JP2020517237A - 抗原特異的免疫エフェクター細胞 - Google Patents
抗原特異的免疫エフェクター細胞 Download PDFInfo
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Abstract
Description
本発明は、一般に分子生物学の分野に関する。より詳細には、それは、抗原特異的免疫エフェクター細胞、例えばT細胞及びNK細胞に関する方法及び組成物に関する。
がんと診断された患者にとって利用可能な診断及び治療オプションにおける技術的進歩にもかかわらず、依然として予後不良のままであることが多く、多くの患者が治癒不能である。免疫療法は、正常組織を損傷させることなく悪性腫瘍細胞を根絶する可能性とともに、様々な腫瘍を有すると診断された患者に対して強力であるが標的化された治療をもたらす可能性を秘めている。理論上、免疫系のT細胞は、腫瘍細胞に特異的なタンパク質パターンを認識する能力があり、種々のエフェクター機構を通じてのそれらの破壊を媒介することになる。養子T細胞療法は、患者自身のT細胞の腫瘍根絶能力を利用・増幅し、次にこれらのエフェクターを、それらが残留腫瘍を有効に除去しても健常組織を損傷しないような状態で患者に戻すという試みである。この手法は腫瘍免疫学の分野にとって新規性はないが、養子T細胞療法の臨床使用における多くの欠点により、がん治療におけるこの手法の十分な利用が損なわれる。
本明細書で用いられるとき、「本質的に含まない」は、特定成分の観点で、組成物に意図的に配合されている、且つ/又はあくまで汚染物質として又は微量で存在するような特定成分がないことを意味するように本明細書で用いられる。したがって、組成物の任意の意図しない汚染に起因する特定成分の総量は、0.05%を十分に下回り、好ましくは0.01%未満である。標準的分析法を用いて特定成分が全く検出できないような組成物が最も好ましい。
特定の実施形態では、多能性幹細胞は、抗原受容体、例えばCARを発現するように改変される。多能性幹細胞は、限定はされないが、人工多能性幹細胞及び胚性幹細胞を含む幹細胞であってもよい。特定の態様では、本明細書で用いられる多能性幹細胞は、本開示の造血前駆細胞を含む、インビトロで長期増殖の能力がある一方で、身体のあらゆる細胞型に分化する潜在能力を保持する、ヒト胚性幹細胞(ESC)又は人工多能性幹細胞(iPSC)である。
特定の態様では、ESCとしての多能性幹細胞。ES細胞は、胚盤胞の内部細胞塊に由来し、高いインビトロ分化能を有する。ES細胞は、発生中の胚の外部栄養外胚葉層を除去し、次いで非増殖細胞の支持細胞層上で内部細胞塊を培養することにより単離されうる。再播種された細胞は、増殖し続け、除去、解離、さらなる再播種、及び増殖放置が可能であるES細胞の新しいコロニーを生成することができる。未分化ES細胞を「継代培養する」このプロセスは、数回反復することで、未分化ES細胞を含有する細胞株を生成可能である(米国特許第5,843,780号明細書;米国特許第6,200,806号明細書;米国特許第7,029,913号明細書)。ES細胞は、増殖する一方でその多能性を維持するような潜在能力を有する。例えば、ES細胞は、細胞に関する、また細胞分化を制御する遺伝子に関する研究において有用である。遺伝子操作及び選択と組み合わせてのES細胞の多能性は、トランスジェニック、キメラ、及びノックアウトマウスの作製を通じたインビボでの遺伝子分析試験において用いることができる。
他の態様では、本明細書で用いられる多能性幹細胞は、一般にiPS細胞又はiPSCと略記される、人工多能性幹(iPS)細胞である。多能性の誘導は当初、2006年にマウス細胞を用いて(Yamanaka et al.2006)、また2007年にヒト細胞を用いて(Yu et al.2007;Takahashi et al.2007)、多能性に関連した転写因子の導入を介した体細胞のリプログラミングにより達成された。iPSCの使用により、ES細胞の大規模臨床使用に関連した倫理的且つ実用的問題の大部分が回避され、またiPSC由来の自家移植片を有する患者は、移植片拒絶を阻止するための生涯にわたる免疫抑制治療を必要としなくてもよい。
本開示の特定の実施形態は、iPSCにリプログラミングされる体細胞(例えば、血球又は皮膚細胞)の開始集団に関する。血球の集団は、末梢血単核球(PBMC)、混合集団を含有する全血又はその画分、脾臓細胞、骨髄細胞、腫瘍浸潤リンパ球、白血球除去によって得られた細胞、生検組織、及びリンパ節、例えば腫瘍からのリンパ節流入を含みうる。好適なドナーは、免疫ドナー、非免疫(ナイーブ)ドナー、処置又は未処置ドナーを含む。「処置」ドナーは、1つ以上の生物学的修飾因子に曝露されているものである。「未処置」ドナーは、1つ以上の生物学的修飾因子に曝露されていない。
いくつかの実施形態では、細胞(例えばT細胞)の開始集団が、例えば米国特許出願公開第2014/0315304号明細書(その全体が参照により本明細書中に援用される)に記載の方法により、iPSCにリプログラミングされる。本開示の特定の態様では、リプログラミング因子が、1つ以上のベクター、例えば組み込みベクター又はエピソームベクターに含まれる発現カセットから発現される。さらなる態様では、リプログラミングタンパク質は、タンパク質形質導入によれば、体細胞に直接的に導入可能である。
本開示の特定の態様では、ウイルスベクターが提供されてもよい。組換えウイルスベクターの作製においては、非必須遺伝子が、典型的には異種(又は非天然)タンパク質における遺伝子又はコード配列で置換される。ウイルスベクターは、核酸、おそらくはタンパク質を細胞に導入するためにウイルス配列を利用する発現構築物の一種である。特定のウイルスが、細胞に感染する、又は受容体媒介エンドサイトーシスを介して細胞に侵入する、そして宿主細胞ゲノムに組み込まれ、ウイルス遺伝子を安定且つ効率的に発現させる能力は、それらを外来核酸の細胞(例えば哺乳動物細胞)への導入における魅力的な候補にしている。本開示の特定の態様の核酸を送達するために用いられてもよいウイルスベクターの非限定例は、下記の通りである。
本開示の特定の態様では、プラスミド又はリポソームに基づく染色体外(即ちエピソーム)ベクターの使用もまた提供されてもよい。かかるエピソームベクターは、例えば、oriPに基づくベクター、及び/又はEBNA−1の誘導体をコードするベクターを含んでもよい。これらのベクターは、DNAの大きい断片の細胞への導入及び染色体外での維持、細胞周期あたり1回の複製、娘細胞への効率的分配を可能にし、且つ実質的に免疫応答を全く誘発しなくてもよい。
特定の態様では、プログラミング因子の送達では、トランスポゾン−トランスポザーゼシステムを用いることができる。例えば、トランスポゾン−トランスポザーゼシステムは、周知のSleeping Beauty、Frog Princeトランスポゾン−トランスポザーゼシステム(後者の説明として、例えば欧州特許第1507865号明細書を参照)、又はTTAAに特異的なトランスポゾンPiggyBacシステムでありうる。
本開示において有用なリプログラミングベクターに含まれる発現カセットは、好ましくは、タンパク質コード配列、介在配列を含むスプライスシグナル、及び転写終結/ポリアデニル化配列に作動可能に連結された真核生物転写プロモーターを(5’→3’方向に)有する。
本明細書に提供される発現構築物は、プログラミング遺伝子の発現を駆動するためのプロモーターを含む。プロモーターは、一般にRNA合成用の開始部位を位置づけるように機能する配列を含む。この最良の公知例は、TATAボックスであるが、TATAボックスが欠けているいくつかのプロモーター、例えば、哺乳動物の末端デオキシヌクレオチジルトランスフェラーゼ遺伝子用のプロモーターや、SV40後期遺伝子用のプロモーターなどでは、開始部位に重なる別々のエレメントが、自ら開始場所を固定することに役立つ。追加的なプロモーターエレメントが、転写開始の頻度を調節する。典型的には、これらは開始部位の30〜110bp上流領域に位置するが、同様にいくつかのプロモーターが開始部位の下流に機能的エレメントを有することが示されている。コード配列をプロモーター「の制御下に」導くため、転写リーディングフレームの転写開始部位の5’末端が、選択されたプロモーターの「下流」(即ち、その3’側)に位置づけられる。「上流」プロモーターは、DNAの転写を刺激し、コードRNAの発現を促進する。
コード配列の効率的翻訳のため、特定の開始シグナルもまた、本開示で提供される発現構築物において用いられてもよい。これらのシグナルは、ATG開始コドン又は隣接配列を含む。ATG開始コドンを含む外因性翻訳制御シグナルが、提供される必要があるかもしれない。当業者であれば、このことを決定し、必要なシグナルを提供することが容易にできるであろう。全インサートの翻訳を保証するため、開始コドンが所望されるコード配列のリーディングフレームと「インフレームで」なければならないことは周知である。外因性翻訳制御シグナル及び開始コドンは、天然又は合成のいずれかでありうる。発現の効率は、適切な転写エンハンサーエレメントの封入により増強されてもよい。
宿主細胞内でベクターを増殖させるため、それは、1つ以上の複製起点部位(「ori」と称されることが多い)、例えば、上記のようなEBVのoriPに対応する核酸配列、又はプログラミングの際に類似の若しくは増強された機能を伴う遺伝子操作されたoriPに対応する核酸配列(複製が開始される特定の核酸配列である)を含有してもよい。或いは、上記のような他の染色体外複製ウイルスの複製起点又は自己複製配列(ARS)が利用可能である。
特定の実施形態では、核酸構築物を含有する細胞が、マーカーを発現ベクター内に含めることにより、インビトロ又はインビボで同定されてもよい。かかるマーカーであれば、細胞に同定可能な変化を与え、発現ベクターを含有する細胞の容易な同定が可能になる。一般に、選択マーカーは、選択を可能にする特性を与えるものである。ポジティブ選択マーカーは、該マーカーの存在がその選択を可能にするようなものである一方、ネガティブ選択マーカーは、その存在がその選択を阻止するようなものである。ポジティブ選択マーカーの例が、薬剤耐性マーカーである。
主要組織適合複合体(MHC)は、同種臓器移植片の免疫拒絶の主因である。3つの主要なMHCクラスIハプロタイプ(A、B、及びC)と3つの主要なMHCクラスIIハプロタイプ(DR、DP、及びDQ)とが存在する。HLA遺伝子座は、高度に多形性であり、染色体6上の4Mbにわたり分布される。領域内部のHLA遺伝子をハプロタイプ化する能力は、この領域が自己免疫及び感染症に関連し、ドナーとレシピエントとの間のHLAハプロタイプの適合性が移植の臨床成績に影響しうることから、臨床的に重要である。MHCクラスIに対応するHLAは、細胞内部からペプチドを提示し、且つMHCクラスIIに対応するHLAは、細胞の外部からTリンパ球に抗原を提示する。移植片と宿主との間でのMHCハプロタイプの不適合性は、移植片に対する免疫応答を惹起し、その拒絶をもたらす。したがって、患者は、拒絶を予防するため、免疫抑制剤で治療されうる。HLA適合幹細胞株は、免疫拒絶のリスクを克服することがある。
PSCは、改変されたTCR又はCARなどの抗原受容体を発現するように遺伝子操作されうる。例えば、PSC(例えば自家又は同種)は、がん抗原に対する抗原特異性を有するTCR又はCARを発現するように修飾される。
いくつかの実施形態では、CARは、a)細胞内シグナル伝達ドメイン、b)膜貫通ドメイン、及びc)抗原結合領域を含む細胞外ドメインを含む。
いくつかの実施形態では、遺伝子操作された抗原受容体は、組換えTCR及び/又は天然に存在するT細胞からクローン化されたTCRを含む。「T細胞受容体」又は「TCR」は、可変a及びβ鎖(各々、TCRα及びTCRβとしても公知)又は可変γ及びδ鎖(各々、TCRγ及びTCRδとしても公知)を有し、且つMHC受容体に結合された抗原ペプチドに特異的に結合する能力がある分子を指す。いくつかの実施形態では、TCRは、αβ形態である。
マクロファージ、Bリンパ球、及び樹状細胞を含むAPCは、特定のMHC分子のそれらの発現により分化される。APCは、抗原を内部移行させ、それらの外部細胞膜上のMHC分子と一緒に、その抗原の一部を再発現する。MHCは、複数の遺伝子座を有する大きい遺伝子複合体である。MHC遺伝子座は、クラスI及びクラスII MHCと称される、MHC膜分子の2つの主要クラスをコードする。Tヘルパーリンパ球は、一般にMHCクラスII分子に関連する抗原を認識し、且つT細胞傷害性リンパ球は、MHCクラスI分子に関連する抗原を認識する。MHCは、ヒトではHLA複合体と称され、マウスではH−2複合体と称される。
遺伝子操作された抗原受容体によって標的にされる抗原の中に、養子細胞療法により標的にされるべき疾患、状態、又は細胞型との関連で発現されるものが挙げられる。疾患及び状態の中で、増殖性、腫瘍性、及び悪性疾患及び障害、例えばがん及び腫瘍、例えば、血液がん、免疫系のがん、例えばリンパ腫、白血病、及び/若しくは骨髄腫、例えばB.T.及び骨髄性白血病、リンパ腫、及び多発性骨髄腫が挙げられる。いくつかの実施形態では、抗原は、疾患又は状態の細胞上、例えば腫瘍又は病原性細胞上で、正常又は非標的化細胞若しくは組織と比べて、選択的に発現又は過剰発現される。他の実施形態では、抗原は、正常細胞上で発現され、且つ/又は改変細胞上で発現される。
A.造血前駆細胞
抗原受容体、例えばCARを発現するように改変された本開示のPSCは、当該技術分野で公知の方法により、HPCに分化されてもよい。一方法では、CAR−PSCは、指向された分化誘導を通じてCD34+HPCに分化される。もう一つの方法では、CAR−PSCは、フォワードプログラミングを通じてCD34+HPCに分化される。
本開示の特定の実施形態は、CAR−PSCのHPCへの分化に関する。CAR−PSCは、例えば米国特許第8,372,642号明細書(参照により本明細書中に援用される)に記載される当該技術分野で公知の方法によりHPCに分化されうる。一方法では、造血分化を促進するため、BMP4、VEGF、Flt3リガンド、IL−3、及びGM−CSFの組み合わせが用いられてもよい。特定の実施形態では、細胞培養物の、分化用のPSCを調製するための第1の培地、BMP4、VEGF、及びFGFを含む第2の培地、次いでFlt3リガンド、SCF、TPO、IL−3、及びIL−6を含む第3の培地中の培養物への逐次的曝露により、多能性細胞がHPC及び造血細胞に分化されうる。第2の限定培地はまた、ヘパリンを含みうる。さらに、BMP4及びVEGFを含有する培地へのFGF−2(50ng/ml)の封入は、多能性細胞からの造血前駆細胞の生成の効率を増強しうる。さらに、第1の限定培地へのグリコーゲンシンターゼキナーゼ3(GSK3)阻害剤(例えば、CHIR99021、BIO、及びSB−216763)の封入は、HPCの生成をさらに増強しうる。
HPCへのPSC分化のための例示的方法は、フィーダーフリー条件下、例えば、Essential 8(E8)培地中、MATRIGEL(商標)又はビトロネクチンでコーティングされたプレート上での維持を含む。凝集体は、50ng/mlのFGF2、50ng/mlのVEGF、2μMのCHIR99021(GSK−3阻害剤)、及びブレビスタチン(ミオシンII阻害剤)(例えば2〜10μM、例えば10μM)が添加されたEssential 3(E3)培地(例えば、E8培地の8中3の成分のみを含有する:DMEM/F12基礎培地、アスコルビン酸(例えば100〜500μM)、2−リン酸マグネシウム及び亜セレン酸ナトリウム)中、特にサブコンフルエント、0.5〜1百万細胞/mlの密度で例えば80%未満のコンフルエンスでのPSCから作られる。凝集体形成、及びその後のステップは、連続撹拌下、超低付着(ULA)フラスコ内での24時間の培養中、実施される。
代替的な例示的方法では、PSCは、HPCの生成用の二次元分化プロトコルを受ける。まず、PSCが、Essential 8(E8)培地中、例えばMATRIGEL(商標)又はビトロネクチンでコーティングされて、フィーダーフリー条件下で、例えば5〜10継代にわたり、低酸素条件に気候順応される。PSCは、個別化され、5uMのブレビスタチン(例えば2〜10μM、例えば10μM)が添加された無血清限定(SFD)培地の存在下、25000/cm2の密度で、PureCoatアミンでコーティングされた6ウェルプレート(Corning Inc.)上に蒔かれる。SFD基礎培地は、75%IMDM(Invitrogen 12200−069)(グルタミン及び25mMヘペス+P/Sを有する)、25%Hams F12(Mediatech 10−080−CV)、0.5%N2添加物(Invitrogen 17502−048)、レチノイン酸を有しない1%B27添加物(Invitrogen 12587−010)、0.05%BSA、50ug/mlのアスコルビン酸、及び4.5×10−4Mのモノチオグリセロールで、50ng/mlのBMP−4、VEGF、及びbFGFが添加されたものを含有してもよい。
本開示の特定の実施形態は、造血細胞の分化/機能にとって重要なプログラミング遺伝子の組み合わせの発現を介したCAR−PSCのフォワードプログラミングにより、HPCを提供する。一方法では、PSCは、例えば国際出願PCT/US2016/057893号明細書(その全体が参照により本明細書中に援用される)に記載の、ETS遺伝子(例えば、ETC2又はERG)、造血発生遺伝子(例えば、GATA2)、及びホメオボックス遺伝子(例えば、HOXA9)などの少なくとも3つの造血前駆体プログラミング遺伝子を発現するように修飾される。特定の態様では、ETV2/ERG、GATA2、及びHOXA9遺伝子は、1つのベクター、例えば誘導性PiggyBacベクターにより、CAR−PSCにトランスフェクトされた双方向Tightプロモーターを用いて、同時発現される。
次に、HPCは、T細胞、NK細胞、及びT/NK細胞を含むリンパ系細胞にさらに分化されうる。いくつかの態様では、分化中のHPCは、リンパ系細胞への分化のため、7〜12日目、例えば8〜11日目、単離される。この段階でのHPCは、CD34及びCD43の発現により同定されてもよい。さらに、リンパ系能力を有するHPCは、CD144、DLL4、CD7及びCD235を、11日目に低下する低いレベルで発現しうるが、これらのマーカーの発現の特定の閾値レベルが、細胞をDLL4の存在下でリンパ系分化に向けて予備刺激するのに必要であることを意味する。
特定の実施形態では、HPCの骨髄又はリンパ系への分化を促進するため、実質的な低酸素条件が用いられてもよい。特定の実施形態では、造血前駆細胞への分化を促進するため、約20%未満、約19%未満、約18%未満、約17%未満、約16%未満、約15%未満、約14%未満、約13%未満、約12%未満、約11%未満、約10%未満、約9%未満、約8%未満、約7%未満、約6%未満、約5%未満、約5%、約4%、約3%、約2%、又は約1%の大気酸素含量が用いられてもよい。特定の実施形態では、低酸素大気は、約5%の酸素ガスを含む。
特定の態様の方法及び組成物によって提供される抗原特異的免疫エフェクター細胞は、種々の用途において使用可能である。これらは、限定はされないが、ほんの数例を挙げれば、インビボでの細胞の移植又は注入;細胞傷害性化合物、発がん物質、突然変異原の増殖/制御因子、医薬化合物などのインビトロでのスクリーニング;血液学的疾患及び損傷の機構の解明;作用剤及び/又は増殖因子が機能する機構の研究;患者におけるがんの診断及び監視;遺伝子治療;並びに生物活性生成物の生成を含む。
本開示の免疫細胞は、本明細書に提供されるリンパ系細胞の特徴に影響を及ぼす因子(溶媒、小分子薬、ペプチド、及びポリヌクレオチドなど)又は環境条件(培養条件又は操作など)をスクリーニングため、使用可能である。
いくつかの実施形態では、本開示は、免疫療法のための方法であって、本開示の免疫細胞を有効量で投与することを含む、方法を提供する。一実施形態では、内科疾患又は障害は、免疫応答を誘発する免疫細胞集団の導入により治療される。本開示の特定の実施形態では、がん又は感染は、免疫応答を誘発する免疫細胞集団の導入により治療される。本明細書では、個体におけるがんの進行を治療する、又は遅延させるための方法であって、を含む、抗原特異的細胞療法剤を有効量で個体に投与することを含む、方法が提供される。本方法は、免疫異常、固形がん、血液がん、及びウイルス感染の治療に適用されてもよい。
さらに、本明細書では、免疫細胞(例えばT細胞又はNK細胞)及び薬学的に許容できる担体を含む医薬組成物及び製剤が提供される。投与は、自家又は非自家でありうる。例えば、T細胞及び/又はNK細胞並びにそれらを含む組成物は、1つの対象から入手され、且つ同じ対象又は異なる適合する対象に投与されうる。本開示の免疫細胞は、カテーテル投与、全身注射、局所注射、静脈内注射、又は非経口投与を含む局所注射を介して投与されうる。本開示の治療組成物を投与するとき、それは一般に、単位用量の注射剤型(例えば、溶液、懸濁液、乳濁液)で配合されることになる。
以下の実施例は、本発明の好ましい実施形態を実証するため、含められる。以下の実施例中に開示される技術が、本発明の実施において十分に機能するような発明者によって発見された技術を表し、ひいてはその実施のための好ましい方法を構成すると考えることができることは、当業者によって理解されるべきである。しかし、当業者は、本開示に照らして、開示される具体的な実施形態において多くの変更を設けられることを理解するだけでなく、本発明の精神及び範囲から逸脱することなく同様又は類似の結果を得る必要がある。
キメラ抗原受容体(CAR)を発現する多能性幹細胞を作製するため、2つの別々の方法を用いた。一方法では、導入遺伝子を含まないPSCを、レトロウイルスベクターを用いて1C細胞を生成し(米国特許出願公開第20160257939号明細書;その全体が参照により本明細書中に援用される)又はエピソームベクターを用いてE11細胞を生成することで、T細胞から誘導した。第2の方法では、PSCに造血プログラミング遺伝子(hematopoietic programming genes)ETV2/ERG、GATA2、及びHOXA9をコードするPiggyBac発現ベクターをトランスフェクトし(H1 ESCをDOX誘導性ETV2−GATA2−HOXA9(EGH)造血プログラミング遺伝子の導入により改変し)、A16細胞を生成した。次に、両方法からのPSCを遺伝子組換えし、FMC63 mAb由来のヒトCD19に結合するscFvドメイン、CD28同時刺激ドメイン及びCD3ζシグナル伝達ドメインからなる第2世代の抗ヒトCD19キメラ抗原受容体(CAR)を構成的に発現した。
CD34+リンパ造血前駆細胞へのPCS分化:実施例1のT細胞由来PSC(レトロウイルス及びエピソームリプログラミングの各々により末梢血T細胞から誘導された1C及びE11 TiPSC)は、凝集体懸濁培養を通じて、CD34+造血前駆細胞に分化した。PSCは、Essential 8(E8)培地中、Matrigel(商標)又はビトロネクチンでコーティングされた6ウェルプレート上、フィーダーフリー条件下で維持した。2μMのCHIR99021(GSK−3阻害剤)及び5μMのブレビスタチン(ミオシン−II阻害剤)を添加したE8培地中、50万細胞/mlの密度でのサブコンフルエントなPSC(<80%のコンフルエンス)から凝集体が作られた。(あらゆるその後の培養ステップを含む)15〜20rpmで、ロッカープラットフォーム上、連続撹拌下、超低付着(ULA)フラスコ内での6時間培養中、凝集体の形成を実施した。
まずPSCを、懸濁細胞凝集体の培養下、8〜10日間、WNT誘導性の分化プライミング、中胚葉誘導及びHPC分化の連続ステップを通じて、CD34+HPCに分化させた(図1B)。HPC画分を濾過により単離した。CD34+HPCのMACs選別は、実施しなかったが、任意選択的には直接CD34常磁性ビーズ(Myltenyi Biotec)を用いて実施してもよい。次に、HPCを、T/NK分化のため、2〜4週間、ヒトDLL4−Fc+レトロネクチンでコーティングしたプレートに移した。T細胞は、抗CD3 mAb(OKT3クローン)でコーティングしたプレート上での培養下で1〜2週間、さらに拡大することができた。
***
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Claims (63)
- 抗原特異的エフェクターT細胞及び/又はNK細胞を生成する方法であって、
(a)多能性幹細胞(PSC)を改変し、キメラ抗原受容体(CAR)を発現し、それによりCAR−PSCを生成することと;
(b)前記CAR−PSCをCD34+造血前駆細胞(HPC)に分化させる、又はフォワードプログラミングすることと;
(c)前記CD34+HPCをT細胞及び/又はNK細胞にさらに分化させることと;
(d)前記T細胞及び/又はNK細胞を拡大させることであって、拡大させることが、抗原特異的標的細胞と共培養し、それにより抗原特異的エフェクターT細胞及び/又はNK細胞を生成することを含む、ことと
を含む、方法。 - ステップ(a)の前記PSCが、人工多能性幹細胞(iPSC)又は胚性幹細胞(ESC)である、請求項1に記載の方法。
- 前記iPSCが、T細胞からリプログラミングされる、請求項2に記載の方法。
- ステップ(b)が、指向された分化誘導を実施することを含む、請求項1〜3のいずれか一項に記載の方法。
- 指向された分化誘導が、
(a)ブレビスタチン、GSK−3阻害剤、FGF2、及びVEGFの存在下で胚様体(EB)を生成することと;
(b)中胚葉誘導を誘導させるため、前記EBをBMP−4、VEGF、及びFGF2と接触させることと;
(c)Flt−3リガンド、IL3、SCF、及びTPOの存在下で前記EBを分化させ、それによりHPCを生成することと、
を含む、請求項4に記載の方法。 - ステップ(c)の分化させることが、BMP4が本質的に不在である、請求項5に記載の方法。
- ステップ(c)の分化させることが、BMP4が不在である、請求項5に記載の方法。
- ステップ(c)の分化させることが、IL−11、cAMP、及び/又はVEGFの存在をさらに含む、請求項5に記載の方法。
- ステップ(c)の分化させることが、IL−11、cAMP、及びVEGFの存在をさらに含む、請求項5に記載の方法。
- 前記GSK−3阻害剤が、CHIR99021である、請求項5に記載の方法。
- 指向された分化誘導が、
(a)個別化されたPSCを、ブレビスタチン、BMP4、VEGF、及びbFGFの存在下、アミンでコーティングされた表面上で培養することと;
(b)前記PSCをBMP−4、VEGF、及びFGF2と接触させることにより、分化を開始させることと;
(c)前記PSCをFlt−3リガンド、IL3、IL6、SCF、TPO、及びヘパリンの存在下でさらに分化させ、それによりHPCを生成することと、
を含み、前記方法がEBの形成を含まない、請求項4に記載の方法。 - 前記PSCが、本質的に導入遺伝子を含まない、請求項1〜11のいずれか一項に記載の方法。
- 前記PSCがヒトである、請求項12に記載の方法。
- 前記T細胞が、CD4+T細胞、CD8+T細胞、細胞傷害性T細胞、制御性T細胞、ナチュラルキラーT細胞、ナイーブT細胞、メモリーT細胞、又はγδT細胞である、請求項1又は3に記載の方法。
- ステップ(a)の前記PSCが、単一の誘導性プロモーターの制御下でERG/ETV2、GATA2、及びHOXA9を発現するようにさらに改変される、請求項1に記載の方法。
- HMGA2、MYCN、NR4A2、SOX17、TFEC、MEIS1、及びHOXA4を発現するように、前記PSCを改変することをさらに含む、請求項15に記載の方法。
- ステップ(b)のプログラミングが、ERG/ETV2、GATA2、及びHOXA9の発現を、HPCを生成するのに十分な期間にわたり誘導することと、ステップ(c)の前に発現の前記誘導を終了させることと、を含む、請求項15又は16に記載の方法。
- 規定されたフィーダーフリー条件下で前記細胞を培養することを含む、請求項1に記載の方法。
- ステップ(b)が、CD34及びCD43を発現する細胞について、抗原特異的T細胞及び/又はNK細胞に分化させる前に選択することをさらに含む、請求項1に記載の方法。
- 選択することが、磁気活性化細胞選別(MACS)を実施することを含む、請求項19に記載の方法。
- CD34及びCD43を発現する前記細胞が、前記全細胞集団の少なくとも35パーセントを含む、請求項19に記載の方法。
- CD34及びCD43を発現する前記細胞が、前記全細胞集団の少なくとも65パーセントを含む、請求項19に記載の方法。
- 前記HPCの少なくとも5パーセントが前記CARを発現する、請求項1に記載の方法。
- 前記HPCの少なくとも10パーセントが前記CARを発現する、請求項1に記載の方法。
- 前記HPCの少なくとも15パーセントが前記CARを発現する、請求項1に記載の方法。
- ステップ(c)の分化させることが、前記HPCを、低酸素条件下、アスコルビン酸及びニコチンアミドの存在下、レトロネクチン及びノッチDLL−4でコーティングされた表面上で培養することを含む、請求項1に記載の方法。
- 前記培養物が、SCF、FLT−3リガンド、TPO、及びIL7をさらに含む、請求項26に記載の方法。
- 前記培養物が、GSK−3阻害剤、IL−2、及び/又はIL−12をさらに含む、請求項27に記載の方法。
- 前記培養物が、GSK−3阻害剤、IL−2、及びIL−12をさらに含む、請求項27に記載の方法。
- ステップ(d)の拡大させることが、前記抗原特異的T細胞を抗CD3抗体、IL−2、及びIL−15の存在下で培養することをさらに含む、請求項1に記載の方法。
- ステップ(d)の拡大させることが、前記抗原特異的T細胞を抗CD3抗体、IL−2、IL−15、及びIL−21の存在下で培養することをさらに含む、請求項1に記載の方法。
- ステップ(d)の拡大させることが、前記抗原特異的T細胞を抗CD3抗体、FLT3リガンド、IL−7、IL−2、IL−15、及び/又はIL−21の存在下で培養することをさらに含む、請求項1に記載の方法。
- ステップ(d)の拡大させることが、SCF及びTPOからなる群から選択される1つ又は2つの追加的な成分をさらに含む、請求項33に記載の方法。
- 前記分化されたCD34+HPCの少なくとも1.5パーセントが、CD3+CAR+T細胞である、請求項26に記載の方法。
- 前記分化されたCD34+HPCの少なくとも2パーセントが、CD3-CAR+NK細胞である、請求項26に記載の方法。
- 前記拡大されたCD34+HPCの少なくとも2パーセントが、CD3+CAR+T細胞である、請求項30に記載の方法。
- 前記拡大されたCD34+HPCの少なくとも10パーセントが、CD3-CAR+NK細胞である、請求項26に記載の方法。
- 前記CAR及び前記抗原特異的標的細胞が、前記同じ抗原に特異的である、請求項1に記載の方法。
- 前記抗原がCD19である、請求項38に記載の方法。
- 前記抗原特異的標的細胞が腫瘍細胞である、請求項1に記載の方法。
- 前記抗原特異的標的細胞がヒトである、請求項1に記載の方法。
- 前記抗原特異的標的細胞がHLAクラスI陰性である、請求項38〜41のいずれか一項に記載の方法。
- 前記抗原特異的エフェクターT細胞の少なくとも5パーセントが、標的細胞に対する細胞傷害性活性を示す、請求項42に記載の方法。
- 前記抗原特異的エフェクターNK細胞の少なくとも40パーセントが、標的細胞に対する細胞傷害性活性を示す、請求項42に記載の方法。
- 前記CARが、前記PSCの前記ゲノムに組み込まれたDNAによってコードされる、請求項1に記載の方法。
- 前記CARが、細胞内シグナル伝達ドメイン、膜貫通ドメイン、及び抗原結合領域を含む細胞外ドメインを含む、請求項1に記載の方法。
- 前記細胞内シグナル伝達ドメインが、CD3ζ及びCD28を含む、請求項46に記載の方法。
- 前記抗原結合領域が、F(ab’)2、Fab’、Fab、Fv、又はscFvである、請求項46に記載の方法。
- 前記PSCがHLAホモ接合性である、請求項1に記載の方法。
- 前記HLAホモ接合性PSCが、遺伝子座対立遺伝子HLA−A、HLA−B、HLA−C、HLA−DR、HLA−DP又はHLA−DQの1つ以上においてホモ接合性である、請求項49に記載の方法。
- 前記HLAホモ接合性PSCが、前記遺伝子座対立遺伝子HLA−A、HLA−B、HLA−C、HLA−DR、HLA−DP又はHLA−DQの2つにおいてホモ接合性である、請求項49に記載の方法。
- 前記HLAホモ接合性PSCが、HLA−A及びHLA−Bにおいてホモ接合性である、請求項51に記載の方法。
- 前記HLAホモ接合性PSCが、HLA−A、HLA−B、及びHLA−Cにおいてホモ接合性である、請求項49に記載の方法。
- 抗原特異的エフェクターT細胞及び/又はNK細胞を生成する方法であって、
(a)PSCを改変し、CARを発現し、それによりCAR−PSCを生成することと;
(b)前記CAR−PSCをブレビスタチン、GSK−3阻害剤、FGF2、及びVEGFの存在下で培養し、それによりEBを生成することと;
(c)中胚葉誘導を誘導するため、前記EBをBMP−4、VEGF、及びFGF2と接触させることと;
(d)EBをFlt−3リガンド、IL3、SCF、及びTPOの存在下で分化させ、それによりCD34+HPCを生成することと;
(e)前記CD34+HPCをT細胞及び/又はNK細胞にさらに分化させることと;
(f)前記T細胞及び/又はNK細胞を拡大させることであって、拡大させることが、抗原特異的標的細胞と共培養し、それにより抗原特異的エフェクターT細胞及び/又はNK細胞を生成することを含む、ことと
を含む、方法。 - 前記GSK−3阻害剤がCHIR99021である、請求項54に記載の方法。
- 抗原特異的エフェクターT細胞及び/又はNK細胞を生成する方法であって、
(a)PSCを改変し、CARを発現し、それによりCAR−PSCを生成することと;
(b)個別化されたCAR−PSCを、ブレビスタチン、BMP4、VEGF、及びbFGFの存在下、アミンでコーティングされた表面上で培養することと;
(c)前記CAR−PSCをBMP−4、VEGF、及びFGF2と接触させることにより、分化を開始させることと;
(d)前記CAR−PSCをFlt−3リガンド、IL3、IL6、SCF、TPO、及びヘパリンの存在下でさらに分化させ、それによりHPCを生成することと;
(e)前記HPCをT細胞及び/又はNK細胞に分化させることと;
(f)前記T細胞及び/又はNK細胞を拡大させることであって、拡大させることが、抗原特異的標的細胞と共培養し、それにより抗原特異的エフェクターT細胞及び/又はNK細胞を生成することを含む、ことと
を含み、前記方法がEBの形成を含まない、方法。 - 抗原特異的エフェクターT細胞及び/又はNK細胞を生成する方法であって、
(a)PSCを改変し、CARを発現し、それによりCAR−PSCを生成することと;
(b)前記CAR−PSCをCD34+HPCに分化させることと;
(c)CD34+CD43+HPCについて選択することと;
(d)前記CD34+CD43+HPCをT細胞及び/又はNK細胞にさらに分化させることと;
(e)前記T細胞及び/又はNK細胞を拡大させることであって、拡大させることが、抗原特異的標的細胞と共培養し、それにより抗原特異的エフェクターT細胞及び/又はNK細胞を生成することを含む、ことと
を含む、方法。 - 請求項1〜57のいずれか一項に従って生成された抗原特異的エフェクターT細胞及び/又はNK細胞の集団。
- 請求項1〜57のいずれか一項に従って生成された前記抗原特異的エフェクターT細胞及び/又はNK細胞を含む医薬組成物。
- 対象におけるがんの治療を意図した、請求項1〜57のいずれか一項に従って生成された前記抗原特異的エフェクターT細胞及び/又はNK細胞を含む組成物。
- 対象におけるがんを治療する方法であって、請求項1〜58のいずれか一項に従って生成された前記抗原特異的エフェクターT細胞及び/又はNK細胞を前記対象に有効量で投与することを含む、方法。
- 前記がんが腫瘍抗原を発現し、且つ前記抗原特異的エフェクターT細胞及び/又はNK細胞が前記腫瘍抗原に特異的である、請求項61に記載の方法。
- 前記対象がヒトである、請求項61に記載の方法。
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JP7181219B2 (ja) | 2022-11-30 |
CA3058779A1 (en) | 2018-10-25 |
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CN110891967A (zh) | 2020-03-17 |
EP3612557A1 (en) | 2020-02-26 |
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WO2018195175A1 (en) | 2018-10-25 |
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AU2018254442A1 (en) | 2019-10-17 |
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