JP5042826B2 - 腫瘍壊死因子関連アポトーシス誘導リガンド(trail)を産生するように遺伝子操作された腫瘍帰巣細胞 - Google Patents
腫瘍壊死因子関連アポトーシス誘導リガンド(trail)を産生するように遺伝子操作された腫瘍帰巣細胞 Download PDFInfo
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Danial,N.N.及びS.J.Korsmeyer、細胞死:重要管理点。Cell、2004、116(2):p.205−19. Blagosklonny,M.V.、がん細胞において細胞死を選択的に実行するための有望な戦略。Oncogene、2004、23(16):p.2967−75. Waxman,D.J.及びP.S.Schwartz、改良された抗がん遺伝子治療のためのアポトーシスの利用。Cancer Res、2003、63(24):p.8563−72. Ashkenazi,A.及びV.M.Dixit、細胞死受容体:シグナル伝達と調節。Science、1998、281(5381):p.1305−8. Ashkenazi,A.及びV.M.Dixit、細胞死受容体とおとり受容体によるアポトーシス制御。Curr Opin Cell Biol、1999、11(2):p.255−60. Wang,S.及びW.S.El−Deiry、TRAIL、及びTNFファミリー細胞死受容体によるアポトーシス誘導。Oncogene、2003、22(53):p.8628−33. Almasan,A.及びA.Ashkenazi、Apo2L/TRAIL:アポトーシスシグナル伝達、生物学、及びがん治療の可能性、Cytokine Growth Factor Rev,2003、14(3−4):p.337−48. LeBlanc,H.ら、プロアポトーシスBcl−2相同体Baxの突然変異による不活性化を介した細胞死受容体誘導性アポトーシスに対する腫瘍細胞の耐性。Nat Med、2002、8(3):p.274−81. Ashkenazi,A.ら、組換え可溶性Apo2リガンドの安全性と抗腫瘍活性。J.Clin.Invest.、1999、104(2):p.155−162. Walczak,H.ら、腫瘍壊死因子関連アポトーシス誘導リガンドのin vivo殺腫瘍活性。Nat Med、1999、5(2):p.157−63. Mitsiades,C.S.ら、TRAIL/Apo2Lリガンドは多発性骨髄腫においてアポトーシスを選択的に誘導し、薬物耐性を克服する:治療への応用。Blood、2001、98(3):p.795−804. Fulda,S.ら、Smacアゴニストは、in vivoでApo2L/TRAIL誘導性又は抗がん剤誘導性アポトーシスに対する感受性を増加させ、悪性神経膠腫の退縮を誘導する。Nature Medicine、2002、8(8):p.808−815. Pollack,I.F.、M.Erff、及びA.Ashkenazi、可溶性Apo2L/腫瘍壊死因子関連アポトーシス誘導リガンドによるアポトーシスシグナル伝達の直接刺激は、神経膠腫細胞を選択的に殺傷する。Clinical Cancer Research、2001、7(5):p.1362−1369. Lawrence,D.ら、組換え型Apo2L/TRAILの特異的肝細胞毒性。Nat Med、2001、7(4):p.383−5. Qin,J.ら、正常内皮細胞の早期アポトーシスの回避。Nature Medicine、2001、7(4):p.385−386. Jo,M.ら、正常ヒト肝細胞において腫瘍壊死因子関連アポトーシス誘導リガンドによって誘導されるアポトーシス。Nat Med、2000、6(5):p.564−7. Johnston,J.B.ら、慢性リンパ性白血病におけるクロラムブシル誘導性及びフルダラビン誘導性アポトーシスにおけるTRAIL/APO2−L細胞死受容体の役割。Oncogene、2003、22(51):p.8356−69. Yamanaka,T.ら、化学療法剤はヒト肝細胞癌細胞株においてTRAIL誘導性アポトーシスを増大させる。Hepatology、2000、32(3):p.482−90. Armeanu,S.ら、腫瘍壊死因子関連アポトーシス誘導リガンドのアデノウイルスによる遺伝子移入は肝癌細胞の応答障害を克服するが、初代培養ヒト肝細胞では重度のアポトーシスを引き起こす。Cancer Res、2003、63(10):p.2369−72. Voelkel−Johnson,C、D.L.King、及びJ.S.Norris、可溶性TNF関連アポトーシス誘導リガンド(TRAIL/Apo2L)に対する前立腺癌細胞の耐性は、ドキソルビシン、又は全長TRAILのアデノウイルスによる送達によって克服することができる。Cancer Gene Ther、2002、9(2):p.164−72. McCormick,F.、がん遺伝子治療:末端又は最先端?Nat Rev Cancer、2001、1(2):p.130−41. Somia,N.及びI.M.Verma、遺伝子治療:試行錯誤。Nat Rev Genet、2000、g(2):p.91−9. Griffith,T.S.及びE.L.Broghammer、TRAIL組換えアデノウイルスによる病変内局注療法後の腫瘍増殖の抑制。Mol.Ther、2001、4(3):p.257−66. Harrington,K.ら、がん遺伝子治療の媒体としての細胞:標的ベクターと全身送達とのあいだの失われた連結?Hum Gene Ther、2002、13(11):p.1263−80. Rafii,S.及びD.Lyden、臓器の血管新生及び再生のための幹細胞及び前駆細胞の治療的移植。Nat Med、2003、9(6):p.702−12. Rosenberg,S.A.、Karnofsky記念講演.がんの免疫療法と遺伝子治療。J Clin Oncol、1992、10(2):p.180−99. Hardy,C.L.、造血幹細胞の骨髄への帰巣。Am J Med Sci、1995、309(5):p.260−6. Lapidot,T.、NOD/SCID及びB2mnull NOD/SCIDマウスにおけるヒト幹細胞の遊走と再増殖のメカニズム。SDF−1/CXCR4相互作用の役割。Ann NY Acad Sci、2001、938:p.83−95. Lapidot,T.及びI.Petit、幹細胞動員に関する最新の理解:ケモカイン、タンパク質分解酵素、接着分子、サイトカイン、及び間質細胞の役割。Exp Hematol、2002、30(9):p.973−81. Srour,E.F.ら、移植造血幹細胞の帰巣、細胞周期動態、及び運命。Leukemia、2001、15(11):p.1681−4. Clark,B.R.、J.T.Gallagher、及びT.M.Dexter、間質による造血調節における細胞接着。Baillieres Clin Haematol、1992、5(3):p.619−52. Deguchi,T.及びY.Komada、ヒトCD34+造血前駆細胞上の帰巣関連細胞接着分子(H−CAM/CD44)。Leuk Lymphoma、2000、40(1−2):p.25−37. Tavassoli,M.及びJ.J.Minguell、造血前駆細胞の骨髄への帰巣。Proc Soc Exp Biol Med、1991、196(4):p.367−73. Verfaillie,C.M.、造血プロセスの調節因子としての接着受容体。Blood、1998、92(8):p.2609−2612. Cooper,M.A.、T.A.Fehniger、及びM.A.Caligiuri、ヒトナチュラルキラー細胞サブセットの生物学。Trends Immunol、2001、22(11):p.633−40. Basse,P.H.、T.L.Whiteside、及びR.B.Herberman、マウス及びヒトにおける腫瘍免疫療法のための活性化ナチュラルキラー細胞の使用。Methods Mol Biol、2000、121:p.81−94. deMagalhaes−Silverman,M.ら、転移性乳癌患者における活性化ナチュラルキラー細胞を用いた移植後の養子免疫療法。J Immunother、2000、23(1):p.154−60. Rosenberg,S.A.ら、進行がん患者を治療するための高用量インターロイキン2単独又はリンホカイン活性化キラー細胞との併用の有望な無作為化試験。J.Natl.Cancer Inst、1993、85(8):p.622−32. Griffith,T.S.ら、TNF関連アポトーシス誘導リガンド/Apo−2リガンド遺伝子のアデノウイルス介在移入は腫瘍細胞アポトーシスを誘導する。J Immunol、2000、165(5):p.2886−94. Kazhdan I.及びR.A. Marciniak、細胞死受容体4(DR4)は、腫瘍壊死因子関連アポトーシス誘導リガンド(TRAIL)に対する感受性にかかわりなく乳癌細胞を効率的に殺傷する。Cancer Gene Ther、2004、11:p.691−698.
本発明によれば、腫瘍帰巣細胞は、アデノウイルス介在遺伝子移入によって、腫瘍壊死因子関連アポトーシス誘導リガンド(TRAIL)を産生するように遺伝子操作されている。本発明による細胞は、上記欠点を引き起こすことなく、腫瘍部位へTRAILを送達するために全身投与することができる。
(i) CD34+幹細胞及びNK細胞は、TRAILを発現するアデノベクターをin vitroで効率的に形質導入することができる;
(ii) 形質導入により、これらの細胞サブタイプは細胞表面でTRAILを一過性に発現する;
(iii) このように短期間のTRAIL発現は、形質導入細胞とともに共培養したTRAIL感受性及びTRAIL耐性腫瘍細胞において検出される強力なアポトーシス効果と関連がある;
(iv) 初期腫瘍又は進行腫瘍を有するNOD/SCIDへの形質導入細胞のin vivo注射は、マウスの生存期間の顕著な延長と関連があり、アデノウイルスで形質導入されたCD34+細胞及びNK細胞は、治療目的の全身TRAIL送達のための媒体として効率的に役立つことができることを示唆している。
リンパ腫細胞株と、アデノウイルス介在遺伝子移入後にTRAILを発現するように遺伝子操作されたCD34+細胞又はNK細胞との共培養の効果について評価した。
ヒトTRAIL遺伝子をコードするアデノウイルス CMVプロモーターから発現されるヒトTRAIL遺伝子をコードする複製欠損性アデノウイルス(Ad−TRAIL)をこれらの実験に用いた[39]。Ad−TRAILは、pAd5CMVK−NpAのXhoI/NotI部位にクローニングされたヒトTRAILの全長コード配列を含有する。得られたプラスミドとE1遺伝子を欠失させたアデノウイルス骨格配列(Ad5)とをヒト胚性腎293細胞へトランスフェクションし、ウイルス粒子を単離し、TRAIL発現の解析のために増幅させる。A549プラークアッセイにより、組換えアデノウイルスを複製適格ウイルスに対してスクリーニングし、293細胞のプラークアッセイによりウイルス力価を決定する。精製ウイルスを、3%ショ糖含有PBS中に保存し、使用するまで−80℃に維持する。TRAIL遺伝子産物を形質導入細胞の細胞表面で発現させ、フローサイトメトリーで測定することができる。
CD34 + 細胞へのアデノウイルス形質導入 予備実験により、CD34+細胞の最適形質導入効率は、CD34+細胞(2×106/ml)を、無血清条件下、段階的MOI(100〜1,000の範囲)のAd−TRAILに2時間(37℃)曝露することによって一貫して達成されたことを実証した。次に等量の血清添加培地(IMDM/FBS 20%)を加え、4時間後、培養物にGene Booster(1:200)を添加し、更に18時間インキュベーションした。最後に、細胞を血清含有培地で大規模に洗浄し(3回)、PE結合−抗TRAIL抗体を用いた直接免疫蛍光法でトランス遺伝子発現について評価した。
Ad−TRAIL/CD34+細胞又はAd−TRAIL/NK細胞による治療可能性について調べるために、NOD/SCIDマウスに、TRAIL感受性KMS−11多発性骨髄腫細胞株を再注入した。その後、マウスにAd−TRAIL/CD34+細胞又はAd−TRAIL/NK細胞を注射し、細胞に基づいたTRAIL送達による抗腫瘍効果の計測値としてマウスの生存を用いた。
Ad−TRAIL/CD34 + 細胞又はAd−TRAIL/NK細胞の抗腫瘍活性の評価 体重20〜25gの6〜8週齢雌性NOD/SCIDマウスは、Charles River(ミラノ、イタリア)から購入した。マウスは、我々の施設の指針にしたがい、標準的実験室条件下で飼育した。動物に対して実施した実験手順は、国立腫瘍学研究所の動物実験に関する倫理委員会によって認可されており、英国癌研究調整委員会の指針にしたがって実施した。
Ad−TRAIL/CD34 + 細胞 KMS−11細胞を異種移植したマウス(0.5×106/マウス)を、2つの異なるスケジュールにしたがい、週1回の頻度でAd−TRAIL/CD34+細胞の4回のIV注射により処置した。即ち、早期腫瘍の治療はKMS−11細胞の注射後7日目に開始し、進行腫瘍の治療は17日目に開始した。再注入したAd−TRAIL/CD34+細胞の平均形質導入効率は83±8%(平均±SD、n=9)であったため、各マウスは、4回の注射にわたり、平均3.32×106TRAIL発現CD34+細胞数を受けた。
かなりの割合の乳癌細胞株は、TRAILおとり受容体によるTRAIL隔離、R1及びR2受容体の発現喪失、FLIP過剰発現などを含めた多くのメカニズムにより、TRAIL誘導アポトーシスに対して耐性である[40]。sTRAIL耐性リンパ腫細胞株は、mTRAILに曝露したとき、実際にTRAIL反応性になることを示した我々の先の結果に基づき、2つの乳癌細胞株のsTRAIL及びmTRAILに対する感受性を調べた。
細胞株 乳癌細胞株MCF−7及びMDA−MB−361は、それぞれ、DSMZ(ブラウンシュワイク、ドイツ、EU)及びATCC(マナッサス、バージニア州、米国)から購入した。細胞は、マイコプラズマの混入に関し、ポリメラーゼ連鎖反応によって定期的に試験した。全てのin vitro実験は、指数関数的に増殖している細胞を用いて行った。
sTRAILとのインキュベーションがアポトーシスの誘発に関連するかどうかを調べるため、MCF−7細胞株及びMDA−MB−361細胞株をsTRAIL(10〜100ng/ml、72時間)に曝露し、次にアポトーシス細胞及び壊死細胞の割合をFACS解析にて検出した。表7に示すように、MCF−7細胞ではsTRAILに曝露してもアポトーシス反応を誘導しなかったが、100ng/mlのsTRAILに72時間曝露したとき、MDA−MB−361細胞によって顕著な細胞死反応が生じた。これらの結果によれば、MCF−7はsTRAIL耐性細胞株であるが、MDA−MB−361はsTRAIL感受性細胞株である。
ヒトTRAIL遺伝子をコードするアデノウイルス CMVプロモーターから発現されるヒトTRAIL遺伝子をコードする複製欠損性アデノウイルス(Ad−TRAIL)をこれらの実験に用いた[39]。Ad−TRAILは、pAd5CMVK−NpAのXhoI/NotI部位にクローニングされたヒトTRAILの全長コード配列を含有する。得られたプラスミドとE1遺伝子を欠失させたアデノウイルス骨格配列(Ad5)とをヒト胚性腎293細胞へトランスフェクションし、ウイルス粒子を単離し、TRAIL発現の解析のために増幅させる。A549プラークアッセイにより、組換えアデノウイルスを複製適格ウイルスに対してスクリーニングし、293細胞のプラークアッセイによりウイルス力価を決定する。精製ウイルスを、3%ショ糖含有PBS中に保存し、使用するまで−80℃に維持する。TRAIL遺伝子産物を形質導入細胞の細胞表面で発現させ、フローサイトメトリーで測定することができる。
CD34 + 細胞へのアデノウイルス形質導入 CD34+細胞の最適形質導入効率は、CD34+細胞(2×106/ml)を、無血清条件下、段階的Ad−TRAILに2時間(37℃)曝露することによって、MOI 500にて一貫して達成された。対照細胞ではバックグラウンドTRAILシグナルが検出されなかったが、TRAIL発現細胞は、TRAIL陽性CD34+細胞の割合が93±8%(平均±SD)を示した。トリパンブルーによる色素排除試験にて評価した細胞生存率は、MOI 1,000もの高率に影響されなかった(生存細胞≧85%)。
Claims (7)
- 腫瘍壊死因子関連アポトーシス誘導リガンドをコードするDNAを形質導入した、造血成長因子で処理されたがん患者の末梢血由来のCD34+造血細胞、但し、該細胞は樹状細胞ではない。
- 造血成長因子で処理されたがん患者の末梢血由来のCD34+造血細胞に、腫瘍壊死因子関連アポトーシス誘導リガンドをコードするアデノウイルスベクターを形質導入することによって得ることが可能な、請求項1に記載の細胞。
- 請求項1または2に記載の細胞を、生理的に許容可能なビヒクルとの混合物で含有する細胞製剤。
- 請求項1または2に記載の細胞を含む、腫瘍治療用医薬。
- 腫瘍がリンパ腫である、請求項4に記載の医薬。
- 腫瘍が乳癌である、請求項4に記載の医薬。
- 静脈内投与される、請求項4又は5に記載の医薬。
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ZA (1) | ZA200701231B (ja) |
Families Citing this family (14)
Publication number | Priority date | Publication date | Assignee | Title |
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BRPI0510886A (pt) * | 2004-06-18 | 2007-12-26 | Genentech Inc | método para aumentar a apoptose ou a citotoxicidade em células de mamìferos |
DE102006020307A1 (de) * | 2006-05-03 | 2007-11-08 | Martin-Luther-Universität Halle-Wittenberg | TNF-related apoptosis-including (TRAIL)stabil transgen exprimierende mesenchymale Stammzellen, Verfahren zu ihrer Herstellung und zu ihrer Verwendung |
WO2008142862A1 (ja) * | 2007-05-18 | 2008-11-27 | National University Corporation Asahikawa Medical College | 血管内皮前駆細胞の移植による抗がん療法 |
CN102154213B (zh) * | 2011-01-19 | 2012-07-25 | 郑骏年 | 一种运载荷载细胞因子的双调控溶瘤腺病毒的新型cik细胞 |
EP2811023B1 (en) * | 2012-02-01 | 2018-10-24 | Postech Academy-Industry Foundation | Vector simultaneously expressing dodecameric trail and hsv-tk suicide genes, and anticancer stem cell therapeutic agent using same |
CN103288966B (zh) * | 2013-05-17 | 2015-01-21 | 华侨大学 | 一种融合受体及其用于治疗大肠癌的基因药物 |
RU2552609C1 (ru) * | 2013-10-28 | 2015-06-10 | Федеральное государственное бюджетное учреждение науки Институт молекулярной биотехнологии им. В.А. Энгельгардта Российской академии наук (ИМБ РАН) | Способ получения системы направленной доставки белковых молекул (онколитических белков) в опухолевые ткани на основе активированных лимфоцитов |
MX2017005325A (es) | 2014-10-24 | 2018-01-11 | Stemimmune Incorporated | Enfoque de inmunoterapias de combinación para el tratamiento del cancer. |
JP6974681B2 (ja) * | 2015-07-29 | 2021-12-01 | オーエヌケー セラピューティクス リミテッド | 細胞傷害性が増加した改変ナチュラルキラー細胞及びナチュラルキラー細胞株 |
US10906951B2 (en) * | 2015-07-29 | 2021-02-02 | Onk Therapeutics Limited | Modified natural killer cells and natural killer cell lines having increased cytotoxicity |
EP3802795A4 (en) * | 2018-06-06 | 2022-03-16 | Stemcell Technologies Canada Inc. | KITS, COMPOSITIONS AND METHODS FOR ENRICHMENT OF SUPPRESSIVE CELLS DERIVED FROM MYELOID CELLS |
EP3712257A1 (en) | 2019-03-21 | 2020-09-23 | ONK Therapeutics Limited | Modified natural killer cells with increased resistance to cell death |
JP2022526504A (ja) | 2019-03-21 | 2022-05-25 | オーエヌケー セラピューティクス リミテッド | 細胞死に対する耐性が増大した改変免疫エフェクター細胞 |
WO2021209625A1 (en) | 2020-04-17 | 2021-10-21 | Onk Therapeutics Limited | High potency natural killer cells |
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EP1717248A1 (en) * | 1997-06-04 | 2006-11-02 | Oxford Biomedica (UK) Limited | Tumor targeted vector |
WO2002022175A2 (en) * | 2000-09-11 | 2002-03-21 | Musc Foundation For Research Development | Method and composition for treating tumors by selective induction of apoptosis |
JP2004529102A (ja) * | 2000-10-24 | 2004-09-24 | イミュネックス・コーポレーション | 併用療法を用いて、腫瘍を治療する方法 |
US7235358B2 (en) * | 2001-06-08 | 2007-06-26 | Expression Diagnostics, Inc. | Methods and compositions for diagnosing and monitoring transplant rejection |
JP4493882B2 (ja) * | 2001-06-19 | 2010-06-30 | 株式会社カネカ | 抗原およびこの抗原を識別するモノクローナル抗体 |
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US20070264231A1 (en) | 2007-11-15 |
AU2005266543B2 (en) | 2012-02-02 |
WO2006010558A8 (en) | 2006-08-24 |
NZ552223A (en) | 2009-01-31 |
CN101076540A (zh) | 2007-11-21 |
AU2005266543A1 (en) | 2006-02-02 |
RU2007107369A (ru) | 2008-09-10 |
DK1771468T3 (da) | 2010-05-25 |
WO2006010558A1 (en) | 2006-02-02 |
HK1110874A1 (en) | 2008-07-25 |
RU2390558C2 (ru) | 2010-05-27 |
BRPI0513855A (pt) | 2008-05-20 |
PT1771468E (pt) | 2010-04-20 |
CN101076540B (zh) | 2012-10-24 |
HRP20100227T1 (hr) | 2010-07-31 |
KR20070047757A (ko) | 2007-05-07 |
NO20070956L (no) | 2007-02-20 |
IL180233A (en) | 2010-12-30 |
JP2008507961A (ja) | 2008-03-21 |
MX2007001152A (es) | 2007-04-18 |
RS51381B (en) | 2011-02-28 |
ATE455847T1 (de) | 2010-02-15 |
CA2571426A1 (en) | 2006-02-02 |
EP1771468A1 (en) | 2007-04-11 |
EP1771468B1 (en) | 2010-01-20 |
ZA200701231B (en) | 2008-08-27 |
EP1621550A1 (en) | 2006-02-01 |
IL180233A0 (en) | 2007-07-04 |
ES2340400T3 (es) | 2010-06-02 |
PL1771468T3 (pl) | 2010-07-30 |
DE602005019050D1 (de) | 2010-03-11 |
SI1771468T1 (sl) | 2010-07-30 |
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