JP6408219B2 - Th1特性と細胞溶解性を発現する細胞 - Google Patents
Th1特性と細胞溶解性を発現する細胞 Download PDFInfo
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Description
癌のワクチン接種治療は免疫療法の一種である。免疫療法は、癌治療のための治療薬の一種として化学療法、放射線治療および手術に加えて浮上している新しい治療方式である。免疫療法は病気を治療するために免疫システムの力を利用しようとする。治療用ワクチン接種は免疫療法の1つであり、存在する腫瘍、ウイルスおよびバクテリア病原体に対する治癒の可能性のある療法である。治療用ワクチンは、通常標的とする疾病から得られた抗原ソースと、所望の免疫反応を促進するように設計されたアジュバントとからなる。ある種の治療用ワクチンプロトコルにおいて、生体免疫細胞は宿主(自己)に由来するかまたはドナー(同種異系)に由来するかに拘わらず、治療用ワクチンの構成成分である。樹状細胞、NK細胞およびT−細胞のような自系または同種異系の生体免疫細胞もまた癌治療のための免疫療法プロトコルとして用いられる。
[概要]
細胞を基礎とする治療用癌ワクチン(細胞免疫療法)は、癌治療のための新しい最小毒性アプローチとして期待されている。このアプローチへの期待は動物モデルによって立証されているが、この期待を臨床に移行させるのは困難である(BodeyとBodeyら、2000年)。最近FDAで認可された最初の細胞免疫療法薬であるプロベンジ(Provenge)(登録商標)(シプリューセル−T)(sipuleucel−T)は、無症候性または低症候性の転移性去勢抵抗前立腺癌を治療するための自己樹枝状細胞免疫治療用(KantoffとHiganoら)であるが、臨床応用するための改良された細胞療法を開発する新たな熱意を有する。
材料
PE結合 CD40Lは、ベックマン コールター社(ブレア、カリフォルニア州)から購入し、7−アミノーアクチノマイシンD(7−AAD)(1000x)は、ケイマン ケミカル社(アナーバー、ミシガン州)から購入し、プラズマライト A(PlasmaLyte A)は、バクスター サイエンティフィック社(ディアフィールド、イリノイ州)から購入し、ヒト血清アルブミン(HSA)は、マッケソン社(サンフランシスコ、カリフォルニア州)から購入し、FcR結合阻害剤は、eバイオサイエンス社(サンディエゴ、カリフォルニア州)から購入し、ダイナビーズ クリネックスビボ(Dynabeads ClinExVivo)(商標)は、インビトロジェン社(カールスバッド、カリフォルニア州)から購入した。
CD4+T細胞は、インビトロジェン社から購入したCD3/CD28 クリネックスビボ ダイナル ビーズ)(ClinEXVivo Dynal Beads)の存在下で9日間培養された(ロケーション)。細胞は、37℃で5%のCO2のライフ セル フラスク(バクスター社)中で培養され、培養の3日目と6日目にビーズで再び刺激された。培養から9日目にビーズを取り除くことができ、これらの細胞はCACと呼ばれる。
CACは、洗浄のためcRPMI培地に置かれた。調合プロトコルの始まりを指示するために時間が記録された。cRPMI培地中の細胞は遠心分離されて上澄み液は除去されて、細胞はcRPMI緩衝液中に再懸濁された。細胞生存率はトリパンブルー法を用いて測定された。生細胞の総数と濃度を用いて生細胞の割合(%)を決定した。生細胞が80%より大きいサンプルの場合には、処置は細胞の再活性化および調合のために続けられた。
細胞および上澄み液は異なる時点で回収された。回収された時点は以下の通りであった:0(起点)、室温(RT)で2時間、4℃で48時間、および4℃で48時間保存後室温で2時間。
50ulの細胞懸濁液は上記150ulから3つのエッペンドルフチューブに移されて、それぞれ染色なし、CD40L、および7−ADDと標識された。染色なしのチューブは、氷上で20分間培養された。CD40Lチューブは、製造者の指示によれば氷上で20分間FcR結合阻害剤とともにプレインキュベートされた。次に、染色バッファ40ul(PBS+1%FBS)とPE−CD40L抗体10ulは、細胞懸濁液に添加されて、さらに20分間暗闇の氷上で培養された。
正常なドナーの抹消血液を得てミルテニーバイオテク社(オーバーン、カリフォルニア州)から入手したミルテニー磁気ビーズとカラムを用いてバフィーコートからCD4+細胞を精製した。図1は、CD4に対する測方散乱(細胞の大きさと密度を測定)のフローサイトメトリープロットである。図1は、CD4+細胞は総数(N=22)の約46%を示す。CD4+細胞の正の選択の結果として、98.69%の純粋CD4+細胞(N=22)が得られた。図1Bに見ることができるように、カラム後のCD4+の集団はリンパ球と単球の両方を含む。
図3は第0日目(デイ0)を示し、CD4+シード細胞は最大ピーク約103(算術平均は541、n=17)の二峰性CD62L平均蛍光強度(MFI)を発現する。MFIは、培養9日後に算術平均は1541まで増加し(CAC)、次いで最後の4時間の活性化の後、極端に減少する(算術平均の平均は190.3)(CFB)。
CD40LのCAC上の発現密度は、CD3/CD28ビーズで4時間刺激した後にCACの表面上で一貫して上昇する。図4は、代表的なバッチにおけるCD40L発現の算術平均と割合の変化を示し、第0日目(図4A)、最終活性前にCACを採取した第9日目(図4B)、および4時間活性化させた後のCFB(図4C)と比較する。見られるように、不活性細胞と活性細胞の違いは、CD40L+細胞の割合においてはさほど大きくはないが、むしろ算術平均において大きい(CFBの算術平均は112であるが(n=29)、CACの算術平均は20(n=29)である)。
第9日目の各生産物バッチからCAC細胞を採取したサンプルはCD3/CD28ビーズで4時間活性化され、上澄み液は収集され、ELISA分析法を用いてサイトカイン生産物(IFN−γ,IL−4,IL−8,TNFαおよびGM−CSF)を試験した。表1は、これらの実験の結果を示す。
活性化Th1/キラー細胞による直接致死
CFBが腫瘍細胞に直接影響があり得るかどうかをテストするために、ARH77細胞株を殺す細胞能力が試験された。ARH77の細胞株は樹立骨髄腫細胞株である。ARH77細胞は、ARH77細胞をCFBと区別するためにCFSEで染色された。CFBは、標的(ARH77)に対して異なるエフェクター(CFB)で18時間染色されたARH77と混合された。その後、7AADが添加されて、細胞はFC500MPLフローサイトメトリーを用いて得られた。この実験は異なるCACバッチを用いて、新鮮で解凍されたCFBを用いて繰り返し行われる。ARH77単独、ダイナビーズ(DynaBeads)、CD4+細胞と供に、またはCACと供にでは、示されてはいないが、著しい致死(10%以下)データは見られない。図5に示される結果は、CAC、CD4+細胞またはビーズではなく、CFBがARH77細胞株に対して直接致死効果があることを示す。
Claims (14)
- Th1/キラー細胞を含む抗腫瘍用組成物の製造方法であって、
前記Th1/キラー細胞が、未感作CD4+細胞をエキソビボで以下のとおりに活性化及び再活性化してなるものであり、
前記Th1/キラー細胞は、外因性サイトカインの添加なしに前記未感作CD4+細胞表面のCD3およびCD28を架橋することで前記未感作CD4+細胞を活性化すること、及び
前記活性化されたCD4+細胞を凍結保存し、患者への投与をする前に解凍して、前記活性化されたCD4+細胞表面のCD3およびCD28を架橋することで前記活性化されたCD4+細胞を前記再活性化させて得られて、
前記Th1/キラー細胞は、Th1特性とARH77腫瘍細胞株に対して細胞溶解活性とを有し、
前記抗腫瘍組成物は、グランザイムBおよびパーフォリンを発現し、前記細胞溶解活性はNK特性を含む、
抗腫瘍用組成物の製造方法。 - 前記Th1/キラー細胞は、
IL−4の発現を減少させるかあるいはIL−4を全く発現しない、請求項1に記載の抗腫瘍用組成物の製造方法。 - 前記Th1/キラー細胞は、
正常なドナーの末梢血液から得られる、請求項1に記載の抗腫瘍用組成物の製造方法。 - 前記Th1/キラー細胞は、
a)CD3およびCD28の架橋剤で調製される、請求項1に記載の抗腫瘍用組成物の製造方法。 - 前記抗腫瘍用組成物は、
a)臨床的に意義のある数の前記Th1/キラー細胞を含む、又は
b)少なくとも1x107個の細胞を含む、又は、
c)少なくとも1x108個の細胞を含む、請求項1に記載の抗腫瘍用組成物の製造方法。 - 前記Th1/キラー細胞の前記細胞溶解活性は、正常細胞ではなく異常細胞を不活性にし、
前記異常細胞は、癌細胞、感染細胞またはそれらの細胞の組合わせを含む、請求項1に記載の抗腫瘍用組成物の製造方法。 - 前記Th1/キラー細胞は、
正常細胞を不活性化しない、請求項1に記載の抗腫瘍用組成物の製造方法。 - 異常細胞を破壊するために用いられる抗腫瘍用組成物の製造方法であって、
前記抗腫瘍用組成物は、同種異系のTh1/キラー細胞を含み、
前記Th1/キラー細胞が、未感作CD4+細胞をエキソビボで以下のとおりに活性化及び再活性化してなるものであり、
前記Th1/キラー細胞は、外因性サイトカインの添加なしに前記未感作CD4+細胞表面のCD3およびCD28を架橋することで前記未感作CD4+細胞を前記活性化すること、
前記活性化されたCD4+細胞を凍結保存し、患者への投与をする前に解凍して、前記活性化されたCD4+細胞表面のCD3およびCD28を架橋することで前記活性化されたCD4+細胞を前記再活性化すること、
を含み、
前記Th1/キラー細胞は、Th1特性とARH77腫瘍細胞株に対して細胞溶解活性を有し、
前記抗腫瘍組成物は、グランザイムBおよびパーフォリンを発現し、前記細胞溶解活性はNK特性を含み、前記異常細胞と前記Th1/キラー細胞との相互作用により前記異常細胞が破壊される、抗腫瘍用組成物の製造方法。 - 前記Th1/キラー細胞が、IL−4の発現を欠く、請求項8に記載の抗腫瘍用組成物の製造方法。
- 前記異常細胞が、癌細胞、感染細胞、またはそれらの細胞の組合せを含む、請求項8に記載の抗腫瘍用組成物の製造方法。
- 前記Th1/キラー細胞が、架橋抗CD3/抗CD28モノクローナル抗体とともにCD4+T細胞の活性化により得られる、請求項8に記載の抗腫瘍用組成物の製造方法。
- 治療に使用される抗腫瘍用組成物の製造方法であって、
前記抗腫瘍用組成物が、臨床的に意義のある数のTh1/キラー細胞を含み、
前記Th1/キラー細胞が、未感作CD4+細胞をエキソビボで以下のとおりに活性化及び再活性化してなるものであり、
前記Th1/キラー細胞は、外因性サイトカインの添加なしに前記未感作CD4+細胞表面のCD3およびCD28を架橋することで前記未感作CD4+細胞を活性化すること、
前記活性化されたCD4+細胞を凍結保存し、患者への投与をする前に解凍して、前記活性化されたCD4+細胞表面のCD3およびCD28を架橋することで前記活性化されたCD4+細胞を前記再活性化すること、
を含み、
前記Th1/キラー細胞は、Th1特性とARH77腫瘍細胞株に対して細胞溶解活性を有し、
前記抗腫瘍組成物は、グランザイムBおよびパーフォリンを発現し、前記細胞溶解活性はNK特性を含む、
抗腫瘍用組成物の製造方法。 - 前記Th1/キラー細胞は、正常なドナーの末梢血液から得られる、又は、
前記Th1/キラー細胞は、患者にとって同種異系である、又は、
前記臨床的に意義のある細胞数は、少なくとも1x108個である、請求項12に記載の抗腫瘍用組成物の製造方法。 - 前記Th1/キラー細胞は、抗CD3/抗CD28モノクローナル抗体に結合され架橋されるビーズにより活性化される、請求項12に記載の抗腫瘍用組成物の製造方法。
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KR101697473B1 (ko) * | 2014-11-26 | 2017-01-18 | 주식회사 녹십자랩셀 | T 세포를 이용한 자연살해세포의 배양방법 |
EP3326641B1 (en) | 2015-04-22 | 2019-06-26 | CureVac AG | Rna containing composition for treatment of tumor diseases |
JP7337373B2 (ja) * | 2019-07-29 | 2023-09-04 | サイアス株式会社 | 抗原特異的t細胞の製造方法 |
US11730313B2 (en) * | 2021-02-24 | 2023-08-22 | Kirsten Wilkins | Slow cooker liner system with integrated dividers |
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US20030050392A1 (en) * | 1998-09-22 | 2003-03-13 | Brother Kogyo Kabushiki Kaisha | Water-based ink for ink jetting and ink jet recording method |
US20030175242A1 (en) | 2001-09-17 | 2003-09-18 | Micheal Gruenberg | Cell therapy system |
US20030134415A1 (en) | 2001-09-19 | 2003-07-17 | Gruenberg Micheal L. | Th1 cell adoptive immunotherapy |
US20030194395A1 (en) * | 2001-09-17 | 2003-10-16 | Gruenberg Micheal L. | Th1 cell adoptive immunotherapy |
DE60331228D1 (de) | 2002-08-23 | 2010-03-25 | Multhoff Gabriele | Granzyme b als ein hsp70/hsp70 peptid-abhängige apoptoseauslöser in tumorzellen |
US7402431B2 (en) | 2004-03-01 | 2008-07-22 | Immunovative Therapies, Ltd. | T-cell therapy formulation |
US7435592B2 (en) * | 2003-05-13 | 2008-10-14 | Immunovative Therapies, Ltd. | Compositions for allogeneic cell therapy |
US7678572B2 (en) * | 2004-02-26 | 2010-03-16 | Immunovative Therapies, Ltd. | Methods for preparing T-cells for cell therapy |
PT2606125T (pt) | 2010-08-20 | 2018-02-27 | Immunovative Therapies Ltd | Células que expressam características th1 e propriedades citolíticas |
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EP2606125A2 (en) | 2013-06-26 |
EP2606125B1 (en) | 2017-11-22 |
HUE036094T2 (hu) | 2018-06-28 |
US10385315B2 (en) | 2019-08-20 |
WO2012024666A3 (en) | 2012-05-18 |
JP6525946B2 (ja) | 2019-06-05 |
CA2808873C (en) | 2020-02-18 |
TR201802334T4 (tr) | 2018-03-21 |
JP2013536232A (ja) | 2013-09-19 |
PL2606125T3 (pl) | 2018-05-30 |
SG187846A1 (en) | 2013-03-28 |
KR20130103485A (ko) | 2013-09-23 |
CN108245673A (zh) | 2018-07-06 |
NO2606125T3 (ja) | 2018-04-21 |
ES2660577T3 (es) | 2018-03-23 |
US20120045423A1 (en) | 2012-02-23 |
KR101900807B1 (ko) | 2018-11-08 |
US20130195825A1 (en) | 2013-08-01 |
AU2011291477B2 (en) | 2016-07-28 |
DK2606125T3 (en) | 2018-03-05 |
SG10201510524TA (en) | 2016-01-28 |
BR112013003989B1 (pt) | 2020-11-24 |
AU2011291477A1 (en) | 2013-04-04 |
US20130196428A1 (en) | 2013-08-01 |
WO2012024666A2 (en) | 2012-02-23 |
IL224813B (en) | 2020-06-30 |
JP2017061558A (ja) | 2017-03-30 |
CN103068973A (zh) | 2013-04-24 |
EP2606125A4 (en) | 2014-03-19 |
CA2808873A1 (en) | 2012-02-23 |
PT2606125T (pt) | 2018-02-27 |
BR112013003989A2 (pt) | 2017-11-14 |
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