JP2019510769A - チェックポイント阻害剤と組み合わされた腫瘍溶解性ウイルスによるがん療法 - Google Patents
チェックポイント阻害剤と組み合わされた腫瘍溶解性ウイルスによるがん療法 Download PDFInfo
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Abstract
Description
(a)蛍光in situハイブリダイゼーション(FISH)
FISHアッセイ:方法手順は、基本的にSilahtarogluら(Molecular and Cellularプローブス.2003年;17:165〜169頁)およびNehmeら(J Neurosci Methods.2011年;196:281〜288頁)により記載されているように行った。FISHアッセイは、インビトロで培養したヒトNBK細胞で最初に確立し、免疫不全ラットのヒト神経膠腫異種移植片に由来するパラフィン包埋腫瘍組織に拡大した。次いでアッセイプロトコルを、患者由来パラフィン包埋または凍結保存腫瘍材料のH−1PV DNAおよびRNA配列の検出に適用した。
NS1−アンチセンス:
5DIGN/TCAGCACACAACAGATGGCAT/3DIGN
VP−アンチセンス:
5DIGN/TACTATCCAGAGCAACCATCAT/3DIGN
NS1−センス:
5DIGN/AATTCGCTAGGTTCAATGCGCT/3DIGN
VP−センス:
5DIGN/TGACCTACCAACATCAGATACA/3DIGN
T細胞を健康なドナーから採取し、短時間の静置後、CD3/CD28被覆96ウェルプレート(BioLegend、USA製の抗CD3、BD、ドイツ製の抗CD8)で一晩刺激した。T細胞培養培地は、RPMI1640(PAA、USA)、10%ヒト血清(56℃で30分間、加熱不活性化した)、1%グルタミン(PAA、USA)、1%ペニシリン/ストレプトマイシン(PAA、USA)、1%非必須アミノ酸(PAA、USA)、および1%HEPES(PAA、USA)を含有した。市販の腫瘍細胞株を、供給者の指示に従って培養した。細胞の定量化は、特に播種直後(すなわち、増殖アッセイのための0.5×105細胞/ml、細胞をプレートに均等に播種)、およびインキュベーション/処理後に、自動細胞カウンターTC10(BioRad、ドイツ)による二重測定により3回ずつ行った。初代細胞株を、最近記載されているように(Castroら、2013年)、Multiplexion(ハイデルベルク、ドイツ)によるMultiplex Cell Authenticationを用いて確認した。SNPプロファイルがマッチした既知のプロファイルは固有であり、ヒト上皮腫瘍細胞株と一致した。全ての細胞株を、PCRによりマイコプラズマ汚染についてテストした。
2レーザーアレイリーダーは、目的とする全てのサイトカインおよびケモカインを同時に定量化する。標準曲線および濃度を、5パラメーターロジスティックプロット回帰式に基づいてBio−Piex Manager4.1.1で計算した。簡単には、切断した凍結組織の小片を150μl冷溶解緩衝液に移し、ボルテックスし、−80℃(10分間)で凍結し、氷上で解凍した。冷超音波浴でインキュベーション(10分間)後、試料を−80℃で再び凍結し、氷上で解凍し、遠心分離した(13,000rpm、20分間、4℃)。上清のタンパク質濃度を判定し、溶解物の濃度を、ヒト血清希釈液(BioRad)を用いて1000μg/ml(生検用には300μg/ml)に調整し、組織溶解物中のサイトカイン/ケモカイン濃度を、製造者の指示(BioRad Laboratories、ハーキュリーズ、CA、USA)に従ってマルチプレックスタンパク質アレイにより定量化した。分析物の検出感度は1pg/mlから100ng/mlに及んだ。プラットフォームにより「範囲外」として認定された値は、分析物ごとに生成した単一標準曲線に基づき外挿した。標準曲線が最小標準偏差を示したことから、最高濃縮標準濃度を外挿に使用した。サイトカインのクラス(降順、例えばTH1、TH2、TH17等の)を形成するために、特定の用語(例えばGO:0043030:マクロファージ活性化の制御、GO:0042104:活性化T細胞増殖の正の制御、またはGO:0006935:走化性)または文献検索の評価においてAMIGOデータベースを使用した(http://amigo.qeneontologv.org/)。TH1、TH2またはTH17優位サイトカインを含む試料由来陽性対照を分析に使用した。
FFPE組織を脱パラフィンし、再水和した(BOND Dewax Solution、Leica、ドイツ)。100℃で熱誘導エピトープ回収(HIER)(BOND Epitope Retrieval Solution 1または2、Leica、ドイツ)後、内因性ペルオキシダーゼ活性を、3%過酸化物ブロックと20分間インキュベーションしてブロックした(BOND Polymer Refine Detection System、Leica、ドイツ)。切片を10%正常ヤギ血清(Vector、USA)でブロックした。使用抗体および希釈のリストは以下に見い出すことができる。これらを、一次抗体として室温で30分間適用した。スライドを、二次抗体(ウサギ抗マウスIgG、Bond Polymer Refine Detection System、Leica、ドイツ)と室温で8分間インキュベートした。シグナルのさらなる増幅は、西洋ワサビペルオキシダーゼとコンジュゲートし、多数のデキストラン分子に結合した三次抗体との室温で8分間のインキュベーションにより達成した(Poly−HRP−マウス抗ウサギIgG、Bond Polymer Refine Detection System、Leica、ドイツ)。抗原検出は、3,3−ジ−アミノ−ベンジジン(DABクロモゲン、Bond Polymer Refine Detection System、Leica、ドイツ)による呈色反応により行った。切片をヘマトキシリン(Bond Polymer Refine Detection System、Leica、ドイツ)で対比染色し、Aquatex(Merck、ドイツ)でマウントした。マッチしたアイソタイプ対照を陰性対照として使用し、隣接する正常組織または既知の陽性細胞を陽性対照として使用した。
染色免疫細胞の数を、パーソナルコンピューターに接続されたNOP Nanozoomer(Hamamatsu Photonics、日本)からなるコンピューター画像解析システムを用いてカウントした。全組織切片の完全な顕微鏡画像を自動的に取得し(バーチャル顕微鏡法)、測定領域にわたる平均細胞密度を分析に使用した。細胞数は、以前に報告されているように(Halamaら、2011b;Halamaら、2010:Halamaら、2009b)、目的とする任意の領域(平均10mm2、最大40mm2)にわたって、特別に開発されたソフトウェアプログラム(VISソフトウェアスイート、Visiopharm、デンマーク)により生成した。全ての評価を生合成について目視でチェックした。
実験ごとに、結腸直腸がん肝転移の浸潤縁由来の組織(最大10g)を、カッティング工程ならびに40μm細胞ストレーナおよびRPMI培地を用いる複数回の洗浄工程により分離した。次いで抽出細胞を、RPMI培地(10%FCSにより補充した)を含む24ウェルプレートに一晩入れ、次いで場合によりモネンシン(BD Biosciences、ドイツ)で3時間ブロックした。次いで細胞を収集し、遠心分離し、フローサイトメトリー標準プロトコルを用いてCD3、CD8、CD4およびCCL5について分析した。
進行肝転移(サイズおよび数の進行)を伴う結腸直腸がん(横行結腸の低分化腺癌;変異状態:KRAS WT、NRAS WT、MSS;初回手術2013年)に罹患している患者を、3日連続注入(4×108pfu;1〜3日目)で適用した1.2×109PFUパルボウイルスH−1の累積用量で治療し、その後、製造者の薬量(適正な処方についての薬理的決定)(2mg/Kg/BW、1日目)に従って、免疫チェックポイント阻害剤ペンブロリズマブ(キイトルーダ(登録商標))により治療した。同じ投与計画によるこの治療を、5週間後に繰り返した。
手術不能の多形性神経膠芽細胞腫に罹患している患者を、3日連続注入で適用した1.2×109PFUパルボウイルスH−1の累積用量で治療し、その後、製造者の薬量(2mg/Kg/BW、H1−PV投与の3日後)に従って、ペンブロリズマブ(キイトルーダ(登録商標))により治療した。
Claims (14)
- (a)腫瘍溶解性ウイルスを(b)チェックポイント阻害剤と組み合わせて含有する医薬組成物。
- 腫瘍溶解性ウイルスが、パルボウイルスH−1、またはLuIII、マウス微小ウイルス(MMV)、マウスパルボウイルス(MPV)、ラット微小ウイルス(RMV)、ラットパルボウイルス(RPV)、もしくはラットウイルス(RV)から選択される、関連するげっ歯類パルボウイルスである、請求項1に記載の医薬組成物。
- チェックポイント阻害剤が抗PD1抗体である、請求項1に記載の医薬組成物。
- 抗PD1抗体がペンブロリズマブである、請求項3に記載の医薬組成物。
- 化学療法剤、生物治療剤、免疫原性剤、免疫刺激サイトカイン、および免疫刺激サイトカインをコードする遺伝子をトランスフェクトされた細胞から選択される、1つまたは複数の追加の治療剤をさらに含む、請求項1から4のいずれか一項に記載の医薬組成物。
- がんを治療する方法における使用のための、請求項1から5のいずれか一項に記載の医薬組成物。
- 腫瘍溶解性ウイルスおよびチェックポイント阻害剤が連続的に投与される、請求項6に記載の使用のための医薬組成物。
- 使用が、固形腫瘍、血液がん、および/またはがん幹細胞を治療するためである、請求項6または7に記載の使用のための医薬組成物。
- がんが、脳がん、結腸がん、膀胱がん、肝臓がん、乳がん、腎臓がん、頭部/頚部扁平上皮細胞癌、肺がん、悪性メラノーマ、卵巣がん、膵臓がん、前立腺がん、腎細胞がん、または胃がんである、請求項6から8のいずれか一項に記載の使用のための医薬組成物。
- 脳がんが多形性神経膠芽細胞腫である、請求項9に記載の使用のための医薬組成物。
- 腫瘍溶解性ウイルスおよび/またはチェックポイント阻害剤が、腫瘍内または静脈内投与により投与される、請求項6から10のいずれか一項に記載の使用のための医薬組成物。
- 第1の容器、第2の容器、および添付文書を含むキットであって、第1の容器が、腫瘍溶解性ウイルスを含有する医薬組成物の少なくとも1つの用量を含み、第2の容器が、チェックポイント阻害剤を含む医薬組成物の少なくとも1つの用量を含み、および添付文書が、医薬組成物を用いてがんを有する個体を治療するための指示を含む、キット。
- がんが、脳がん、結腸がん、膀胱がん、肝臓がん、乳がん、腎臓がん、頭部/頚部扁平上皮細胞癌、肺がん、悪性メラノーマ、卵巣がん、膵臓がん、前立腺がん、腎細胞がん、または胃がんである、請求項12に記載のキット。
- 脳がんが多形性神経膠芽細胞腫である、請求項13に記載のキット。
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PCT/EP2017/056886 WO2017167626A1 (en) | 2016-04-01 | 2017-03-22 | Cancer therapy with an oncolytic virus combined with a checkpoint inhibitor |
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CN109022616B (zh) * | 2018-07-25 | 2021-11-12 | 广州烨善生物科技有限公司 | 一种检测溶瘤病毒的探针及其应用 |
EP3657172A1 (en) | 2018-11-22 | 2020-05-27 | Deutsches Krebsforschungszentrum, Stiftung des öffentlichen Rechts | Method for predicting the clinical response of oncolytic parvovirus h1 (h-1pv) treatment in a patient suspected of suffering from cancer by measuring the expression levels of laminins and/or galectins as biomarkers in a patient´s sample |
CN113924317A (zh) * | 2019-02-01 | 2022-01-11 | 葛兰素史克知识产权开发有限公司 | 贝兰他单抗莫福汀与派姆单抗组合用于治疗癌症 |
CA3131259A1 (en) * | 2019-02-28 | 2020-09-03 | Shattuck Labs, Inc. | Combination therapies |
WO2021050093A1 (en) * | 2019-09-10 | 2021-03-18 | Novocure Gmbh | A method of reducing viability of cancer cells by applying alternating electric fields and administering checkpoint inhibitors to the cancer cells |
CN111154806A (zh) * | 2020-01-08 | 2020-05-15 | 深圳普菲科生命科技有限公司 | 一种嵌合外源超级细胞因子的溶瘤病毒载体系统及其在药物中的应用 |
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EA201891679A1 (ru) | 2019-04-30 |
KR102195055B1 (ko) | 2020-12-24 |
EP3225253A1 (en) | 2017-10-04 |
AU2017242089A1 (en) | 2018-08-30 |
CL2018002793A1 (es) | 2019-02-01 |
US11027013B2 (en) | 2021-06-08 |
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WO2017167626A1 (en) | 2017-10-05 |
ZA201805548B (en) | 2019-11-27 |
EA037354B1 (ru) | 2021-03-17 |
US11964015B2 (en) | 2024-04-23 |
CA3019634A1 (en) | 2017-10-05 |
US20210228714A1 (en) | 2021-07-29 |
CN109069601A (zh) | 2018-12-21 |
LT3436058T (lt) | 2020-02-10 |
MX2018010709A (es) | 2019-01-14 |
AU2017242089B2 (en) | 2019-08-15 |
KR20180127468A (ko) | 2018-11-28 |
NZ745264A (en) | 2020-10-30 |
BR112018069927A2 (pt) | 2019-02-05 |
JP6689400B2 (ja) | 2020-04-28 |
IL261554A (en) | 2018-10-31 |
SG11201807977XA (en) | 2018-10-30 |
CN109069601B (zh) | 2022-05-10 |
IL261554B (en) | 2022-05-01 |
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