JP6802159B2 - ガンマデルタt細胞増殖手順 - Google Patents
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Description
先行研究において、本出願人らは、健康なドナーが19,916±29,887(平均±SD、n=21)個の循環γδT細胞を有することを示している。対して、新規EOC診断患者は、14,240±15,215個のγδ細胞/mL血液を有した(平均±SD、n=13;統計学的に有意差なし(NS))[16]。
本発明によるT細胞の増殖
次に、本発明者らは、形質転換増殖因子(TGF)−βが常にIL−2と一緒に添加されるように、方法1を改変した。このアプローチは、本明細書中で以後、方法2と呼ぶ。
代替的な細胞増殖工程
異なる基礎培地、具体的にはRPMI+ヒトAB血清を使用して上記実施例1の方法を反復した。特に、ゾレドロン酸(1μg/mL)+IL−2(100U/mL;方法1)またはゾレドロン酸(1μg/mL)+IL−2(100U/mL)+TGF−β(5ng/mL;方法2)を含有するRPMI+10%ヒトAB血清中でPBMC(細胞3×106個/mL)を培養した。第15日に細胞数を評価し、結果を図9Aで示す。培養開始日(第1日)およびさらに14日後(第15日)に各培養中に存在するγδT細胞のパーセンテージを評価し、結果を図9Bで示す。
インビボ治療活性
さらに、悪性疾患の確定負荷量に対する増殖Vγ9Vδ2T細胞のインビボ治療活性を比較した。20匹のSCID Beigeマウスに尾静脈注射により1×106個のホタルルシフェラーゼ発現U937白血病細胞を接種し、次いでマウスを各5匹の4つの群に分けた。4日後、マウスを次のように処置した:群1は、PBSのみを投与した対照群である。群2にはパミドロン酸(200μg IV)のみを投与した。群3にはパミドロン酸(第4日に200μg IV)、続いて、方法1を用いて増殖された20×106個(第5日)および10×106個(第6日)個のVγ9Vδ2T細胞(IV)を投与した。群4には、パミドロン酸(第4日に200μg IV)、続いて方法2を用いて増殖された20×106個(第5日)および10×106個(第6日)個のVγ9Vδ2T細胞を投与した(IV投与)。その後、連続生体発光イメージングによって白血病細胞量を監視した。
IL−2と合わせた本発明の細胞のインビボ活性
個別の実験において、静脈内投与された、SCID Beigeマウスにおける悪性疾患の確定負荷量(U937白血病)に対する本発明の方法(M2)を用いて得られた増殖Vγ9Vδ2T細胞のインビボ治療活性を測定した。マウスを5匹の4つの群に分け、それぞれ第1日に100万個のU937細胞をIV投与した。その後、1つの群に、次のようにまとめられ得る処置を行った。
乳癌に対するインビボ治療効果
この実験において、マウスの乳房脂肪体に移植したMDA−MB−231トリプルネガティブ乳癌の形態の悪性疾患の確定負荷量を有する20匹のSCID Beigeマウスを使用した。再び、マウスを処置に対して4つの群に分けた。マウスを次のように処置した:群1は、PBSのみを投与した対照群である。群2には20μgゾレドロン酸を静脈内投与した。群3には、方法2を使用して増殖された20×106個(第2日)および10×106個(第3日)のVγ9Vδ2T細胞を静脈内投与した。群4には、第1日に20μgゾレドロン酸を静脈内投与し、続いて方法2を使用して増殖された20×106個(第2日)および10×106個(第2日)のVγ9Vδ2T細胞を投与した。
増殖γδT細胞の精製
第一の実験において、CD19および/またはαβT細胞マイクロビーズ単離キットを用いた陰性選択により、新鮮単離PBMCからVγ9Vδ2T細胞を精製した。両キットを使用した場合、図13(A)で示されるように、残留する混入CD19およびαβT細胞は<0.1%であった。
増殖された細胞の遺伝子操作
本発明に従い増殖されたγδT細胞の機能性をさらに確認するために、レトロウイルス形質導入によってこれらを遺伝子操作した。ウイルスベクターをRetroNectinコーティング固体相に前負荷することによるか、または増殖細胞へのウイルス上清の添加によるかの何れかで細胞に対して形質導入を行った。
化学療法剤とγδT細胞の併用の効果
U937腫瘍細胞またはKG−1腫瘍細胞の何れかを含有する96ウェルプレート中で1:1エフェクター:標的比において3つ組で細胞毒性アッセイを確立した。指示される場合、本発明の方法(M2)または上記の比較例の方法(M1)の何れかを使用して作製されたγδT細胞の添加前に、腫瘍細胞に指定濃度のシタラビンを24時間にわたり添加した。M2細胞に対して3名のドナーおよびM1細胞に対して2名のドナーが存在した。対照群にはシタラビンを投与しなかった。
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Claims (19)
- γδT細胞の集団を増殖させるための方法であって、前記方法が、癌に対する治療活性を有するエフェクターγδT細胞の産生に有利となるように、形質転換増殖因子ベータ(TGF−β)及びインターロイキン−2を含む培地中において単離活性化末梢血単核球(PBMC)を培養するステップを備え、前記培地が、ウシ胎児血清またはウシ胎仔血清を含有しないことを特徴とする、方法。
- 請求項1に記載の方法において、前記培地中にさらなるサイトカインが存在しないことを特徴とする、方法。
- 請求項1又は2に記載の方法において、前記培地が血清不含培地であるか、またはヒトAB血清を含有することを特徴とする、方法。
- 請求項1乃至3の何れか1項に記載の方法において、工程の最初の段階でVγ9Vδ2T細胞に対する活性化因子が添加されることを特徴とする、方法。
- 請求項4に記載の方法において、前記活性化因子がゾレドロン酸、アレンドロン酸、パミドロン酸、イバンドロン酸などのアミノビスフォスフォネートまたはその塩であることを特徴とする、方法。
- 請求項5に記載の方法において、前記活性化因子がゾレドロン酸またはその塩であることを特徴とする、方法。
- 請求項1乃至6の何れか1項に記載の方法において、前記PBMCがヒトPBMCであることを特徴とする、方法。
- 請求項7に記載の方法において、前記PBMCがヒト患者由来であることを特徴とする、方法。
- 請求項7に記載の方法において、前記PBMCが健康なヒト由来であることを特徴とする、方法。
- 請求項1乃至9の何れか1項に記載の方法において、増殖された生成物からCD19 +B細胞および/またはαβT細胞が除去されることを特徴とする、方法。
- インビトロで増殖されるγδT細胞の収率を向上させるための方法において、前記方法が、請求項1乃至10の何れか1項に記載の方法を行うことを備えることを特徴とする、方法。
- インビトロで増殖されるγδT細胞の抗癌効果を促進するための方法において、前記方法が、請求項1乃至10の何れか1項に記載の方法を行うことを備えることを特徴とする、方法。
- 請求項1乃至10の何れか1項に記載の方法によって得られること特徴とする、γδT細胞。
- 請求項13に記載のγδT細胞において、治療での使用のためのものであることを特徴とする、γδT細胞。
- 請求項13に記載のγδT細胞において、癌の処置での使用のためのものであることを特徴とする、γδT細胞。
- 請求項13に記載のγδT細胞と、活性化因子との組み合わせ。
- 請求項16に記載の組み合わせにおいて、前記活性化因子がビスホスホネート薬であることを特徴とする、組み合わせ。
- 請求項13に記載のγδT細胞と、化学療法剤との組み合わせ。
- 請求項18に記載の組み合わせにおいて、前記化学療法剤がシタラビンであることを特徴とする、組み合わせ。
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CN108588023B (zh) * | 2018-05-09 | 2020-02-14 | 河北森朗生物科技有限公司 | 一种生产嵌合抗原受体修饰的γδT细胞的方法 |
SG11202100260QA (en) | 2018-07-13 | 2021-02-25 | Univ Kyoto | METHOD FOR PRODUCING γδ T CELLS |
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EP1720567A2 (en) | 2004-02-10 | 2006-11-15 | Innate Pharma | Composition and method for the treatment of carcinoma |
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AU2005274649B2 (en) * | 2004-08-19 | 2010-09-09 | University College Cardiff Consultants Limited | Preparation of antigen-presenting human gamma delta T cells and use in immunotherapy |
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ITRM20070437A1 (it) * | 2007-08-10 | 2009-02-11 | Istituto Naz Per Le Malattie I | Metodo per la generazione ed espansione di cellule t gamma/delta regolatorie cellule cosi' ottenute e loro impieghi |
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CN103436493B (zh) * | 2013-08-29 | 2016-02-03 | 浙江大学 | 雷帕霉素诱导调节性γδT细胞的培养方法 |
GB201421716D0 (en) | 2014-12-05 | 2015-01-21 | King S College London | Cell expansion procedure |
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EP3227435B1 (en) | 2020-01-29 |
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US20200123502A1 (en) | 2020-04-23 |
RU2017121191A3 (ja) | 2019-07-29 |
MX2017007214A (es) | 2018-01-30 |
GB201421716D0 (en) | 2015-01-21 |
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