JP7057748B2 - 遺伝子改変された抗第三者中枢性メモリーt細胞および免疫療法におけるその使用 - Google Patents
遺伝子改変された抗第三者中枢性メモリーt細胞および免疫療法におけるその使用 Download PDFInfo
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Description
一実施形態において、本発明のCARは、抗原結合部分とも呼ばれる標的特異的な結合エレメントを含む。部分の選択は、標的細胞の表面を定義するリガンド(すなわち抗原)の種類および数に依存する。例えば、抗原結合ドメインは、特定の疾患状態に関連する標的細胞上の細胞表面マーカーとして作用するリガンド(すなわち抗原)を認識するように選択され得る。したがって、CARにおいて抗原部分ドメインに対するリガンドとして作用し得る細胞表面マーカーには、ウイルス、細菌および寄生虫による感染、自己免疫疾患、ならびに癌細胞に関連するものが含まれ得る。
本発明のCAR分子の細胞質ドメイン(「細胞内シグナル伝達ドメイン」または「T細胞受容体シグナル伝達モジュール」とも呼ばれる)は、CARの配置された細胞の正常なエフェクター機能の少なくとも1つの活性化を担う。
CARの膜貫通ドメインは、天然または合成の供給源に由来し得る。供給源が天然である場合、ドメインは、任意の膜結合タンパク質または膜貫通タンパク質に由来し得る。本発明において特に使用される膜貫通領域は、T細胞受容体のアルファ鎖、ベータ鎖またはゼータ鎖、CD28、CD3イプシロン、CD45、CD4、CD5、CD4、CD5、CD8、CD9、CD16、CD22、CD33、CD37、CD64、CD80、CD86、CD134、CD137、CD154に由来し(つまり、それらの(1つ以上の)膜貫通領域を少なくとも含み)得る。あるいは、膜貫通ドメインは合成であってもよく、その場合、ロイシンおよびバリンなどの、主として疎水性である残基を含むであろう。好ましくは、フェニルアラニン、トリプトファンおよびバリンの三つ組が合成膜貫通ドメインの各末端に見出されるであろう。
さらなる実施形態では、本発明のいくつかの実施形態の細胞は、化学療法、放射線、免疫抑制剤(例えば、シクロスポリン、アザチオプリン、メトトレキサート、ミコフェノール酸エステルおよびFK506)、抗体、またはその他の免疫破壊剤と組み合わせて使用してもよい(以下にさらに詳しく述べる)。
本発明のいくつかの実施形態の方法によって処置することができる悪性疾患(癌とも呼ばれる)は、任意の固体もしくは非固体の腫瘍および/または腫瘍転移であることができる。
感染症の例には、慢性感染症、亜急性感染症、急性感染症、ウイルス性疾患、細菌性疾患、原生動物疾患、寄生虫疾患、真菌性疾患、マイコプラズマ病およびプリオン病が含まれるが、これらに限定されない。
アレルギー性疾患の例には、喘息、皮疹、蕁麻疹、花粉アレルギー、チリダニアレルギー、毒アレルギー、化粧品アレルギー、ラテックスアレルギー、化学物質アレルギー、薬物アレルギー、昆虫刺咬アレルギー、動物垢アレルギー、有棘植物アレルギー、ドクヅタアレルギーおよび食物アレルギーが含まれるが、これらに限定されない。
自己免疫疾患としては、限定されないが例えば、心血管疾患、リウマチ疾患、腺疾患、胃腸疾患、皮膚疾患、肝疾患、神経疾患、筋疾患、腎疾患、生殖関連疾患、結合組織疾患および全身性疾患が挙げられる。
動物
雌の6~12週齢のBALB/c、CB6(F1)およびC57BL/6マウスを、Harlan Laboratoriesから入手したか、またはWeizmann Institute of Scienceの動物施設で成育させた。全てのマウスを小さなケージに(各ケージに5匹ずつ)入れ、滅菌食品と酸性水を与えた。全ての研究は、Weizmann Institute of Science Institutional Animal Care and Use Committeeによって承認された。
以前に[Ophir Eら、Blood(2010)115:2095-2104]に簡単に記載されているとおりに抗第三者Tcmを調製し、サイトカイン欠乏下で提供者マウスの脾細胞を、照射された第三者脾細胞に接触させ60時間培養した。続いて、磁気粒子(BD Pharmingen)を使用してCD8+細胞の正の選択をし、無抗原環境下で培養した。2日ごとにrhIL-15(20ng/mL;R&D Systems)を添加した。培養終了時(16日目)に精製母集団を得るために、磁気活性化細胞選別[MACS、Miltenyi、Bergisch Gladbach、ドイツ]によってCD62L発現のあるTcm細胞の正の選択をした。
1.長い骨をBalb/cまたはC57BL/6マウス[ヌード型または野生型(WT)のどちらか]から採取した。骨を洗浄または粉砕することによって骨髄を抽出して単一の細胞懸濁液を得た。WTマウスから採取したいくつかの調製物を、磁気活性化細胞選別によってT細胞除去に供した。骨髄の数を数え、正しい濃度にし、マウスに尾静脈へのi.v.注射または眼窩内注射をした。
OT-1遺伝子組換えマウスからリンパ節および/または脾臓を採取した。マウスは、CD45.1遺伝子を保有しかつ/またはRAG-/-突然変異の素性を有するOT-1マウスであった。あるいは、OT-1マウスは、同種異系現象の排除に有用な、宿主XOT-1マウスの子孫であるF1-OT1マウスであった。単一細胞懸濁液を作製し、その後、磁気活性化細胞選別[MACS、Miltenyi、Bergisch Gladbach、Germany]によってT細胞精製に供した。得られたOT-1 T細胞集団の純度をFACSにより試験した。次いで、細胞を「新しい」細胞として注入するかさもなければ生体外で培養して、上記のTcm細胞を生じさせた(つまり、オボアルブミン発現マウス由来の照射脾細胞に対する第三者活性化によって生じさせた)。次いで、OT-1 Tcm細胞を、本明細書において記載しているとおりに注射した。
蛍光活性化細胞選別(FACS)分析は、改造したBecton Dickinson FACScanを使用して行った。Vα2、Vβ5、H2Dd、H2Kb、CD45.1、CD45.2、CD8a、CD4、CD25、CD69、CD19に特異的な標識抗体(Biolegend;BD;Miltenyi)で細胞を染色した。
マウスを屠殺し、脾臓およびLNを採取し、CD8+の細胞を選抜した(さらに、H-2Ddに関して負の選択をして「Tcm」を除外した)。これらのナイーブHTCを、それらがC3H(H-2k)またはBALB/c(H-2d)標的を殺傷する能力についてクロム放出アッセイで試験した。標的細胞として使用したBALB/cおよびC3H脾臓細胞は、2μg/mlのコンカナバリンA(Sigma、St.Louis、MO)で48時間前処理し、70μCi51Cr(Perkin Elmer、Wellesley、MA)に1時間暴露した。エフェクター細胞をC57BL/6マウス由来のCD8+選抜細胞から調製し、様々な希釈度でBALB/cまたはC3H脾臓細胞と接触させて6日間インキュベートすることを、IL-2(20U/ml)を含む96ウェルプレートで各希釈度について12回反復して行った。6日目に、滴定された数のエフェクター細胞および5×103個の51Cr標識した標的を、様々なエフェクター/標的(E:T)比でV字底プレート内で混合した。細胞傷害活性は、4時間51Cr放出アッセイで測定した。特異的溶解のパーセンテージは、(実験時放出-自然放出)/(最大放出-自然放出)×100として計算した。培地単独で培養したかまたは1%SDSで溶解した場合の標的細胞による51Crの放出をそれぞれ自然放出または総放出として定義した。
PBMCを患者および健常ボランティアの全血からFicoll密度勾配遠心分離により単離した。示している場合には以前に記載されている血清学的方法[Manual of Tissue Typing Techniques、Washington DC、National Institute of Allergy and Infectious Diseases、NIH DHEW Publication 76-545、1976、p22]によって細胞をクラスI HLAに分類した。
単球をプラスチック接着により単離し、1%のヒト血清と、ペニシリン/ストレプトマイシンおよびGM-CSF(800IU/ml)と、IL-4(20ng/ml)(Peprotech、ハンブルク、ドイツ)とを補充した3mlのCellgro DC培地を使用して6ウェルプレートで培養した。培養48時間後、1.5mlの培地を添加した(1600IU/mlの+GM-CSFおよび20ng/mlのIL4)。24時間後、非付着性細胞を採集し、大きい細胞(ほとんどが未熟DC)の数を数え、GM-CSF 800IU/ml、IL-4 20ng/ml、大腸菌O55:B5由来の10ng/mlのLPS(Sigma、ドイツ、ダイセンホーフェン))およびIFNγ(Peprotech、100IU/ml)を含有する新鮮な培地中に再懸濁させ、ウェル当たりDC約106個で2mlを播種し、一晩インキュベートした。翌日、非付着性細胞を捨て、氷上で20分間インキュベートした後に冷PBS/1%HSを使用して付着DCを静かに取り外した。成熟DCから構成される大きい細胞の数を数えた。潜在的に混入している小数のNK細胞またはメモリーT細胞の増殖を回避するために細胞を、30Gyで照射し、その後、T細胞刺激のために使用した。
CD8負選択キット(Miltenyi、Bergisch Gladbach、ドイツ)を製造者の指示に従って使用して最初の負の選択によってナイーブCD8 T細胞を単離した。抗原を経験したCD8+T細胞は、その後にCD45ROビーズおよびLDカラムを使用して除去した。
ナイーブCD8 T細胞を単離し、IL-21(Peprotech、30ng/ml)を補充したT細胞培地中に再懸濁させた。48ウェルプレートの1ウェル当たりT細胞を4×105個として1:4のDC:T細胞比で、照射されたDCを添加した。各ウェルの総容量は500μlであった。
生存率データの解析は、Kaplan-Meier曲線(対数順位検定)を用いて行った。平均の比較は、スチューデントのt検定を用いて行った。
MHC不一致Tcmは同系骨髄環境下で宿主マウスにおいて生存し、特異的veto活性を発揮する
ヒトにおいて同系骨髄移植(BMT)は、致死的全身照射(TBI)との関連で施される場合でさえ同種異系BMTよりもはるかに安全である、ということを考慮して、本発明者らはまず、養子移入させたF1-Tcm細胞が、同系TDBMTと一緒に注入された場合に宿主抗提供者HTCの攻撃に耐え抜くか否かについて、判定することを試みた(図1A~B)。図2A~Bから分かるように、F1-Tcmは移植後60日目に末梢血中に存続していた。Tcm細胞は、CD8+総画分の約13%±10を占めていた(データは示さず)。次に、Tcmが野生型多クローン性HTC母集団内での抗原特異的クローンの消滅を引き起こす能力を評価するため、および残存するHTCがその機能性を保持することを検証するために、クロム放出殺傷アッセイを採用した。結果は、Tcm処置マウス由来のH2bCD8+HTCがH-2d標的殺傷の著しい軽減を呈し、かつH-2k標的殺傷の能力を保持した一方、Tcmで処置しなかったマウス(すなわちBM単独群)がどちらの細胞タイプに対しても同様のレベルの殺傷を呈した、ということを示している(図3)。これらの結果は、Tcmが多クローン性HTC母集団に対して特異的なveto活性を発揮することを指し示しており、Tcmによって消滅しなかったクローンがその機能性を保持することを裏付けている。続いて、臨床実施により適する強度減弱前処置(RIC)で調整したマウスにおいてこれらの実験を繰り返した。それゆえ、同系T細胞除去骨髄(TDBMT)および同種異系(Balb x Black)F1 Tcm(図1Cに示す)を注射された、5.5GyのTBIで亜致死的に照射されたBalb/cマウスにおける研究では、同様の結果が得られた(図4)。Tcm細胞は、これらのマウスの末梢血中に15ヶ月以上存在した(実験終了時。データは示さず)。したがって、MHC不一致Tcmの生存率は、亜致死的な5.5Gy TBIおよび自家BMTによる調整を含む非常に安全な手順のもとで誘導される。
MHC不一致Tcmは宿主マウスにおいて骨髄移植片の非存在下で生存する
上記のデータに照らして、BMの非存在下でTcm細胞単独が寛容を誘導する能力を評価した。そのようなプロトコルの行き届く範囲ははるかに広いであろう。具体的には、安全な調整下で抗第三者Tcm細胞のみを投与することによる免疫寛容の誘導は、免疫低下状態の個体にとって有益となるだけでなく、非悪性の血液病(例えば貧血およびサラセミア)、自己免疫疾患の処置をおそらくは可能にすることができ、細胞療法を施すための土台を提供できるであろう。最初に、本発明者らは、宿主における寛容誘導を試験することのできるモデルを確立するために、F1起源のTcm細胞が生着する最小照射線量を定義することを試みた。この目的のために、CB6 F1-Tcm細胞の養子移入の有り無し両方でBalb/cマウスを様々な亜致死的調整の線量に曝露した。末梢全血をH2db陽性Tcm細胞に関して分析することにより、Tcmを検出できた(すなわち、Tcm細胞が拒絶されなかった)最小照射線量が5.5Gy TBIであったことが示された(図5)。よって、5.5Gyの亜致死的TBI線量のもとで生存する完全に同種異系のC57BL/6由来Tcmの持続性を試験した(図1C中に描かれているとおり)。この実験は、同種異系起源の細胞がGVHDを誘導しないこと、および抗提供者T細胞の消滅を媒介しているのがアロ反応性ではなくveto活性であることを検証することを意図したものであった。さらに、一旦ヒトに翻訳されれば、「既成の」寛容誘導性Tcmを生成するために、細胞はおそらく同種異系の非一致型の供給源から派生するであろう。結果は、C57BL/6由来の同種異系Tcmが5.5Gyで照射された(図1Cに描写されている)Balb/c宿主内で生存することができ、CB6 F1 Tcmを受けているマウスよりも末梢血中のTcmパーセンテージがわずかに低いことを示した(図6A~B)。この結果は、Tcm細胞の非常に遅い拒絶プロセスに起因している可能性がある。Tcm細胞は、ゆうに1年超に亘って血中に存続するが、クロム放出アッセイで検出された抗宿主クローンの排除を考え合わせれば注射後の最初の数ヶ月に亘るそれらの数の減少は、Tcmが末梢性寛容を誘導することを強く示唆している。
MHC不一致Tcmは同じ提供者からの細胞の養子移入を支援する
Tcm細胞を養子細胞療法に使用できるという仮説を試験するために、本発明者らは、オボアルブミンペプチドに対するTCRを有する遺伝子組換えOT1マウスを利用した。この文脈でOT1遺伝子組換え細胞を使用する動機は、これらの細胞を、提供者T細胞の全母集団またはウイルス抗原もしくは腫瘍抗原に対する抗原特異的T細胞でのドナーリンパ球輸注(DLI)として知られる細胞療法のモデルとして使うことができるという考えに端を発する。
1.C57BL/6 Tcmおよび(BalbxC57BL)F1 Tcmは、同種異系受容者において存続することができる。
2.C57BL/6 Tcmは、同時注入された場合にはC57BL/6 Tcmの背景(OT-1+CD45.1+RAG-)のもとに増殖したCD8+OT-1ナイーブ細胞の保護をもたらすことができ、さらにOT-1細胞自体は循環系から消失する。
3.C57BL/6(H-2b)マウスのMHCハプロタイプを発現するCB6(F1)Tcmもまた、OT-1ナイーブ細胞の保護をもたらすことができる。
OT-1マウスの細胞から作り出された抗第三者Tcm veto細胞は生体内で生着および生存する
実験は、臨床実施により適する強度減弱前処置(RIC)で調整したマウスにおいて行った。こうして、5.5GyのTBIで亜致死的に照射されたBalb/cマウスに、OT-1マウス起源の様々な濃度の非同系Tcm細胞を注射した(図9に示す)。Tcm細胞は、これらのマウスの末梢血中に少なくとも30日間存在した。したがって、MHC不一致T細胞の生存は、安全なRIC手順のもとに誘導される。
Claims (22)
- 中枢性メモリーTリンパ球(Tcm)表現型を有する単離細胞であって、
前記Tcm表現型が、CD3+、CD8+、CD62L+、CD45RA-、CD45RO+の特徴を含み、
前記細胞は寛容誘導性の非GVHD誘導性細胞であり、かつ移植後にリンパ節へ帰巣することができ、
前記細胞が、
(a)抗原反応性細胞の富化を可能にすべくIL-21の存在下で末梢血単核細胞(PBMC)を1つ以上の第三者抗原と接触させること;
(b)前記中枢性メモリーTリンパ球(Tcm)表現型を含む抗第三者細胞の増殖を可能にすべく、ステップ(a)の結果として生じる前記細胞をIL-21、IL-15およびIL-7の存在下で培養し、それにより、Tcm表現型を有する細胞であって、寛容誘導性細胞であり、かつ移植後にリンパ節へ帰巣することができる、細胞を生じさせること;ならびに
(c)T細胞受容体シグナル伝達モジュールおよび疾患抗原に対する細胞外ドメインを含む異種細胞表面受容体を発現するように前記Tcm表現型を有する前記細胞を変換すること、を含む方法によって生じるものである、細胞。 - 中枢性メモリーTリンパ球(Tcm)表現型を有する単離細胞であって、
前記Tcm表現型が、CD3+、CD8+、CD62L+、CD45RA-、CD45RO+の特徴を含み、
前記細胞は寛容誘導性の非GVHD誘導性細胞であり、かつ移植後にリンパ節へ帰巣することができ、
前記細胞が、
(a)抗原反応性細胞の富化を可能にすべくIL-21の存在下で末梢血単核細胞(PBMC)を1つ以上の第三者抗原と接触させること;
(b)前記中枢性メモリーTリンパ球(Tcm)表現型を含む抗第三者細胞の増殖を可能にすべく、ステップ(a)の結果として生じる前記細胞をIL-21、IL-15およびIL-7の存在下で培養し、それにより、Tcm表現型を有する細胞であって、寛容誘導性細胞であり、かつ移植後にリンパ節へ帰巣することができる、細胞を生じさせること;ならびに
(c)疾患抗原に対する細胞外ドメインを有するキメラ抗原受容体(CAR)を発現するように前記Tcm表現型を有する前記細胞を変換すること、を含む方法によって生じるものである、細胞。 - 中枢性メモリーTリンパ球(Tcm)表現型を有する単離細胞であって、
前記Tcm表現型が、CD3+、CD8+、CD62L+、CD45RA-、CD45RO+の特徴を含み、
前記細胞は寛容誘導性の非GVHD誘導性細胞であり、かつ移植後にリンパ節へ帰巣することができ、
前記細胞が、
(a)抗原反応性細胞の富化を可能にすべくIL-21の存在下で末梢血単核細胞(PBMC)を1つ以上の第三者抗原と接触させること;
(b)前記中枢性メモリーTリンパ球(Tcm)表現型を含む抗第三者細胞の増殖を可能にすべく、ステップ(a)の結果として生じる前記細胞をIL-21、IL-15およびIL-7の存在下で培養し、それにより、Tcm表現型を有する細胞であって、寛容誘導性細胞であり、かつ移植後にリンパ節へ帰巣することができる、細胞を生じさせること;ならびに
(c)キメラ抗原受容体(CAR)を発現するように前記Tcm表現型を有する前記細胞を変換することであり、前記CARが1つの共刺激ドメインおよび疾患抗原に対する細胞外ドメインを含んでいる、変換すること、を含む方法によって生じるものである、細胞。 - 請求項1~3のいずれか1項に記載の単離細胞を生体外で生じさせる方法であって、前記T細胞受容体シグナル伝達モジュールまたは前記キメラ抗原受容体(CAR)を含む前記異種細胞表面受容体をコードしているポリヌクレオチドで、前記Tcm表現型を有する前記細胞を変換することを含む、方法。
- 前記変換することが前記ポリヌクレオチドを含むベクターで変換することである、請求項4に記載の方法。
- 前記ポリヌクレオチドが遺伝子組換えT細胞受容体(tg-TCR)またはキメラ抗原受容体(CAR)をコードしている、請求項4または5に記載の方法。
- 前記異種細胞表面受容体が、遺伝子組換えT細胞受容体(tg-TCR)またはキメラ抗原受容体(CAR)を含む、請求項1に記載の単離細胞。
- 前記異種細胞表面受容体が遺伝子組換えT細胞受容体(tg-TCR)またはキメラ抗原受容体(CAR)を含む、請求項4に記載の方法。
- 前記CARが、抗体または抗原結合断片である抗原結合ドメインを含むか、
CD3ζを含むか、
CD28、CD134/OX40、CD137/4-1BB、Lck、ICOSおよびDAP10から構成される群から選択される少なくとも1つの共刺激ドメインを含むか、
CD28、CD134/OX40、CD137/4-1BB、Lck、ICOSおよびDAP10から構成される群から選択される少なくとも2つの共刺激ドメインを含む、
請求項2~3もしくは7のいずれか1項に記載の単離細胞。 - 前記CARが、抗体または抗原結合断片である抗原結合ドメインを含むか、
CD3ζを含むか、
CD28、CD134/OX40、CD137/4-1BB、Lck、ICOSおよびDAP10から構成される群から選択される少なくとも1つの共刺激ドメインを含むか、
CD28、CD134/OX40、CD137/4-1BB、Lck、ICOSおよびDAP10から構成される群から選択される少なくとも2つの共刺激ドメインを含む、
請求項4または8に記載の方法。 - 前記細胞がさらに、前記細胞における少なくとも1つの内因性免疫チェックポイント遺伝子の発現を抑制すべく遺伝子改変されている、請求項1~3、7または9のいずれか1項に記載の単離細胞。
- 前記細胞がさらに、前記細胞における少なくとも1つの内因性免疫チェックポイント遺伝子の発現を抑制すべく遺伝子改変されている、請求項4~6、8または10のいずれか1項に記載の方法。
- 前記方法が、IL-21の存在下で1つ以上の第三者抗原と接触させる前に前記PBMCから付着性細胞を除去するステップをさらに含む、請求項1~3のいずれか1項に記載の単離細胞。
- 前記方法が、IL-21の存在下で1つ以上の第三者抗原と接触させる前に前記PBMCからCD4+およびCD56+細胞を除去するステップを含む、請求項1~3または13のいずれか1項に記載の単離細胞。
- 前記方法が、ステップ(c)の前にステップ(b)の結果として生じる前記細胞を単一細胞懸濁液中へと分離させることをさらに含む、
請求項1~3または13~14のいずれか1項に記載の単離細胞。 - 前記方法が、ステップ(a)の後であってステップ(b)の前に活性細胞を選抜することをさらに含み、前記活性細胞を選抜することが、CD137+ の細胞、CD25 + の細胞またはCD137 + CD25+の細胞を選抜することによって成し遂げられる、
請求項1~3または13~15のいずれか1項に記載の単離細胞。 - 前記CD3+CD8+細胞のうち少なくとも50%が前記特徴を有する、請求項1~3のいずれか1項に記載の単離細胞。
- 前記CD3+CD8+細胞のうち少なくとも50%が前記特徴を有する、請求項1~3または13~17のいずれか1項に記載の単離細胞。
- 請求項1~3、7、9、11または13~18のいずれか1項に記載の単離細胞を含む、細胞集団。
- 請求項19に記載の細胞集団と、薬学的に活性なキャリアとを含む、医薬組成物。
- 処置を必要とする被験体の疾患を処置するために使用される、治療上有効な量の請求項19に記載の細胞集団。
- 前記疾患抗原が腫瘍抗原、ウイルス抗原、細菌抗原、真菌抗原、原生動物抗原、寄生虫抗原、から選ばれる、請求項1~3、7、9、11または13~18のいずれか1項に記載の単離細胞。
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EP3322424A1 (en) | 2018-05-23 |
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EP3322425A1 (en) | 2018-05-23 |
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WO2017009852A1 (en) | 2017-01-19 |
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US20180207247A1 (en) | 2018-07-26 |
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