JP2023526091A - がんの予防または治療用薬学的組成物 - Google Patents
がんの予防または治療用薬学的組成物 Download PDFInfo
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Abstract
Description
免疫チェックポイント阻害剤は、同時に(simultaneous)、別々に(separate)または順次に(sequential)投与されるものであってもよいが、これに限定されるものではない。
実験に使用された動物は、7~8週齢の雌BALB/Cマウスであり、ナラバイオテック(Nara Biotech.,Seoul,South Korea)から購入した。マウスは、バイロキュア研究所の動物実験室で7日間の適応期間後に実験を進め、適応期間中に水と飼料を制限しなかった。実験動物に標準化された環境を提供し、12時間間隔で昼と夜を維持し、室内温度(23±2℃)を適正レベルに維持させた。図1に示されたように、マウスに発がん物質であるAzoxymethane(AOM)(Merk,Cat#.25843-45-2)を12mg/kgの濃度で単回腹腔注入し、1週間後に一般飲用水を2.5%(W/V)のDextran Sulfate Sodium(DSS)に変えて1週間供給し、以後、2週間休止期を与え、AOM処理を除く1週間のDSS処理および2週間の休止期を4回繰り返すことによって、大腸炎関連大腸がん(Colitis associated Colon Rectal Cancer)を誘導した。
実験に使用されたマウスを正常対照群、AOM/DSS誘導大腸がん群、レオウイルス経口投与群、免疫チェックポイント阻害剤(anti-PD-L1抗体)腹腔投与群、およびレオウイルス/免疫チェックポイント阻害剤の併用投与群に分けて実験を進めた。前記大腸がん動物モデルにレオウイルスを投与する方式は、経口投与方法(Oral administration)を使用し、抗体投与方式は、腹腔内直接投与方法(Intraperitoneal injection)を使用して進めた。
レオウイルス(type 3,Dearing)は、1×108 TCID50/100μL PBS(Reovirus/0.1%(w/v)Human serum albumin(HAS)in 1xPBS)で図1に示されるように5日間連続して経口投与し、anti-PD-L1抗体(BioXcell,Cat# BE0101)は、5mg/kgで隔日で3回腹腔内に投与した。このような投与は、図1のように計4回にわたって繰り返し施行した。
AOM最初処理後に39日目から重さ測定、便と肛門状態、生存率およびがんの形成と成長に対する観察を通じて大腸がんの発病有無と症状の程度を観察しつつ実験を進めた。
統計学的分析は、GraphPad Prism 6を使用して行った。One-way ANOVA検定法中、Dunnett’s multiple comparison testを用いて正常対照群、AOM/DSS誘導大腸がん群、レオウイルス経口投与群、免疫チェックポイント阻害剤腹腔投与群およびレオウイルス/免疫チェックポイント阻害剤の併用投与群の間の差異を比較した。0.05未満のp値を有する差異を統計的に有意的なものと見なした。データは、平均およびSEMで示した。
実施例2のレオウイルスを含む組成物の経口投与およびanti-PD-L1抗体の腹腔内処理された大腸がん動物モデルマウスの大腸がん関連疾患の重症度を測定するために、体重変化、便の固まりおよび便や肛門で肉眼的に観察される血便の有無を図2に記載された基準の疾患活動性指標(DAI)の等級によって確認して、疾患活動性指標を測定した。
図3に示されたように、AOM/DSSを投与したマウスでは、投与後に4日目から軟便および肉眼的血便が見始め、7日目にすべてのマウスで下痢と血便を観察することができた。一方、レオウイルスの経口投与およびanti-PD-L1抗体の腹腔内併用投与群では、下痢および血便の程度が統計的に有意に大きく改善されることを確認した。
このような結果は、レオウイルスを含む組成物(経口投与)と免疫チェックポイント阻害剤(例えば、anti-PD-L1抗体)の併用投与が、大腸がんに対して優れた抗がん効果を示すことを示す。
大腸がん動物モデルは、大腸での持続的炎症およびこれによるがんの形成を通じて死亡に至る。
図4に示されたように、本大腸がん動物モデルにおいて病の進行につれてAOM/DSS誘導大腸がん群および単独投与群(ウイルスまたは抗体投与群)において死亡事例が現れたが、併用投与群では、死亡事例が現れなかった。
このような結果は、レオウイルスを含む組成物(経口投与)と免疫チェックポイント阻害剤(例えば、anti-PD-L1抗体)の併用投与が、大腸がんで生存率を大きく改善させることができることを示す。
本大腸がん動物モデルにおいて病の進行につれて単独投与群(ウイルスまたは抗体投与群)において部分的ながんの形成抑制または微々たる効果が予想される。一方、併用投与群では、このような炎症によるがんの形成が大きく抑制されることが予想される。
したがって、レオウイルスを含む組成物(経口投与)と免疫チェックポイント阻害剤(例えば、anti-PD-L1抗体)の併用投与は、大腸がんでがんの形成および成長を大きく抑制すると期待される。
実験に使用された動物は、7~8週齢の雌BALB/Cマウスであり、ナラバイオテック(Nara Biotech.,Seoul,South Korea)から購入した。マウスは、バイロキュア研究所の動物実験室で7日間の適応期間後に実験を進め、適応期間中に水と飼料を制限しなかった。実験動物に標準化された環境を提供し、12時間間隔で昼と夜を維持し、室内温度(23±2℃)を適正レベルに維持させた。マウスに大腸がん細胞株(CT26 cells、1×106cells/10μL PBS)を大腸壁に注入して移植した。移植2週後にがんが形成されることを確認して、大腸がん動物モデルを確立した。
実験に使用されたマウスは、正常対照群、CT26細胞移植大腸がん群、レオウイルス経口投与群、およびレオウイルス/免疫チェックポイント阻害剤の併用投与群に分けて実験を進めた。前記大腸がん動物モデルにレオウイルスを投与する方式は、経口投与方法(Oral administration)を使用し、抗体投与方式は、腹腔内直接投与方法(Intraperitoneal injection)を使用して進めた。
CT26細胞移植後4日後にレオウイルス(type 3,Dearing)を1×109/100μL PBS(Reovirus/0.1%(w/v)Human serum albumin(HAS)in 1x PBS)で3週間連続して経口投与し、anti-PD-L1抗体(BioXcell,Cat# BE0101)は、2.5mg/kgで3日ごとに3回腹腔内に投与した(図5)。
本大腸がん動物モデルにおいて病の進行につれて図6に示されたようにCT26細胞移植大腸がん群に比べて治療群(ウイルス単独またはanti-PD-L1抗体併用投与)において生存率が改善されることを観察した。
このような結果は、レオウイルスを含む組成物(経口投与)の単独または免疫チェックポイント阻害剤(例えば、anti-PD-L1抗体)の併用投与が、大腸がんで生存率を大きく改善させることができることを示す。
実験に使用された動物は、5~8週齢の雌C57BL/6マウスであり、ナラバイオテック(Nara Biotech.,Seoul,South Korea)から購入した。マウスは、バイロキュア研究所の動物実験室で7日間の適応期間後に実験を進め、適応期間中に水と飼料を制限しなかった。実験動物に標準化された環境を提供し、12時間間隔で昼と夜を維持し、室内温度(23±2℃)を適正レベルに維持させた。マウスに黒色腫細胞株(B16F10 cells、1×105 cells/50μL PBS)を脇腹に皮下注射した。
抗がん効果試験には、vehicle、0.1%(w/v)Human serum albumin(HAS)in 1x PBSを投薬した対照群、レオウイルス経口投与群、免疫チェックポイント阻害剤(anti-PD-L1抗体)腹腔投与群、およびレオウイルス/免疫チェックポイント阻害剤の併用投与群に分けて実験を進めた。前記大腸がん動物モデルにレオウイルスを投与する方式は、経口投与方法(Oral administration)を使用し、抗体投与方式は、腹腔内直接投与方法(Intraperitoneal injection)を使用して進めた。
図7に示されたように、B16F10細胞移植後1週間後にレオウイルス(type 3,Dearing)を1×109 TCID50/100μL PBS(Reovirus/0.1%(w/v)Human serum albumin(HAS)in 1x PBS)で1、2、3、6、7、8日の6回経口投与し、anti-PD-L1抗体(BioXcell,Cat# BE0101)は、5mg/kgで隔日で3回腹腔内に投与した。
8-1.がんの成長測定による評価
図8に示されたように、本皮膚がん動物モデルにおいて無処理対照群は、マウスに腫瘍が生成された後、持続的に成長することを確認できた。病の進行につれて単独投与群(ウイルスまたは抗体投与群)において、対照群に比べて、がんの成長遅延効果が観察された。一方、併用投与群では、がんの成長が大きく抑制された。
したがって、レオウイルスを含む組成物(経口投与)と免疫チェックポイント阻害剤(例えば、anti-PD-L1抗体)の併用投与は、皮膚がんの予防または治療に有用に使用されると期待される。
図9に示されたように、本皮膚がん動物モデルにおいて病の進行につれて対照群および単独投与群(ウイルスまたは抗体投与群)に比べて、併用投与群では、生存率が大きく向上した。
したがって、レオウイルスを含む組成物(経口投与)と免疫チェックポイント阻害剤(例えば、anti-PD-L1抗体)の併用投与は、皮膚がんで生存率を大きく改善させると期待される。
実験に使用された動物は、5~8週齢の雄BALB/Cマウスであり、ナラバイオテック(Nara Biotech.,Seoul,South Korea)から購入した。マウスに腎臓がん細胞株(RENCA cells、2×105 cells/50μL PBS)を脇腹に皮下注射した。
RENCA細胞移植1週間後にレオウイルス(type 3,Dearing)を1×109 TCID50/100μL PBS(Reovirus/0.1%(w/v)Human serum albumin(HAS)in 1x PBS)で1回/日で10日間経口投与した(図10)。
図11に示されたように、本腎臓がん動物モデルにおいて無処理対照群は、マウスに腫瘍が生成された後、持続的に成長することを確認できた。また、病の進行につれてレオウイルス経口投与群において、対照群に比べて、がんの成長遅延効果が観察された。
本実施例では、レオウイルス経口投与により抗がん免疫細胞CD8+ T細胞の腫瘍内浸透増加が誘導されるか否かをin vivoで確認した。
C57BL6結腸腺がん細胞に由来するMC38細胞株を50μl PBS中に1.0×105細胞数の濃度で再懸濁させ、6週齢の雄C57BL6マウスの脇腹に皮下注射した。MC38細胞移植後1週間後にレオウイルス(type 3,Dearing)を1×109 TCID50/100μL PBS(Reovirus/0.1%(w/v)Human serum albumin(HAS)in 1x PBS)で1回/日で10日間経口投与した(図12)。
図13に示されたように、本大腸がん動物モデルにおいて無処理対照群は、マウスに腫瘍が生成された後、持続的に成長することを確認できた。また、病の進行につれてレオウイルス経口投与群において、対照群に比べて、がんの成長遅延効果が観察された。
投薬3日、10日後にマウスから腫瘍を採取して、PBSで洗浄して、2~4mmのサイズに切った後、0.1~0.5% type I collagenase(Gibco,Cat No.P2031)を含むPBS 1mlを追加して、37℃で30分~1時間処理した。そこへFACSバッファー(0.1%BSA+0.01%sodium azide in PBS)10mlを追加して混合した後、300~400gで5分間遠心分離して、上澄み液を捨てた後、沈殿物を7ml FACSバッファーで回収して、70μm cell strainerでろ過した。ろ過した単一細胞をFACSバッファー10mlを追加して混合した後、300~400gで5分間遠心分離して、沈殿物を回収した。上澄み液を捨てた後、ACK lysisバッファー(Lonza cat no.10-548E)1~2mlを入れ、常温で1分間放置した後、FACSバッファー10mlを追加して混合した後、300~400gで5分間遠心分離して回収した。適正量のFACSバッファーで再懸濁した後、CD8単クローン抗体(BD Biosciences,Cat no.563234)で染色して、CD8+ T細胞の増加程度を確認し、これは、FACSDiVaソフトウェア(BD Biosciences)を用いてフローサイトメトリーにより分析した。
図14に示されたように、投薬10日後に腫瘍内に浸透したCD8+ T細胞の量が、レオウイルス経口投与群において5倍以上増加することを確認できた。
すなわち、免疫抗がん剤の腫瘍抑制効果の代表的なバイオマーカーである腫瘍内に浸透したCD8+ T細胞の増加を通じて、レオウイルスを含む経口投与用組成物が、抗がん免疫活性化を通じてがんの治療に作用すると期待される。
投薬3日、および10日後にマウスから腫瘍とリンパ節を採取して、アセトンで固定した後、OCT溶液(Sakura Finetek,Cat No.4583)に入れ、-80℃超低温冷凍庫で保管して、冷凍組織ブロックを製造した。冷凍組織ブロックをCryostat(Leica Biosystems,CM3050S)で5~10μmの厚さに切って、スライドガラスを製作した。組織切片スライドをCoplin Jarを使用してPBSで洗浄した後、200μl Superblock(ThermoFisher Scientific,Cat no.37515)で覆って、10分間室温に放置して処理した。その後、PBSに希釈した蛍光ラベルされたCD8単クローン抗体(Biolegend,Cat no.100723)、CD31単クローン抗体(Biolegend,Cat no.102416)で室温で1~2時間光を遮断した状態で染色した後、3回PBSで洗浄した後、ProLong Diamond Antifade Mountant(Thermofisher Scientific,Cat no.P36965)を塗布した後、Coverslipで覆った。その後、蛍光顕微鏡で染色程度を観察した。核染色は、DAPI solution(BD Biosciences,Cat no.564907)で1分間進めた。
図15に示されたように、投薬後、腸間膜リンパ節内に浸透したCD8+ T細胞の量が、レオウイルス経口投与群では増加する傾向を示し、特に10日目の増加程度が顕著に大きいことを確認できた。
また、図16に示されたように、投薬10日後に腫瘍内に浸透したCD8+ T細胞の量が、レオウイルス経口投与群においてフローサイトメトリー分析結果と同一に顕著に増加することを確認できた。
腫瘍内に浸透したCD8+ T細胞の増加は、免疫抗がん剤の腫瘍抑制効果の代表的なバイオマーカーであるから、レオウイルスを含む経口投与用組成物が抗がん免疫活性化を通じてがんの治療に作用すると期待される。
実験に使用された動物は、5~8週齢の雄BALB/Cマウスであり、ナラバイオテック(Nara Biotech.,Seoul,South Korea)から購入した。マウスは、バイロキュア研究所の動物実験室で7日間の適応期間後に実験を進め、適応期間中に水と飼料を制限しなかった。実験動物に標準化された環境を提供し、12時間間隔で昼と夜を維持し、室内温度(23±2℃)を適正レベルに維持させた。マウスに大腸がん細胞株(CT26 cells、2×105 cells/50μL PBS)を脇腹に皮下注射した。
抗がん効果試験には、vehicle、0.1%(w/v)Human serum albumin(HAS)in 1x PBSを投薬した対照群、レオウイルス経口投与群、免疫チェックポイント阻害剤(anti-PD-1抗体)腹腔投与群、およびレオウイルス/免疫チェックポイント阻害剤の併用投与群(anti-PD-1抗体単独またはanti-CTLA-4抗体併用)に分けて実験を進めた。前記大腸がん動物モデルにレオウイルスを投与する方式は、経口投与方法(Oral administration)を使用し、抗体投与方式は、腹腔内直接投与方法(Intraperitoneal injection)を使用して進めた。
CT26細胞移植後1週間後にレオウイルス(type 3,Dearing)を1×109 TCID50/100μL PBS(Reovirus/0.1%(w/v)Human serum albumin(HAS)in 1x PBS)で1回/日で12日間経口投与した。anti-PD-1抗体(BioXcell,Cat# BE0033-2)は、8mg/kgでanti-CTLA4抗体(BioXcell,Cat# BE0164)は、4mg/kgで3日間隔で4回腹腔内に投与した(図17)。
図18に示されたように、本大腸がん動物モデルにおいて無処理対照群は、マウスに腫瘍が生成された後、腫瘍の体積が持続的に成長することを確認できた。しかしながら、病が進行されるにつれて、単独投与群(ウイルスまたは抗体投与群)では、対照群に比べてがんの成長遅延効果が観察された。
一方、併用投与群、特に2種の免疫チェックポイント阻害剤を同時併用した処理群(RC402+aPD-1+aCTLA-4)では、がんの成長が84.6%抑制され、完全寛解(Complete Response,CR)になった個体が発生した。
投薬13日後、マウスから腫瘍を採取して、フローサイトメトリーまたは組織免疫化学染色法を用いてCD8+ T細胞の浸透程度を比較評価した。
図19に示されたように、対照群または抗体単独処理群に比べて、ウイルス単独または併用投与群において、CD8+ T細胞の腫瘍浸透程度は、がん成長抑制程度と相関関係をもって増加することを確認し、特に2種の免疫チェックポイント阻害剤を同時併用した処理群におけるCD8+ T細胞の腫瘍浸透程度が有意に増加したことを確認できた。
12-1.がんの成長測定による評価
レオウイルスを含む組成物(経口投与)と免疫チェックポイント阻害剤(anti-PD-1抗体の併用投与を通じて腫瘍の完全寛解となったマウスにCT26を再移植した。対照群としては、新しいBALB/Cマウスを使用した。
図20に示されたように、対照群では、CT26大腸がん細胞株が正常に成長するのに対し、完全寛解後にCT26大腸がんを再移植する場合には、腫瘍が成長しないことを確認した。これは、抗がん免疫効果が持続することを意味する。
したがって、レオウイルスを含む組成物(経口投与)と免疫チェックポイント阻害剤(例えば、anti-PD-1抗体、anti-CTLA4抗体)の併用投与が、臨床的に長期的な抗がん免疫を活性化できると期待される。
完全寛解に到達したマウスから脾臓を採取して、10mlを追加して破砕して、70μm cell strainerでろ過した。300~400gで5分間遠心分離して回収した。上澄み液を捨てた後、ACK lysisバッファー(Lonza cat no.10-548E)1~2mlを入れ、常温で1分間放置した後、FACSバッファー10mlを追加して混合した後、300~400gで5分間遠心分離して回収した。適正量のFACSバッファーで再懸濁した後、CD8単クローン抗体(BD Biosciences,Cat no.563234)、CD44抗体(Biosciences,Cat no.560569)、CD62抗体(BD Biosciences,Cat no.553150)で染色して、FACSDiVaソフトウェア(BD Biosciences)を用いてフローサイトメトリーにより分析した。
図21に示されたように、CT26大腸がん細胞株が移植されたマウス脾臓内にメモリーT cell(CD44+Cd62+CD8+)の割合が増加することを確認できた。したがって、長期的抗がん免疫にメモリーT cellが関与していると判断された。
すなわち、CD8+ T細胞の増加を通じて、免疫抗がん剤の腫瘍抑制効果が再発防止など長期的な抗がん免疫を活性化できると期待される。
MC38細胞株を50μl PBS中に1.0×105細胞数の濃度で再懸濁させ、6週齢の雄C57BL6マウスの脇腹に皮下注射した。MC38細胞株移植後1週間後にレオウイルス(type 3,Dearing)を1×109 TCID50/100μL PBS(Reovirus/0.1%(w/v)Human serum albumin(HAS)in 1x PBS)で1回/日で10日間経口投与した。
投薬10日後にマウスから腸間膜リンパ節を採取して、MC38特異抗原ペプチドKSPWFTTLがロードされた四量体(tetramer)合成MHC複合体(MBL,Cat No.TS-M507)を使用してこれと特異的に結合するT細胞受容体(T-cell receptor,TCRs)を発現するCD8+ T細胞の変化をフローサイトメトリーを用いて分析した。
マウスから採取した腸間膜リンパ節をPBSで洗浄して軽く破砕して、70μm cell strainerでろ過した。ろ過した単一細胞をFACSバッファー10mlに追加して混合した後、300~400gで5分間遠心分離して回収した。適正量のFACSバッファーで2×107 cells/mlの濃度で細胞を再懸濁した。この中から50μlを10μlのClear Back溶液を保管した試験管に移して5分間室温に待機させた。そこへ10μlのT-Select MHC 四量体を追加して軽く混ぜて、30分~60分間冷蔵したり、室温で遮光条件で反応させた。CD8に対する単クローン抗体(BD Biosciences,Cat no.563234)を追加して、冷蔵温度で30分間遮光した条件でさらに反応させた。400gで5分間遠心分離して、上澄み液を除去した後、沈殿物を0.5%パラホルムアルデヒドやホルマリンを含むリン酸緩衝溶液に再懸濁した。遮光された冷蔵条件で1時間~24時間待機した後、FACSDiVaソフトウェア(BD Biosciences)を用いてフローサイトメトリーを用いて分析した。MHC 四量体とCD8+ T細胞の頻度は、全CD8+ T細胞に対する割合で表現した。
図22に示されたように、レオウイルスを含む経口投与用組成物投与群において、腫瘍抗原特異性があるCD8+ T細胞(KSP-tetramer+ CD8+)が有意に増加することを確認できた。
腸間膜リンパ節を採取して、PBSで洗浄して軽く破砕した後、70μm cell strainerでろ過した。ろ過した単一細胞をFACSバッファー10mlに追加して混合した後、300~400gで5分間遠心分離して回収した。
血液をEDTA(またはヘパリン)でコートされたチューブに入れ、1:1の割合でPBSを混合して、Ficoll-Paque PLUSを入れた15mLチューブに移して遠心分離した後、マウスPBMC(peripheral blood mononuclear cell)を回収した。PBMCは、400gで遠心分離して、上澄み液を除去した後、上澄み液を捨てた後、ACK lysisバッファー(Lonza cat no.10-548E)1~2mlを入れ、常温で1分間放置した。その後、FACSバッファー10mlを追加して混合した後、300~400gで5分間遠心分離して回収した。リンパ節や血液から分離回収した免疫細胞を適正量のFACSバッファーで再懸濁した後、CD8単クローン抗体(BD Biosciences,Cat no.563234)とPD-1に対する単クローン抗体(Biosciences,Cat no.25-9985-80)で染色して、フローサイトメトリーを用いてPD-1を発現するCD8+ T細胞の増加程度を確認した。
図23に示されたように、血液から分離したPBMCでPD-1を発現するCD8+ T細胞の変化は観察されなかったが、腸管膜リンパ節では、変化が明らかであり、2.5倍以上CD8+ T細胞が増加することを確認できた。
Claims (13)
- レオウイルス(Reovirus);またはレオウイルスで処理された生物学的サンプルを有効成分として含むがんの予防または治療用薬学的組成物。
- 前記がんは、子宮頸がん、肺がん、膵臓がん、非小細胞性肺がん、肝がん、結腸がん、大腸がん、骨がん、皮膚がん、頭部がん、頸部がん、皮膚黒色腫、眼内黒色腫、子宮がん、卵巣がん、直腸がん、脳腫瘍、血液がん、胃がん、肛門周囲がん、乳がん、卵管がん、子宮内膜腫瘍、膣がん、外陰がん、ホジキン病(Hodgkin’s disease)、食道がん、小腸がん、内分泌腺がん、甲状腺がん、副甲状腺がん、副腎がん、軟部組織肉腫、尿道がん、陰茎がん、前立腺がん、膀胱がん、腎臓がん、尿管がん、腎細胞がん、腎臓骨盤がん、中枢神経系(CNS central nervoussystem)腫瘍、原発CNSリンパ腫、脊髄腫瘍、脳幹神経膠腫および脳下垂体腺腫からなる群から選ばれた1つ以上であることを特徴とする請求項1に記載のがんの予防または治療用薬学的組成物。
- 前記薬学的組成物は、免疫チェックポイント阻害剤をさらに含むことを特徴とする請求項1に記載のがんの予防または治療用薬学的組成物。
- 前記免疫チェックポイント阻害剤は、PD-L1阻害剤、PD-1阻害剤、およびCTLA-4阻害剤からなる群から選ばれた1つ以上であることを特徴とする請求項3に記載のがんの予防または治療用薬学的組成物。
- 前記レオウイルス、またはレオウイルスで処理された生物学的サンプル;および
免疫チェックポイント阻害剤は、同時に(simultaneous)、別々に(separate)または順次に(sequential)投与されることを特徴とする請求項3に記載のがんの予防または治療用薬学的組成物。 - 前記レオウイルス;またはレオウイルスで処理された生物学的サンプルは、経口投与されることを特徴とする請求項1に記載のがんの予防または治療用薬学的組成物。
- 前記薬学的組成物は、CD8+ T細胞の腫瘍内浸透を増加させることを特徴とする請求項1に記載のがんの予防または治療用薬学的組成物。
- レオウイルス(Reovirus);またはレオウイルスで処理された生物学的サンプルを有効成分として含む再発がんの予防または治療用薬学的組成物。
- 前記薬学的組成物は、免疫チェックポイント阻害剤をさらに含むことを特徴とする請求項8に記載の再発がんの予防または治療用薬学的組成物。
- 前記免疫チェックポイント阻害剤は、PD-L1阻害剤、PD-1阻害剤、およびCTLA-4阻害剤からなる群から選ばれた1つ以上であることを特徴とする請求項9に記載の再発がんの予防または治療用薬学的組成物。
- レオウイルス(Reovirus);またはレオウイルスで処理された生物学的サンプルを有効成分として含む組成物を個体に投与する段階を含む、がんまたは再発がんの予防または治療方法。
- レオウイルス(Reovirus);またはレオウイルスで処理された生物学的サンプルを有効成分として含む組成物のがんまたは再発がんの予防または治療用途。
- レオウイルス(Reovirus);またはレオウイルスで処理された生物学的サンプルを有効成分として含む組成物のがんまたは再発がんの予防または治療薬剤を製造するための用途。
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