JP6914851B2 - 核酸ワクチン接種によるcar操作t細胞の効果の増強 - Google Patents
核酸ワクチン接種によるcar操作t細胞の効果の増強 Download PDFInfo
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Description
哺乳動物から細胞の試料を得る工程であって、試料は、T細胞又はT細胞前駆体を含む、工程と
細胞にCARをコードする核酸をトランスフェクトして、CARを発現するように遺伝的に修飾されたT細胞をもたらす工程と
を更に含む。
NH2-シグナルペプチド-抗原結合ドメイン-スペーサー領域-膜貫通ドメイン-T細胞シグナル伝達ドメイン-COOH
を含む。
材料及び方法
末梢血単核細胞(PBMC)、単球、及び樹状細胞(DC)
PBMCは、フィコール-ハイパック(Amersham Biosciences社、Uppsala、Sweden)密度勾配遠心分離によってバフィーコートから単離した。単球は、抗CD14マイクロビーズ(Miltenyi Biotech社、Bergisch-Gladbach、Germany)で濃縮した。未成熟DC(iDC)は、Kreiterら(2007)、Cancer Immunol. Immunother.、CII、56、1577〜87に記載されているようにサイトカイン補充培養基で5日間単球を分化させることによって得た。
ナイーブC57Bl6マウスの脾細胞を単離し、1*107個を培養基(RPMI1640)中に移し、2μg/ml 抗CD3(eBioscience社)、1μg/mL 抗CD28(Novus Biologicals社)、並びに5ng/mL組換えヒト(rh)IL-7及び10ng/mL rh IL-15(Miltenyi社)で予備活性化した。
非組織プレート(non tissue plate)を、2.1μg/cm2 RetroNectin(Clontech社)で4℃にて一晩コーティングした。コーティング後、RetroNectinを除去し、次いで、各ウェルについてPBS/2% BSA[w/v]500μlで室温にて30分ブロックした。BSA溶液を除去し、ウェルをPBSで1回洗浄した。PBSを、CLDN6-CAR、対照-CAR、又はeGFP導入遺伝子を含有するレトロウイルス(MLV-E)ベクターと置き換え、プレートを1300×gで15分遠心分離した。このプロセスを、新鮮なウイルス培養上清を用いて更に2回繰り返した。次いでウェルをPBSで慎重にフラッシュした後、1×106個の24時間予備活性化したマウス脾細胞をコーティングしたウェル上でインキュベートした。4時間インキュベートした後、ウイルス上清を添加し、スピン形質導入を300×g 37℃で実施し、細胞をインキュベーター内で追加の1時間インキュベートした後、ウイルス上清を5ng/mLのIL-7及び10ng/mLのIL-15を含有する培養基と置き換えた。全形質導入手順を1日後に繰り返した。第2の形質導入工程の後、ウイルス上清を、新たな培養基によって置き換えた。CFSEベース増殖アッセイについて、細胞を単離後7日目に回収し、フィコール-Paque PREMIUM(1.084)でフィコール浄化した後、CFSE染色を行った。
IVT RNAの生成を以前に記載されたように実施し(Holtkamp, S.ら(2006)、Blood 108、4009〜4017)、示した量のIVT RNA(マウスBMDC内にCLDN6又は対照抗原:6μg;ヒトT細胞内にCAR:15〜20μg;ヒトT細胞内にTCR:各鎖20μg;iDC内にCLDN6又はgp100:10μg)を予め冷却した4-mmギャップ滅菌電気穿孔キュベット(Peqlab社)内のX-VIVO 15培地(Lonza社、Basel、Switzerland)250μL中に懸濁した細胞に添加した。電気穿孔は、ECM830矩形波電気穿孔システム装置(BTX)(マウスBMDC:400V、3ms、1パルス、ヒトT細胞 500V、3ms、1パルス、ヒトiDC:300V、12ms、1パルス)で実施した。
マウス細胞を5μM CFSEで標識し、ヒトT細胞を0.8μMで標識した。標識細胞を洗浄し、示したエフェクター標的比でIVT-RNAトランスフェクト細胞APC(例えば、BMDC又はiDC)とともに共培養した。共培養の2日後又は4日後に、細胞を回収し、増殖を細胞分裂後の娘細胞内のCFSE蛍光の段階的半減に基づいてフローサイトメトリーによって分析した。
形質導入CARの細胞表面発現を、scFv断片を認識する蛍光色素コンジュゲートイディオタイプ-特異的抗体(Ganymed pharmaceuticals社)及びIgG1-リンカー(すべてのCAR構築物中に含有される)を認識するヒトIgG-PE抗体を使用して分析した。CLDN6の細胞表面発現を、Alexa-Fluor-647コンジュゲートCLDN6特異的抗体IMAB027(Ganymed pharmaceuticals社)を使用して実施した。フローサイトメトリー分析を、FACS Divaソフトウェア(BD Biosciences社)を使用してFACS CANTO IIフローサイトメーターで実施した。
マウスは、市販の提供者から購入した。年齢(8〜10週齢)及び性別(雄又は雌)の一致した動物を実験全体にわたって使用した。
ナイーブBALB/c-Thy1.1+の脾細胞を単離し、5ng/mL rh IL-7及び1.5〜10ng/mL rh IL-15(Miltenyi社)の存在下で2μg/mL コンカナバリンA(Sigma-Aldrich社)によって予備活性化した。予備活性化した細胞を、セクション「マウス脾細胞のレトロウイルス形質導入」に記載したように形質導入した。対照CAR又はCLDN6-CARを含有するレトロウイルスベクターは、高感度ホタルルシフェラーゼ(effLuc; Rabinovich B.A.ら(2008) Proc. Natl. Acad. Sci. U. S. A. 105、14342〜14346)及びeGFP(高感度緑色蛍光タンパク質)レポーター遺伝子を同様にコードし、これらは、「自己切断型」T2A-エレメント(Szymczak A.L.ら(2004) Nat. Biotechnol. 22、589〜594)を使用して別個に発現された。フィコール浄化後、細胞をPBSで2回洗浄して血清タンパク質を除去し、次いで養子細胞移入(ACT)のために調製した。
異なる量のCLDN6又は対照IVT RNAを、WO2013/143683に以前に記載されたように、DOTMA/DOPE(1,2-ジ-O-オクタデセニル-3-トリメチルアンモニウムプロパン/1,2-ジオレオイル-sn-グリセロ-3-ホスホエタノールアミン(2:1 mol:mol))を含むF12-リポソームと複合体形成させた。
200μL中の5×106個のCAR-T2A-effLuc-T2A-eGFP形質導入BALB/c-Thy1.1+ T細胞を、各BALB/cドナーマウス中に静脈内(i.v.)移入した。引き続いて、マウスに養子T細胞移入(ACT)の24時間後に1.3:2のF12:RNA比のRNA(Lip)をi.v.ワクチン接種した。末梢血供与及び全身生物発光イメージングを実施した。
CAR-effLuc-GFP形質導入T細胞の拡大及び分布を、IVIS Luminaイメージングシステム(Caliper Life Sciences社)を使用してin vivo生物発光イメージングによって評価した。簡単に言えば、D-ルシフェリンの水溶液(80mg/体重1kg; Perkin Elmer社)を、ACTの1時間(0日目)、72時間(3日目)、及び96時間(4日目)後にi.p.注射した。その5分後に、放出された光子を定量化した(1分の積分時間)。目的の領域(ROI)内のin vivo生物発光を、IVIS Living Image 4.0ソフトウェアを使用して平均放射輝度(光子/秒/cm2/sr)として定量化した。動物内のルシフェラーゼ発現細胞に由来する透過光の強度を、グレースケール画像として表した。ここで黒色は、最も弱く、白色から暗灰色は、最も強い生物発光シグナルである。マウスのグレースケール参照画像は、LED低光照射下で得た。画像を、Living Image 4.0ソフトウェアを使用して重ね合わせた。
移入Thy1.1+ T細胞の細胞組成を、低張性を用いて溶解した末梢血試料(ACK緩衝液;GIBCO社)中でACTの72時間後(3日目)に査定した。マウスCD90.1/Thy1.1(BD Pharmingen社)、CD8α(eBioscience社)、及びCD4(BD Pharmingen社)を検出する蛍光色素結合モノクローナル抗体を使用した。フローサイトメトリーデータを、FACS-Canto II分析用フローサイトメーターで取得し、FlowJo X(Tree Star社)ソフトウェアを使用することによって分析した。
in vitroでのIVT RNAパルスAPCを用いたCAR操作T細胞の拡大
患者におけるCAR操作T細胞の増殖及び持続性に重要な必要条件は、血液悪性腫瘍におけるCD19特異的CARの有望な臨床トライアルによって実証されたように、抗原の存在である。MHC-ペプチド複合体によるTCR刺激を介したRNA免疫化による内在性T細胞の拡大に類似して、本発明者らは、養子移入CAR T細胞を、標的細胞のリポソーム媒介RNA-ワクチン接種を使用して拡大して、CAR T細胞刺激のための天然の表面発現抗原をもたらすことができるか否かを分析したいと望んだ。このような「切り換え」は、少量のCAR操作T細胞を患者中に最初に移すことを可能にすることができる。この移入が患者において重度の副作用をもたらさない場合、操作されたT細胞を、リポソーム製剤化RNAを用いて拡大することができる。更に、この方法は、一部の状況において、養子T細胞移入のための空間を人工的に作る化学療法を回避するための腫瘍患者の機会であり得る。
in vivoでのIVT RNAパルスAPCを用いたCAR操作T細胞の拡大
生理的な設定においてこの画期的な概念を試験するために、本発明者らは、完全に免疫適格性であり、したがって、患者の免疫状態をより密接に反映し、移入CAR T細胞の持続性の分析を可能にする同系マウスモデルを確立した。
Claims (28)
- 哺乳動物において抗原を発現する標的細胞集団又は標的組織に対する免疫応答を提供するための方法であって、哺乳動物に対して、(a)前記抗原を標的にしたキメラ抗原受容体(CAR)を発現するように遺伝的に修飾されたT細胞を投与する工程と、(b)前記抗原をコードする核酸を含む医薬組成物を投与する工程とを含む方法において使用するための、前記抗原をコードする核酸を含む医薬組成物であって、
前記核酸がリポソーム中に製剤化されているRNAである、医薬組成物。 - 免疫応答が、T細胞媒介免疫応答である、請求項1に記載の医薬組成物。
- 免疫応答が、抗腫瘍免疫応答であり、標的細胞集団又は標的組織が、腫瘍細胞又は腫瘍組織である、請求項1又は2に記載の医薬組成物。
- 抗原の発現又は発現の上昇に関連した疾患、障害、又は状態を有する哺乳動物を処置する方法において使用するための、請求項1から3のいずれか一項に記載の医薬組成物。
- 疾患、障害、又は状態が、がんである、請求項4に記載の医薬組成物。
- 抗原が腫瘍抗原である、請求項1から5のいずれか一項に記載の医薬組成物。
- 抗原が、クローディン、例えば、クローディン18.2及びクローディン6等、CD19、CD20、CD22、CD33、CD123、メソテリン、CEA、c-Met、PSMA、GD-2、並びにNY-ESO-1からなる群から選択される、請求項1から6のいずれか一項に記載の医薬組成物。
- 抗原が病原体抗原である、請求項1、2、及び4のいずれか一項に記載の医薬組成物。
- 抗原をコードする核酸が、哺乳動物の細胞内で発現されて抗原をもたらす、請求項1から8のいずれか一項に記載の医薬組成物。
- 抗原の発現が、細胞表面におけるものである、請求項1から9のいずれか一項に記載の医薬組成物。
- 抗原をコードする核酸が、哺乳動物の細胞内で一過性に発現される、請求項1から10のいずれか一項に記載の医薬組成物。
- 抗原をコードする核酸が、in vitroで転写されたRNAである、請求項1から11のいずれか一項に記載の医薬組成物。
- CARを発現するように遺伝的に修飾されたT細胞及び/又は抗原をコードする核酸が、全身に投与される、請求項1から12のいずれか一項に記載の医薬組成物。
- 抗原をコードする核酸を全身投与した後、脾臓内での抗原の発現が起こる、請求項1から13のいずれか一項に記載の医薬組成物。
- 抗原をコードする核酸を全身投与した後、抗原提示細胞、好ましくはプロフェッショナル抗原提示細胞内での抗原又の発現が起こる、請求項1から14のいずれか一項に記載の医薬組成物。
- 抗原提示細胞が、樹状細胞、マクロファージ、及びB細胞からなる群から選択される、請求項15に記載の医薬組成物。
- 抗原をコードする核酸を全身投与した後、肺及び/又は肝臓内での抗原の発現が起こらず、又は本質的に起こらない、請求項1から16のいずれか一項に記載の医薬組成物。
- 抗原をコードする核酸を全身投与した後、脾臓内での抗原の発現が、肺内での発現の量の少なくとも5倍である、請求項1から17のいずれか一項に記載の医薬組成物。
- 抗原をコードする核酸が、哺乳動物の細胞内で発現されて、CARを発現するように遺伝的に修飾されたT細胞による結合のための抗原をもたらし、前記結合が、CARを発現するように遺伝的に修飾されたT細胞の刺激、プライミング、及び/又は拡大をもたらす、請求項1から18のいずれか一項に記載の医薬組成物。
- 前記方法が、
哺乳動物から細胞の試料を得る工程であって、試料は、T細胞又はT細胞前駆体を含む、工程と
細胞にCARをコードする核酸をトランスフェクトして、CARを発現するように遺伝的に修飾されたT細胞をもたらす工程と
を更に含む、請求項1から19のいずれか一項に記載の医薬組成物。 - CARを発現するように遺伝的に修飾されたT細胞が、CARをコードする核酸を安定に又は一過性にトランスフェクトされる、請求項1から20のいずれか一項に記載の医薬組成物。
- T細胞及び/又は細胞の試料が、CARを発現するように遺伝的に修飾されたT細胞及び抗原をコードする核酸が投与される哺乳動物由来である、請求項1から21のいずれか一項に記載の医薬組成物。
- T細胞及び/又は細胞の試料が、CARを発現するように遺伝的に修飾されたT細胞及び抗原をコードする核酸が投与される哺乳動物と異なる哺乳動物由来である、請求項1から21のいずれか一項に記載の医薬組成物。
- CARを発現するように遺伝的に修飾されたT細胞が、内在性T細胞受容体及び/又は内在性HLAの発現について不活化されている、請求項1から23のいずれか一項に記載の医薬組成物。
- CARが、抗原結合ドメイン、膜貫通ドメイン、及びT細胞シグナル伝達ドメインを含む、請求項1から24のいずれか一項に記載の医薬組成物。
- 抗原結合ドメインが、抗原に対するモノクローナル抗体のscFv配列を含む、請求項25に記載の医薬組成物。
- (a)抗原を標的にしたCARをコードする核酸又は抗原を標的にしたCARを発現するように遺伝的に修飾されたT細胞、及び
(b)前記抗原をコードする核酸
を含み、
前記抗原をコードする核酸がRNAであり、リポソーム中に製剤化されている、キット。 - 哺乳動物において抗原を発現する標的細胞集団又は標的組織に対する免疫応答を提供するための方法であって、哺乳動物に対して、(a)抗原を標的とするキメラ抗原受容体(CAR)をコードする核酸又は、抗原を標的としたCARを発現するように遺伝的に修飾されたT細胞を投与する工程と、(b)抗原をコードする核酸を投与する工程とを含む方法におけるキットの使用のための指示書を更に含む、請求項27に記載のキット。
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