JP6474499B2 - 癌治療用細胞治療剤およびその併用療法 - Google Patents
癌治療用細胞治療剤およびその併用療法 Download PDFInfo
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Description
1.1 間葉系幹細胞の分離および培養
亜洲大学校医療院のIRB審査後、供与を受けたヒト骨髄4mlを滅菌した15ml試験管で4mlのヒストパック(HISTOPAQUE)1077(Sigma‐Aldrich社製)にオーバレイした後、遠心分離機を用いて室温で400xgで30分間遠心分離した。遠心分離後、パスツールピペットを用いて中間のバフィーコート(buffy coat)0.5mlを注意深く採取し、滅菌したリン酸塩緩衝溶液(pH7.4)10mlで満たされた試験管に移した。また、250xgで10分間遠心分離した後、上澄み液を捨て、10mlのリン酸塩緩衝溶液を加えてスムーズに懸濁させた後、10分間250xgで遠心分離した。この過程を2回繰り返し実施した後、最終沈殿物を10%FBS(Hyclone社製)が添加されたDMEM培地(Gibco社製)に加えて、100mm動物細胞培養用容器に1×109細胞になるように分注した。培養容器を培養器に入れて37℃で5%二酸化炭素および95%空気を供給しながら4時間培養した。次いで、培養容器の底部にくっついていない細胞を除去するために上澄み液を除去し、新たな培地を添加して培養器で培養した。
自殺遺伝子であるシトシンデアミナーゼ(cytosine deaminase;以下、CD)を発現するレトロウイルスを作製した。より具体的には、以下のとおりである。
前記1.1で分離培養された間葉系幹細胞に1.2で製造されたCD含有レトロウイルスを用いてCD遺伝子を導入させた。より具体的には、間葉系幹細胞を100mm培養容器に70%程度満たされるように培養した後、レトロウイルス溶液3mlと新鮮な間葉系幹細胞培地3mlおよび4μg/mlのポリブレン(polybrene、Sigma‐Aldrich社製)を添加して8時間培養した。次いで、ウイルス溶液を除去して16時間10mlの間葉系幹細胞培地を加えて培養した後、またレトロウイルスで感染させた。この過程を1〜3回行った後、最終的に間葉系幹細胞をトリプシンで剥離し、培地で1:20希釈して継代培養した。継代培養の際、ピューロマイシン(puromycin、Sigma‐Aldrich社製)を2μg/mlになるように培地に添加してレトロウイルスが感染された細胞だけが生き残るように2週間スクリーニングし、最終的に自殺遺伝子であるCDを発現し続ける間葉系幹細胞株(以下、MSC/CD)を作製した。
1.1 細胞死滅効果の確認
シトシンデアミナーゼ(CD)は、自殺遺伝子であり、これを発現する間葉系幹細胞であるMSC/CDは、図1に図式化したように、前駆薬物であるフルオロシトシン(5‐fluorocytosine;以下、5‐FC)をフルオロウラシル(5‐fluorouracil;以下、5‐FU)に転換し、自分自身も死滅する自殺効果と、周辺細胞を死滅する傍観者効果を有し得る。したがって、前記1.3で製造されたMSC/CDの細胞死滅効果および傍観者効果を確認した。先ず、10,000個のMSC/CDあるいは間葉系幹細胞(MSC)を12‐ウェルプレートで培養した。翌日から前駆薬物5‐FCを0‐1,000μMの濃度で処理し、二日に一回薬物が含まれた新たな培地に変えた。5‐FCを処理して6日目に生きている細胞を測定することができるMTT(3‐(4,5‐dimethyl‐thiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide、Sigma‐Aldrich社製)が、0.5mg/ml濃度で含まれた細胞培養培地に変えて2時間37℃で反応させた後、MTT溶液を除去した。500μlのDMSOを各ウェルに入れて発色反応をさせた後、96‐ウェルプレートに移してELISAリーダー(E‐max、Molecular device社製)で540nmで吸光度を測定した。実験方法の模式図およびその結果を図2に示す。
10,000個のGFPを発現するU87MG(韓国細胞株銀行KCLBNo.30014)神経膠腫細胞と10,000個のMSC/CDあるいは間葉系幹細胞(MSC)を12‐ウェルプレートで培養した。翌日から前駆薬物5‐FCを0〜1,000μMの濃度で処理して二日に一回薬物が含まれた新たな培地に変えた後、6日後に細胞を取得した。かかる実験方法を図3のAに簡単に示す。
細胞治療剤の場合、様々な条件による細胞の状態変化に応じてその効果が異なり得る。したがって、MSC/CDの状態に応じて細胞の能力が変化するか否かを確認するために、凍結後に直ちに解凍した状態の細胞(以下、「F細胞(frozen cell)」)および培養中の細胞をすぐ収穫した状態の細胞(以下、「I細胞(immediately harvested cell)」を製造した。
1.1.F細胞の傍観者効果
F細胞がMSC/CDの傍観者効果を正常に示すことができるか否かおよびかかる傍観者効果が培地の種類のような製造方法と関係なく効果的に示されるか否かを確認するための実験を行った。製造例2の方法によって製造されたI細胞と、10%DMSO凍結培地で製造されたF細胞(DMSO)およびCryostor CS10で製造されたF細胞(CS10)10,000個をプラズマソリューションAで洗浄した後、韓国細胞株銀行から供与を受けたU87MG(KCLB No.30014)に蛍光を発現するようにGFP遺伝子を移入させた神経膠腫U87/GFP細胞とともに12‐ウェルプレートで共培養した。翌日から前駆薬物である5‐FCを0〜1,000μMの濃度で処理して二日に一回薬物が含まれた新たな培地に変えた後、6日後に細胞を取得した。1×パッシブライシスバッファー(passive lysis buffer、Promega社製)を200μl入れて10分間氷上に放置した後、細胞溶解物をE‐tubeに移して12,000rpmで5分間遠心分離後上澄み液を新たな容器に移した。このうち100μlを光が遮断される黒色の96‐ウェルプレートに移した後、フルオロミト(GEMINIEM、molecular device社製)を用いてexcitation 488nm、emission 530nmの条件で蛍光の程度を測定した。かかる実験過程の模式図および傍観者効果を図4に示す。
前記製造例2のように凍結および解凍により製造されたF細胞がI細胞と比較して増殖能の差を示すか否かを確認するために、コロニー形成能(Colony forming unit assay)を確認した。製造例2のように製造され、同じpassageに相当するI細胞と10%DMSO凍結培地により製造されたF細胞をCountess(Invitrogen社製)に計数した後、細胞100個ずつ100mm培養容器に入れて二日に一回新たな培地に変えて培養した。2週後10%ホルマリン(formalin)で10分間固定してリン酸塩緩衝液(Gibco社製)で洗浄した後、クリスタルバイオレット溶液(crystal violet solution、Sigma‐Aldrich社製)で10分間染色して水で3回洗浄した後、Versa doc(BioRad社製)でイメージを取得しており、細胞一つが2週間生育して生成されたコロニーを目視で計数した結果を図5に示す。
2.1.脳腫瘍に対するF細胞の抗癌効果
F細胞の脳腫瘍に対する抗癌効果を確認するために、脳腫瘍同所移植モデル(orthotopic glioma model)を作製した。先ず、生後7週の免疫不全ヌードマウス(中央実験動物)を麻酔させた後、マウスフレーム(sterotaxic frame)に口と耳を固定させた。切開する頭部分を70%エタノールで消毒し、頭頂部を0.5cm程度に垂直切開した。LacZを発現させたU87MG神経膠腫細胞3×105/3μlを脳の座標AP=+0.5mm、ML=‐1.8mm、DV=‐3mmである点に0.3μl/分の速度で移植して脳腫瘍同所移植モデルを作製した。LacZを発現するU87MG神経膠腫細胞を移植してから3日後、製造例2で製造されたF細胞をプラズマソリューションA溶液に懸濁させた後、500xgで5分間遠心分離した。上澄み液を捨て洗浄過程を1回または2回繰り返した後、3×105/6μl濃度になるように準備した。これを脳の座標AP=+0.5mm、ML=‐1.8mm、DV=‐3mmである点に0.3μl/分の速度で移植した。細胞移植翌日から5‐FC(15mg/ml生理食塩水)を500mg/kgの容量で一週間腹腔内注射した。F細胞の抗癌効果と比較するために製造例2で製造されたI細胞を同じ方法で移植して細胞移植翌日から5‐FC(15mg/ml生理食塩水)を500mg/kgの容量で一週間腹腔内注射した。
1×105のHuh7肝癌細胞(Lver cancer、Huh7、KCLB No.60104)、20%マトリゲル(Matrigel、BD社製)が含有されたリン酸塩緩衝液100μlに懸濁して、生後7週齢の免疫不全ヌードマウス(Balb/c nude)の皮下に移植した。移植して14日後、腫瘍のサイズが10〜100mm3になったときに、製造例2で製造されたI細胞とF細胞を注入した。より具体的には、製造例2で製造されたI細胞とF細胞をリン酸塩緩衝液に懸濁させた後、500xgで5分間遠心分離した。この過程を2回繰り返した後、リン酸塩緩衝液に1×106/100μlになるように準備した後、注射器を使用してIまたはF細胞を腫瘍に直接注入した。I細胞とF細胞を注入した翌日から7日間、5‐FC(15mg/ml生理食塩水)を500mg/kgの容量で一週間腹腔内注射した。毎週、デジタル測定器(caliper)を用いて1〜2回腫瘍のサイズを測定し、以下の数式を使用して腫瘍の体積を計算し、その結果を図7に示す。
図7のAに示すように、腫瘍の体積はF細胞を処理した実験群でさらに効果的に減少し、I細胞よりF細胞がさらに優れた抗癌効果を奏するということを確認し、かかる増加した抗癌効果は、図7のBのように肝癌細胞で作製した皮下腫瘍モデルから目視でも確認され、F細胞の治療効果に非常に優れていることを確認した(*、p<0.05 PBS群との比較時)。
BxPC3膵臓癌細胞(pancreatic cancer、BxPC3、ATCC No.CRL‐1687TM)は、成長速度が速く潰瘍がひどいため、1×106BxPC3膵臓癌細胞とI細胞とF細胞を同時に注入した。より具体的には、製造例2で製造されたI細胞とF細胞をリン酸塩緩衝液に懸濁させた後、500xgで5分間遠心分離した。この過程を2回繰り返した後、リン酸塩緩衝液に1×106/100μlになるように準備した後、1×106I細胞またはF細胞を20%マトリゲル(Matrigel、BD社製)が含有されたリン酸塩緩衝液100μlに懸濁し、生後7週齢の免疫不全ヌードマウス(Balb/c nude)の皮下に同時移植した。細胞を注入した翌日から7日間、5‐FC(15mg/ml生理食塩水)を500mg/kgの容量で一週間腹腔内注射した。
5×106のA549肺癌細胞(Lung cancer、A549、ATCC No.CCL‐185TM)を20%マトリゲル(Matrigel、BD社製)が含有されたリン酸塩緩衝液100μlに懸濁し、生後7週齢の免疫不全ヌードマウス(Balb/c nude)の皮下に移植した。移植してから8日後、20〜50mm3の腫瘍サイズになったときに、製造例2で製造されたI細胞とF細胞を注入した。より具体的には、製造例2で製造されたI細胞とF細胞をリン酸塩緩衝液に懸濁させた後、500xgで5分間遠心分離した。
5×106のHT29大腸癌細胞(colon cancer、HT29、ATCC No.HTB‐38TM)を20%マトリゲル(Matrigel、BD社製)が含有されたリン酸塩緩衝液100μlに懸濁し、生後7週齢の免疫不全ヌードマウス(Balb/c nude)の皮下に移植した。移植してから、腫瘍サイズが40〜100mm3になったときに、製造例2で製造されたI細胞とF細胞を注入した。より具体的には、製造例2で製造されたI細胞とF細胞をリン酸塩緩衝液に懸濁させた後、500xgで5分間遠心分離した。
3.1 テモゾロミドとのin vitro併用治療の効果
10,000個のGFPを発現するU87MG(韓国細胞株銀行KCLBNo.30014)神経膠腫細胞と、10,000個のF細胞あるいは間葉系幹細胞(MSC)を12‐ウェルプレートで培養した。翌日からテモゾロミド(temozolomide;TMZ)0‐1000μMと前駆薬物5‐FCを0‐1,000μMの濃度で処理し、二日に一回薬物が含まれた新たな培地に変えた後、6日後に細胞を取得した。本実験の模式図を図9のAに示す。解剖蛍光顕微鏡(Olympus社製)を用いてウェル全体に残っているGFPを発現するU87MGの蛍光イメージ写真を撮り、細胞死滅を確認し結果を図9のDに示す。
GFPを発現させたU87MG(韓国細胞株銀行KCLBNo.30014)神経膠腫細胞であるU87/GFP10,000個とF細胞(MSC/CD)10,000個を12‐ウェルプレートで培養した。翌日からカルムスチン(Carmustin、BCNU、Sigma社製)0〜300μMと前駆薬物5‐FCを0〜300μMの濃度で処理し、二日に一回薬物が含まれた新たな培地に変えながら6日間培養した。7日目になる日に培養液を除去した後、各ウェルに1×パッシブライシスバッファー(passive lysis buffer、Promega社製)を200μl入れて10分間4℃で放置した。細胞溶解物を収去して12,000rpmで5分間遠心分離し、上澄み液を取得した。このうち100μlを光が遮断された黒色の96‐ウェルプレートに移し、蛍光測定器(GEMINI EM、Molecular Device社製)を用いてexcitation 488nm、emission530nmの条件で蛍光の強度を測定した。本実験の模式図を図10のAに示す。
U87/GFP10,000個とF細胞(MSC/CD)10,000個を12‐ウェルプレートで培養した。翌日からイリノテカン(irinotecan、Sigma社製)0〜30μMと前駆薬物5‐FCを0〜300μMの濃度で処理し、二日に一回薬物が含まれた新たな培地に変えながら6日間培養した。7日目になる日に培養液を除去した後、各ウェルに1×パッシブライシスバッファーを200μlを入れて10分間4℃で放置した。細胞溶解物を収去し、12,000rpmで5分間遠心分離し、上澄み液を取得した。このうち100μlを光が遮断された黒色の96‐ウェルプレートに移し、蛍光測定器(GEMINI EM)を用いてexcitation 488nm、emission530nmの条件で蛍光の強度を測定した。2種の抗癌剤を同時に処理して取得した実際のIC50値をアイソボログラム(isobologram)で表示し、その結果を図10のCに示す。
前記3.1〜3.3で確認された相乗効果をin vivoでさらに確認および検証した。LacZを発現するU87MG神経膠腫細胞を移植した後、6日が過ぎた後、製造例2で製造されたF細胞をプラズマソリューションA溶液に懸濁させた後、500xgで5分間遠心分離した。上澄み液を捨てて洗浄過程を2回繰り返した後、3×105/6μlの濃度になるように準備した。これを脳の座標AP=+0.5mm、ML=‐1.8mm、DV=‐3mmである点に0.3μl/分の速度で移植した。細胞移植した翌日からフルオロシトシン(15mg/ml生理食塩水)を500mg/kgの容量で一週間腹腔内注射した。4日が過ぎた後、テモゾロミド(1mg/ml in DMSO:生理食塩水=1:1)を5mg/kgの容量で5日間腹腔内注射した。28日になったときに各動物群から8匹ずつ脳組織を取得して実施例2と同じ方法でX‐gal染色を行って脳腫瘍のサイズを測定した。かかる実験過程を図11のAに図式化して示し、測定された脳腫瘍サイズの変化を図11のBおよびCに示す。
脳腫瘍以外の腫瘍でもF細胞が抗癌効果を奏することができるか確認するために、U87MG神経膠腫細胞を皮下組織に移植し、他臓器癌モデル(non‐brain cancer model)を作製した。1×106のU87MG神経膠腫細胞を20%マトリゲル(Matrigel、BD社製)が含有されたリン酸塩緩衝液100μlに懸濁し、生後7週齢の免疫不全ヌードマウスの皮下に移植した。デジタルカリパス(caliper)を用いて一週間に2回腫瘍のサイズを測定し、以下の数式を使用して腫瘍の体積を計算した。
Claims (12)
- 1)間葉系幹細胞(mesenchymal stem cells;MSC)にシトシンデアミナーゼ(cytosine deaminase;CD)をコードする遺伝子を導入してMSC/CDを製造するステップと、
2)製造されたMSC/CDを凍結し、凍結されたMSC/CDを製造するステップと、3)凍結されたMSC/CDを解凍し懸濁してF細胞を製造するステップと、を含むF細胞の製造方法であって、前記F細胞は、凍結及び解凍後、培養ステップを行わない、F細胞の製造方法。 - 前記F細胞は、癌治療用である、請求項1に記載のF細胞の製造方法。
- 前記癌は、扁平細胞癌、小細胞肺癌、非小細胞肺癌、肺癌、腹膜癌、結腸癌、胆管腫瘍、鼻咽頭癌、喉頭癌、気管支癌、口腔癌、骨肉腫、胆嚢癌、腎臓癌、白血病、膀胱癌、黒色腫、脳癌、神経膠腫、脳腫瘍、皮膚癌、膵臓癌、乳癌、肝癌、骨髄癌、食道癌、大腸癌、胃癌、子宮頸癌、前立腺癌、卵巣癌、頭頸部癌および直腸癌からなる群から選択される1種以上である、請求項2に記載のF細胞の製造方法。
- 前記F細胞は、抗癌用アジュバントである、請求項1〜3のいずれか一項に記載のF細胞の製造方法。
- 1)間葉系幹細胞(mesenchymal stem cells;MSC)にシトシンデアミナーゼ(cytosine deaminase;CD)をコードする遺伝子を導入してMSC/CDを製造するステップと、
2)製造されたMSC/CDを凍結し、凍結されたMSC/CDを製造するステップと、3)凍結されたMSC/CDを解凍し懸濁してF細胞を製造するステップと、
4)前記F細胞を、治療を要する個体に投与するステップと、
5)5‐フルオロシトシン(5‐FC)を、治療を要する個体に投与するステップと、を含む癌の予防または治療用医薬の製造における請求項1に記載の製造方法により調製されたF細胞の使用であって、前記F細胞は、凍結及び解凍後、培養ステップを行わない、F細胞の使用。 - 6)抗癌剤を、治療を要する個体に投与するステップをさらに含む請求項5に記載の使用。
- 前記4)ステップのF細胞の投与の前またはF細胞投与と同時に、抗癌剤を、治療を要する個体に投与するステップを含む請求項5に記載の使用。
- 前記抗癌剤は、ナイトロジェンマスタード、イマチニブ、オキサリプラチン、リツキシマブ、エルロチニブ、トラスツズマブ、ゲフィチニブ、ボルテゾミブ、スニチニブ、カルボプラチン、ソラフェニブ、ベバシズマブ、セツキシマブ、ビスカムアルバム、アスパラギナーゼ、トレチノイン、ヒドロキシカルバミド、ダサチニブ、エストラムスチン、ゲムツズマブ・オゾガマイシン、イブリツモマブ・チウキセタン、ヘプタプラチン、メチルアミノレブリン酸、アムサクリン、アレムツズマブ、プロカルバジン、アルプロスタジル、硝酸ホルミウムキトサン、ゲムシタビン、ドキシフルリジン、ペメトレキセド、テガフール、カペシタビン、ギメラシル、オテラシル、アザシチジン、シタラビン、フルダラビン、エノシタビン、デシタビン、メルカプトプリン、チオグアニン、クラドリビン、カルモフール、ラルチトレキセド、ドセタキセル、パクリタキセル、ベロテカン、トポテカン、ビノレルビン、エトポシド、ビンクリスチン、ビンブラスチン、テニポシド、イダルビシン、エピルビシン、ミトキサントロン、ミトマイシン、ブレオマイシン、ダウノルビシン、ダクチノマイシン、ピラルビシン、アクラルビシン、ぺプロマイシン、テモゾロミド、ブスルファン、イホスファミド、シクロホスファミド、メルファラン、アルトレタミン、ダカルバジン、チオテパ、ニムスチン、クロラムブシル、ミトラクトール、タキソテレ、グリベック、タキソール、ハーセプチン、タルセバ、アバスチン、ゾラデックス、アドリアマイシン、イリノテカン(irinotecan)、10058‐F4、シスプラチン(cisplatin)、シクロホスファミド(cyclophosphamid)、ニトロソウレア‐基盤抗癌剤、メトトレキサート(Methotrexate)およびドキソルビシン(doxorubicin)からなる群から選択される1種以上である、請求項6又は7に記載の使用。
- 前記4)ステップのF細胞と5)ステップの5‐フルオロシトシンは、同時にまたは順次に投与されることを特徴とする、請求項5〜8のいずれか一項に記載の使用。
- 前記5)ステップの5‐フルオロシトシンと6)ステップの抗癌剤は、同時にまたは順次に投与されることを特徴とする、請求項6〜9のいずれか一項に記載の使用。
- 前記4)ステップのF細胞の投与は10日〜30日の周期に繰り返して行わることを特徴とする、請求項6〜10のいずれか一項に記載の使用。
- 前記癌は、扁平細胞癌、小細胞肺癌、非小細胞肺癌、肺癌、腹膜癌、結腸癌、胆管腫瘍、鼻咽頭癌、喉頭癌、気管支癌、口腔癌、骨肉腫、胆嚢癌、腎臓癌、白血病、膀胱癌、黒色腫、脳癌、神経膠腫、脳腫瘍、皮膚癌、膵臓癌、乳癌、肝癌、骨髄癌、食道癌、大腸癌、胃癌、子宮頸癌、前立腺癌、卵巣癌、頭頸部癌および直腸癌からなる群から選択される1種以上である、請求項5〜11のいずれか一項に記載の使用。
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