒の範囲の時間にわたり連続的に適用され、超音波周波数は0.01〜10MHzの範囲である、トランスデューサーと
を含み、
超音波刺激療法装置は、第1の量の超音波及び第2の量の免疫療法が被験体に施されるよう、免疫療法と組み合わせて使用され、ここで、第1及び第2の量は共に、被験体の腫瘍を処置するのに十分なものである。
B16黒色腫腫瘍は、腫瘍に特異的なCD4+T細胞によるIL−2及びIFNγの生成を抑止する:黒色腫細胞がどのようにして腫瘍により誘発されたエフェクターCD4+T細胞応答を調節するのかを判定するために、3つの異なるマウスモデルを使用した。最初に、B16−F1黒色腫腫瘍を、腰椎の側腹部にB16細胞を皮下注射することにより、C57B1/6Jマウスにおいて誘発させた。腫瘍は7−8mmの大きさに成長し、その後CD4+T細胞を、同側の鼠蹊部の流入領域リンパ節(DLN)と遠位の対側の非流入領域頚リンパ節(NDLN)の両方から単離した。T細胞も、腫瘍を抱いていなかった対照マウスから得た。マウスの黒色腫における腫瘍抗原に特異的なT細胞寛容の以前の報告を支持すると(18、21)、腫瘍DLNから単離されたCD4+T細胞は、抗CD3及び抗CD28抗体によりエキソビボでの刺激時に、同じマウスの遠位の対側のNDLNから、又は対照の腫瘍の無いマウスのリンパ節から単離された細胞よりも著しく少ないIL−2を生成した。同様であるが、あまり明白でない効果も、IFNy(図1のAとB)について観察した。
適応免疫系は、悪性に変形した細胞を絶えず調査する(surveys)。これは、抗腫瘍免疫応答を開始するために適切なT細胞レパートリーを刺激する、腫瘍関連抗原の認識により主に達成される。しかし、腫瘍はまた、適応免疫系を回避し、且つ抗腫瘍T細胞応答を妨害するための多様な機構を利用する(1)。その結果、癌に対する優れた治療は、腫瘍に誘発された耐性の主な障害を克服しなければならない(36)。様々な機構が、異なるT細胞の亜型において腫瘍がどのようにして耐性を誘発するのかを説明するために記載されており、腫瘍抗原の不完全な提示及び抗原提示細胞の不適切な活性化、共阻害受容体によるシグナル伝達、腫瘍内微小環境内に放出された因子による免疫抑制、及び抑制細胞の局所動員を含む(9、15−17、20、37−39)。癌細胞の免疫原性細胞死(ICD)を促進する処置は、耐性を軽減し、且つその逆転を駆り立てることができる。ICDの特徴は、損傷に関連する分子パターン(DAMP)の放出、細胞表面への特定のシャペロン複合体の転位、及び腫瘍関連抗原の樹状細胞を媒介とする交差提示の増大を含む(40)。この研究において、非切除的LOFUを使用する黒色腫の新たな処置が、腫瘍により誘発される耐性の予防、逆転、又は緩和、並びにそれ故抗腫瘍免疫応答の増強を結果としてもたらすかどうかを調べることが、求められた。
actinb:F−GTGACGTTGACATCCGTAAAGA(SEQ ID NO:1)、R−GCCGGACTCATCGTACTCC(SEQ ID NO:2);
Cblb:F−GCAGCATCATTGACCCTTTCA(SEQ ID NO:3)、R−ATGTGACTGGTGAGTTCTGCC(SEQ ID NO:4);
Grail:F−ATGCAAGAGCTCAAAGCAGGAAGC(SEQ ID NO:5)、R−GTGCGCAGCTGAAGCTTTCCAATA(SEQ ID NO:6);
Ikaros:F−GCTGGCTCTCGGAGGAG(SEQ ID NO:7)、R−CGCACTTGTACACCTTCAGC(SEQ ID NO:8);
Caspase3:F−ACGCGCACAAGCTAGAATTT(SEQ ID NO:9)、R−CTTTGCGTGGAAAGTGGAGT(SEQ ID NO:10);
Egr2:F−TCAGTGGTTTTATGCACCAGC(SEQ ID NO:11)、R−GAAGCTACTCGGATACGGGAG(SEQ ID NO:12);
Grg4:F−TCACTCAAGTTTGCCCACTG(SEQ ID NO:13)、R−CACAGCTAAGCACCGATGAG(SEQ ID NO:14);
Itch:F−GTGTGGAGTCACCAGACCCT(SEQ ID NO:15)、R−GCTTCTACTTGCAGCCCATC(SEQ ID NO:16);
Foxp3:F−GGCCCTTCTCCAGGACAGA(SEQ ID NO:17);
R−GCTGATCATGGCTGGGTTGT(SEQ ID NO:18)。
低酸素腫瘍微小環境は、酸化小胞体(ER)ストレスをもたらし、結果として、タンパク質のミスフォールディングおよび小胞体ストレス応答(UPR)につながる。UPRは、UPRの延長された活性化が細胞死を誘発するが、タンパク質のミスフォールディングを補正し、癌細胞の生存および殺腫瘍性の治療に対する耐性を改善する、熱ショックタンパク質90(HSP90)を含む幾つかの分子シャペロンを誘発する。HSP90阻害剤、17AAGは、前立腺癌(PC)を含む、様々な固形腫瘍に対する見込みを示した。しかしながら、17AAGの治療量は全身毒性を引き出す。本明細書には、新しいパラダイムが開示され、ここで非切除性および非侵襲性の低エネルギー焦点式超音波(LOFU)と無毒な低用量の17AAGとの併用療法が、マウスおよびヒトのPC異種移植片中の合成致死および有意な殺腫瘍効果を引き起こす。LOFUは、細胞死を誘発することなく、腫瘍細胞においてERストレスおよびUPRを誘発する。無毒な用量の17AAGによる処置はさらに、LOFU処置したPCにおいてERストレスを増加させ、腫瘍においてUPRを細胞保護的な応答からアポトーシス応答に切り替え、結果として、アポトーシスおよび腫瘍増殖遅滞の有意な誘発をもたらした。LOFU誘発性のERストレスは、超音波処置した腫瘍を17AAGなどの化学療法剤に対してより感受性にする。LOFU誘発性の化学増感は、腫瘍、例えば、局所に進行した及び再発性の腫瘍に対して使用することができる新しい治療である。
結果は、LOFUと化学療法の併用療法が、腫瘍中のアポトーシス促進性の遺伝子の発現を再プログラムし、腫瘍異種移植片中の広範なアポトーシスを誘発し、結果として、マウスおよびヒトのPC腫瘍の有意な腫瘍増殖遅滞をもたらすことを実証している。LOFUの効果は化学療法に対する耐性を改善することができ、化学増感を達成することができる。
<動物>
5〜6週齢の雄のC57Bl/6(NCI−Fort Dietrich, MD, USA)マウスおよび胸腺欠損ヌード(BalbCnu/nuマウス、Jackson Laboratory, Bay Harbor, ME, USA)マウスを、自由に維持し、すべての試験を、the Institutional Animal Care and Use Committee of the Albert Einstein College of Medicineのガイドラインおよびプロトコルの下で実行した。
C57Bl/6およびBalbCnu/nuマウスの側腹部に、それぞれ、1×105RM−1(マウス前立腺癌細胞株)および1×106PC3(ヒト前立腺癌細胞株)の細胞を皮下注射した。およそ10日後に、腫瘍が触知可能になる(直径3−5mm)と、LOFU処置を開始した。マウスを、処置を受けない群、LOFU、17AAG(InvivoGen, San Diego, CA, USA)、および17AAG+LOFUを受ける群の4つの群(n=5/群)に分けた。触知可能な腫瘍を、2週間にわたって投与される5つの分画に対して3−4日ごとにLOFUにより処置した。動物は、この間に17AAGを1週当たり3回受けた。腫瘍体積の測定を、全身毒性の徴候(倦怠感および下痢)の同時の物理的評価とともに、ノギスを使用して週2回実行した。
治療および画像化プローブシステム(TIPS, Philips Research North America, Briarcliff Manor, NY, USA)を、すべての超音波照射に対して利用した。該システムは、8要素の球殻環状アレイトランスデューサー(8−element spherical shell annular array transducer)(80mmの曲率半径、80mmの開口部)の他に、トランスデューサーの移動および正確な位置決めを可能にする移動ステージも含む。トランスデューサーは1.0MHzで操作され、結果として、直径およそ1.5mmおよび長さ12mm(−6dBの圧力)の焦点がもたらされた[12、13]。
処置日に、ケタミンおよびキシラジン(100l/マウスに対して7:1mg/ml、腹腔内(i.p.))で動物に麻酔をかけた。治療のために位置付けられると、腫瘍を脱気水および超音波ゲルを使用してTIPSシステムに音響的に結合した。
侵襲性の手段による腫瘍内の温度の予測は、併用療法の治療効果を不必要に変調し得る。それ故、上に記載されたセットアップおよび治療プロトコルを使用して腫瘍内の温度上昇を予測するために、超音波照射を、組織模倣ファントム内の6mm×6mmの領域内で実行し、[76]そこに、T型熱電対(直径200μm)を3mmの深さで埋め込んだ。これらのインビトロでの照射を5回繰り返し、結果を平均した。
アポトーシス細胞を、TUNEL(TdT媒介性のジゴキシゲニン標識したdUTPニック末端標識)染色を行うことによってインサイツで検出した。簡潔には、パラフィン包埋の切片を、脱パラフィンし、段階的なアルコールによって再水和し、ApopTagキット(Intregen Co, Norcross, GA, USA)を使用して染色した。腫瘍細胞におけるアポトーシスの比率を、各々の高倍率視野におけるアポトーシス細胞のパーセントをカウントすることによって定量化した。
LOFUの24時間後に、腫瘍細胞を採取し、リン酸緩衝食塩水で洗浄し、TPER (Thermo Fisher Scientific, Rockford, IL, USA)を使用して溶解した。細胞溶解物を、SDS−PAGEにさらし、フッ化ポリビニリデン膜に移し、PERK、pPERK、eIF2、peIF2、ERp72、ERp44、ERp57、ベクリン(細胞シグナル伝達、Danvers, MA, USA)、Lamp2a(Abcam, Cambridge, MA, USA)に対する一次抗体、および西洋ワサビペルオキシダーゼ抱合二次抗体でイムノブロットした。ブロットを、ECLキット(GE Healthcare, Piscataway, NJ, USA)を使用して発展させた。各ブロットの免疫反応性バンドのデンシトメトリー分析を撮影し、その後、画像をデジタル化し、Gel Doc XRシステム(Bio−Rad, Hercules, CA, USA)を使用することによって分析した。
様々なコホートにおいて、LOFU、17AAG、およびLOFU+17AAGにより、側腹部腫瘍を処置した。処置の24時間後に、腫瘍細胞を、コラゲナーゼ消化によって分離し、前立腺癌幹細胞マーカー、SCA1、CD44、およびCD133の発現のためにフローサイトメトリーによって分析した。単離した腫瘍細胞を、FITCと抱合した抗SCA1(BD Biosciences, La Jolla, CA, USA)、pacific blueと抱合した抗CD133(eBioscience, San Diego, CA, USA)、およびPEと抱合した抗CD44(BD Biosciences, La Jolla, CA, USA)で染色した。LSRII(BD Biosciences)を使用して、データ取得を実行し、FlowJo v.7.1(Treestar Inc, Ashland, OR, USA)ソフトウェアによって分析した。
異なる処置群におけるマウス生存/死亡率を、Sigma−PlotおよびGraphPad Prism (version 4.0 for OS X, San Diego, CA, USA)ソフトウェアを使用して放射線量に応じたカプラン・マイヤー法によって分析した。
デジタル画像に関して、サンプリング領域を、データ定量化のためのデジタル取得に対してランダムに選択した。デジタル画像データを、あらゆる処置に関して盲検方法で評価した。両側スチューデントt検定を使用して、代表的な平均値の標準誤差(SEM)を有する実験コホート間の有意差(p<0.05)を判定した。
幾つかの実施形態では、トランスデューサーアプリケーターは、臨床医または介護者によって携帯され得るように設計されている。幾つかの実施形態では、アプリケーターは、図19に例証される位置決め装置(500)などの、機械的位置決め装置に取り付けられる。位置決め装置(500)は、手動で操作されるか、またはロボット制御され得る。本実施形態では、位置決め装置(500)は、トランスデューサーが移動する円弧状のレールであり、特に、トランスデューサーは、順にレールに載せられるケーブル駆動の運び台に取り付けられてもよい。トランスデューサーが三次元で位置決めされ得るように、レール自体は回転可能であってもよい。位置決め装置(500)は、トランスデューサーの下に及びその目標範囲内に患者が適合することができるように十分に大きくあり得る。図19は、レール上に位置決めされた1つのトランスデューサーのみを示すが、1つを超えるトランスデューサーがレール上に配されること、及び/又は1つ以上の他のトランスデューサーを支持する他のレールが設けられてもよいことが認識されるべきである。幾つかの実施形態では、時にヘキサポッドと呼ばれる、スチュワートプラットホームが、位置決め装置において使用されてもよい。処置パラメーターを設定し、位置決め装置を操作するために、コンピュータープログラミングが使用されてもよい。
幾つかの実施形態では、処置システムは、超音波エネルギーまたは他のエネルギーに暴露された皮膚を冷却するための患者冷却機構を含む。
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Claims (14)
- 超音波刺激療法装置であって、超音波刺激療法装置は、
制御システム、および、
制御システムに結合され、且つ、1つ以上の超音波ビームの周波数波形が処置ゾーンで1−1000W/cm2の空間ピーク時間平均音響出力強度(Ispta)を持つように1つ以上の超音波ビームを生成するように構成された1つ以上のトランスデューサーを含み、1つ以上の超音波ビームは0.5〜5秒間適用され、および、1つ以上のトランスデューサーは0.01〜10MHzの範囲の1つ以上の超音波周波数を生成し、1つ以上のトランスデューサーは、−3dBのビームプロファイルウエストが5mm以上となるように、カラム状の超音波を生成するように構成される少なくとも2つのトランスデューサーを含む、超音波刺激療法装置。 - 1つ以上のトランスデューサーは、0.05〜5または0.5〜1.5MHzの範囲の1つ以上の超音波周波数;及び20〜1000W/cm2のIsptaを生成するように構成される、請求項1に記載の超音波刺激療法装置。
- トランスデューサーは、単一のトランスデューサー素子または複数のトランスデューサー素子を随意に含む、請求項1に記載の超音波刺激療法装置。
- 2つ以上のトランスデューサーまたはトランスデューサー素子は、2つ以上の周波数を生成するように構成される、請求項3に記載の超音波刺激療法装置。
- 1つ以上のトランスデューサーまたはトランスデューサー素子は、300kHz〜3MHzの範囲内の超音波周波数を生成するように構成され、1つ以上の追加のトランスデューサーまたはトランスデューサー素子は、30kHz〜300kHzの範囲内の超音波周波数を生成する、請求項4に記載の超音波刺激療法装置。
- 2つ以上の超音波トランスデューサーは、処置ゾーンを通過する超音波ビームを生成し、各ビームは、10〜500W/cm2の範囲で処置ゾーンにおいてIsptaを有している、請求項1に記載の超音波刺激療法装置。
- 超音波刺激療法装置は、少なくとも1立方センチメートルの腫瘍に対して5秒未満の処置時間のために構成されてなる、請求項1に記載の超音波刺激療法装置。
- 2つのトランスデューサーまたは3つのトランスデューサーは、実質的に同位相であり且つ処置ゾーン内で交差する超音波ビームを生成し;各ビームは70〜100W/cm 2 の範囲で、交差ゾーンにおいてI spta を有し;超音波は連続して処置ゾーン当たり1〜5秒間適用される、請求項1に記載の超音波刺激療法装置。
- 2つ以上のトランスデューサーを含み、ここで、第1の大きなトランスデューサーは処置ゾーンよりも大きく;第2の小さなトランスデューサーは処置ゾーンよりも小さい、請求項1に記載の超音波刺激療法装置。
- 超音波は、1時間未満の時間にわたり2つ以上の塊の腫瘍に適用される、請求項1に記載の超音波刺激療法装置。
- 各トランスデューサーから処置ゾーンに加えられる音圧は0.1〜10MPaであり、および随意に、1つ以上のトランスデューサーは、10%、20%、30%、40%、50%、60%、70%、80%、90%
、または100%のデューティーサイクルで構成される、請求項1に記載の超音波刺激療法装置。 - 1つ以上のトランスデューサーは、単周波音あるいは多周波数チャープの超音波を生成するように構成され、または、1つ以上のトランスデューサーは超音波の周波数が適用中に掃引されるように構成される、請求項1に記載の超音波刺激療法装置。
- 1つ以上のトランスデューサーは、処置ゾーンで到達した最高温度が45°C未満であるように超音波を生成するように構成され;超音波は約2秒以下のあいだ処置ゾーンに適用され;および随意に、1つ以上のトランスデューサーは腫瘍において非切除性のストレスを誘発するように構成される、請求項1に記載の超音波刺激療法装置。
- 超音波刺激療法装置は、HSP90阻害剤を含む化学療法薬と組み合わせて使用される、請求項1に記載の超音波刺激療法装置。
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US11179581B2 (en) | 2015-03-09 | 2021-11-23 | The Research Foundation For The State University Of New York | Systems and methods for promoting cellular activities for tissue maintenance, repair, and regeneration |
JP2021058618A (ja) * | 2015-06-03 | 2021-04-15 | モンテフィオーレ メディカル センターMontefiore Medical Center | 癌と転移を処置するための低密度焦点式超音波 |
JP7105294B2 (ja) | 2015-06-03 | 2022-07-22 | モンテフィオーレ メディカル センター | 癌と転移を処置するための低密度焦点式超音波 |
JP2022165965A (ja) * | 2015-06-03 | 2022-11-01 | モンテフィオーレ メディカル センター | 癌と転移を処置するための低密度焦点式超音波 |
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