JPWO2020027094A1 - iPS細胞を介して再生T細胞集団を製造する方法 - Google Patents
iPS細胞を介して再生T細胞集団を製造する方法 Download PDFInfo
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Abstract
Description
〔1〕
iPS細胞を介して再生T細胞集団を製造する方法であって、
(工程1)T細胞集団を、1種以上の腫瘍関連抗原または1種以上の腫瘍関連抗原を含む生体組織もしくはその破砕物もしくはその溶解物と接触させ、前記腫瘍関連抗原に対する指向性を有するT細胞集団を濃縮する工程、
(工程2)前記濃縮したT細胞集団をiPS細胞へと初期化し、前記濃縮したT細胞集団の遺伝的多様性を維持したまま培養する工程、および、
(工程3)前記培養したiPS細胞から再生T細胞集団を製造する工程、
を含む、方法。
〔2〕
前記再生T細胞集団が、前記濃縮したT細胞集団の遺伝的多様性を維持し、かつ前記腫瘍関連抗原に対する指向性を有する再生T細胞集団である、〔1〕に記載の方法。
〔3〕
前記工程1におけるT細胞集団が、哺乳動物に由来する、〔1〕または〔2〕に記載の方法。
〔4〕
前記哺乳動物がヒトである、〔3〕に記載の方法。
〔5〕
前記ヒトが、がん患者または非がん患者である、〔4〕に記載の方法。
〔6〕
前記がん患者また非がん患者が、がんワクチンを以前に投与されたことがあるか、現在投与されているか、または今後投与される予定である、〔5〕に記載の方法。
〔7〕
前記工程1におけるT細胞集団が、体液由来である、〔1〕〜〔6〕のいずれかに記載の方法。
〔8〕
前記体液が、血液、リンパ液、組織液、ならびに腹水、胸水、心嚢液、脳脊髄液、関節液および眼房水を含む体腔液、ならびに鼻汁および尿からなる群より選ばれる、〔7〕に記載の方法。
〔9〕
前記工程1におけるT細胞集団が、腫瘍組織由来T細胞である、〔1〕〜〔6〕のいずれかに記載の方法。
〔10〕
前記工程1におけるT細胞集団が、αβT細胞、γδT細胞、ヘルパーT細胞、レギュラトリーT細胞、細胞傷害性T細胞、ナチュラルキラーT細胞またはこれらの混合物である、〔1〕〜〔9〕のいずれかに記載の方法。
〔11〕
前記工程1における生体組織が、がん原発組織およびがん転移組織である、〔1〕〜〔10〕のいずれかに記載の方法。
〔12〕
前記工程1におけるT細胞集団を濃縮する工程が、1種以上の腫瘍関連抗原と接触させることにより活性化し、増殖したT細胞を分離する工程を含む、〔1〕〜〔111〕のいずれかに記載の方法。
〔13〕
前記工程1におけるT細胞集団を濃縮する工程が、前記T細胞集団より、CD137発現T細胞を選択する工程およびIFN-γ産生T細胞を選択する工程からなる群より選ばれる1以上の工程を含む、〔1〕〜〔12〕のいずれかに記載の方法。
〔14〕
前記工程1におけるT細胞集団を濃縮する工程が、前記T細胞集団より、CD137発現T細胞を選択する工程、IFN-γ産生T細胞を選択する工程、および抗原ペプチド‐HLA複合体が結合するT細胞を選択する工程からなる群より選ばれる1以上の工程を含む、〔1〕〜〔12〕のいずれかに記載の方法。
〔15〕
前記工程2が、iPS細胞をクローン化することなく回収し、継代するステップを含む、〔1〕〜〔14〕のいずれかに記載の方法。
〔16〕
前記工程3で得られた再生T細胞集団が、T細胞補充療法に使用するものである、〔1〕〜〔15〕のいずれかに記載の方法。
〔17〕
前記再生T細胞集団は、維持されるVβの種類が、2種類以上である、〔1〕〜〔16〕のいずれかに記載の方法。
〔18〕
〔1〕〜〔17〕のいずれかに記載の方法により製造された再生T細胞集団。
〔19〕
生体内に存在するT細胞集団の遺伝的多様性を維持している、〔18〕に記載の再生T細胞集団。
〔20〕
〔18〕または〔19〕に記載の再生T細胞集団を含有する医薬組成物。
〔21〕
自家的または同種的な移植によりがん治療対象を処置するための、〔20〕に記載の医薬組成物。
〔22〕
〔20〕または〔21〕に記載の医薬組成物を用いる、がん治療方法。
本発明の工程1は、遺伝的多様性を有するT細胞集団を、1種以上の腫瘍関連抗原または1種以上の腫瘍関連抗原を含む生体組織またはその破砕物もしくは溶解物と接触させ、該腫瘍関連抗原に対する指向性を有するT細胞集団を濃縮する工程である。
本発明の工程2は、前記濃縮したT細胞集団をiPS細胞へと初期化し、前記濃縮したT細胞集団の遺伝的多様性を維持したまま培養する工程である。
本発明の工程3は、前記培養したiPS細胞から再生T細胞集団を製造する工程である。本発明の一態様において、該再生T細胞は、工程1において濃縮されたT細胞集団の遺伝的多様性を維持し、かつ工程1において使用された腫瘍関連抗原に対する指向性を有する。
腫瘍関連抗原を培養液に添加してT細胞集団と接触させ、200 U/mL IL-2、10 ng/mL IL-15および10 ng/mL IL-21を添加したRPMI-1640培養液(10%ヒトAB血清、1%ペニシリン−ストレプトマイシン−グルタミンを含む)中で12日間培養を行った。培養液に添加する腫瘍関連抗原は、ペプチドの場合は1〜100 mg/mLの濃度で添加し、また、腫瘍関連抗原として生体組織またはその破砕物を用いる場合は、1〜2 mm角に細断した組織片を、培養液を含むチューブあたり1〜5個程度添加してT細胞集団と接触させることが好ましい。生体組織の溶解物の場合は、該溶解物を培養液に添加してT細胞集団と接触させることが好ましい。培養後12日目に、同一の腫瘍関連抗原ペプチドを再度接触させ、さらに24時間培養することにより、腫瘍関連抗原に指向性を有するT細胞に対して活性化マーカーを発現させた。培養した細胞集団に対し、CD8分子以外の血球分画マーカーを用いたネガティブセレクション(CD8+ T cell isolation kit, Miltenyi Biotech社)、および活性化マーカーであるCD137またはIFN-γに対するポジティブセレクション(CD137 MicorBead KitまたはCytokine capture system-IFN-γ, Miltenyi Biotech社)を行うことにより、腫瘍関連抗原に指向性を有するCD8シングルポジティブT細胞のみを濃縮した。
続いて、T細胞を15mlチューブに回収し、約250μLのRPMI-1640培養液に浮遊させた後、CytoTune-iPS 2.0キット(株式会社IDファーマ社:カタログ番号DV-0304)を用いて、MOI=5となる力価で初期化に必要な4因子(Oct3/4、Sox2、Klf4およびc-Myc)を含むセンダイウイルスを培養液に添加し、37℃で2時間インキュベートした。インキュベーション後には、RPMI-1640培養液を用いてT細胞を洗浄し、培養液中からウイルスを除去した。
iPS細胞のコロニーが肉眼で確認できる程度に成長した段階で、iPS細胞を、新しくiMatrix-511をコーティングした6 cmディッシュへと継代した。
超低接着処理された6ウェルプレート(CORNING社:カタログ番号3471)に、工程2で得られたiPS細胞を3×105〜6×105個/ウェルで播種し(DayO)、EB培養液(10μg/mL ヒトインスリン、5.5μg/mL ヒトトランスフェリン、5 ng/mL 亜セレン酸ナトリウム、2 mM L-グルタミン、45 mM α-モノチオグリセロールおよび50μg/mL アスコルビン酸を含むStemPro34)に10 ng/mL BMP4、5 ng/mL bFGF、15 ng/mL VEGF、2μM SB431542を加えて、低酸素条件下(5%O2)で5日間培養した(Day5)。
細胞傷害活性(%)=[(再生T細胞存在下での培養上清中の蛍光量)−(再生T細胞非存在下での培養上清中の蛍光量)]/[(全標的細胞を溶解した溶解液中の蛍光量)−(再生T細胞非存在下での培養上清中の蛍光量)]×100
共培養時の再生T細胞と標的細胞との細胞数比は、20:1、10:1および5:1とした。その結果、GPC3ペプチド発現標的細胞に対する再生T細胞集団の細胞傷害活性が示され、その活性は標的細胞に対する再生T細胞の細胞数の増加に応じて増強された(図10B)。一方、再生T細胞集団は、GPC3ペプチドを発現しない標的細胞に対して、細胞傷害活性を示さなかった(図10B)。これらの結果から、得られた再生T細胞集団は、GPC3に対する抗原特異性を維持し、GPC3を発現する標的細胞に対する抗原特異的な細胞傷害活性を有することか示される。
Claims (22)
- iPS細胞を介して再生T細胞集団を製造する方法であって、
(工程1)T細胞集団を、1種以上の腫瘍関連抗原または1種以上の腫瘍関連抗原を含む生体組織もしくはその破砕物もしくはその溶解物と接触させ、前記腫瘍関連抗原に対する指向性を有するT細胞集団を濃縮する工程、
(工程2)前記濃縮したT細胞集団をiPS細胞へと初期化し、前記濃縮したT細胞集団の遺伝的多様性を維持したまま培養する工程、および、
(工程3)前記培養したiPS細胞から再生T細胞集団を製造する工程、
を含む、方法。 - 前記再生T細胞集団が、前記濃縮したT細胞集団の遺伝的多様性を維持し、かつ前記腫瘍関連抗原に対する指向性を有する再生T細胞集団である、請求項1に記載の方法。
- 前記工程1におけるT細胞集団が、哺乳動物に由来する、請求項1または2に記載の方法。
- 前記哺乳動物がヒトである、請求項3に記載の方法。
- 前記ヒトが、がん患者または非がん患者である、請求項4に記載の方法。
- 前記がん患者また非がん患者が、がんワクチンを以前に投与されたことがあるか、現在投与されているか、または今後投与される予定である、請求項5に記載の方法。
- 前記工程1におけるT細胞集団が、体液由来である、請求項1〜6のいずれか1項に記載の方法。
- 前記体液が、血液、リンパ液、組織液、ならびに腹水、胸水、心嚢液、脳脊髄液、関節液および眼房水を含む体腔液、ならびに鼻汁および尿からなる群より選ばれる、請求項7に記載の方法。
- 前記工程1におけるT細胞集団が、腫瘍組織由来T細胞である、請求項1〜6のいずれか1項に記載の方法。
- 前記工程1におけるT細胞集団が、αβT細胞、γδT細胞、ヘルパーT細胞、レギュラトリーT細胞、細胞傷害性T細胞、ナチュラルキラーT細胞またはこれらの混合物である、請求項1〜9のいずれか1項に記載の方法。
- 前記工程1における生体組織が、がん原発組織およびがん転移組織である、請求項1〜10のいずれか1項に記載の方法。
- 前記工程1におけるT細胞集団を濃縮する工程が、1種以上の腫瘍関連抗原と接触させることにより活性化し、増殖したT細胞を分離する工程を含む、請求項1〜11のいずれか1項に記載の方法。
- 前記工程1におけるT細胞集団を濃縮する工程が、前記T細胞集団より、CD137発現T細胞を選択する工程およびIFN-γ産生T細胞を選択する工程からなる群より選ばれる1以上の工程を含む、請求項1〜12のいずれか1項に記載の方法。
- 前記工程1におけるT細胞集団を濃縮する工程が、前記T細胞集団より、CD137発現T細胞を選択する工程、IFN-γ産生T細胞を選択する工程、および抗原ペプチド‐HLA複合体が結合するT細胞を選択する工程からなる群より選ばれる1以上の工程を含む、請求項1〜12のいずれか1項に記載の方法。
- 前記工程2が、iPS細胞をクローン化することなく回収し、継代するステップを含む、請求項1〜14のいずれか1項に記載の方法。
- 前記工程3で得られた再生T細胞集団が、T細胞補充療法に使用するものである、請求項1〜15のいずれか1項に記載の方法。
- 前記再生T細胞集団は、維持されるVβの種類が、2種類以上である、請求項1〜15のいずれか1項に記載の方法。
- 請求項1〜17のいずれか1項に記載の方法により製造された再生T細胞集団。
- 生体内に存在するT細胞集団の遺伝的多様性を維持している、請求項18に記載の再生T細胞集団。
- 請求項18または19に記載の再生T細胞集団を含有する医薬組成物。
- 自家的または同種的な移植によりがん治療対象を処置するための、請求項20に記載の医薬組成物。
- 請求項20または21に記載の医薬組成物を用いる、がん治療方法。
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