JP2019508027A - T細胞免疫療法のための方法および組成物 - Google Patents
T細胞免疫療法のための方法および組成物 Download PDFInfo
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Abstract
Description
この出願は、2016年1月15日に出願された米国仮特許出願第62/279,275号(この全体の内容は、参考として援用される)の利益を主張する。
本発明は、T細胞に基づく免疫治療薬、および免疫療法、例えば、がんの処置においてその治療薬を使用する方法に関する。
本明細書中の刊行物、特許、および特許出願は全て、あたかも個々の刊行物、特許、または特許出願が、具体的かつ個々に参照により援用されていると示されているかの如く同程度に、参照により援用される。本明細書の用語と援用された文献の用語が矛盾する場合は、本明細書の用語が優先する。
本明細書には、治療適用のために細胞および核酸を遺伝子改変するのに有用な組成物および方法が開示されている。全体にわたって記載されている組成物および方法は、腫瘍特異的CARを発現させるために、核酸媒介性遺伝子操作プロセスを使用することができる。有効な養子細胞移入に基づく免疫療法(ACT)は、がん(例えば、転移がん)患者の処置に有用であり得る。例えば、非ウイルス法またはウイルス法を使用して自系末梢血リンパ球(PBL)を改変して、がん細胞に特有な抗原を認識し、本開示の組成物および方法で使用することができるキメラ抗原受容体(CAR)を発現させることができる。ある特定の態様は、ヒトまたはヒト化キメラ抗原受容体(図1)を使用して、がんを含むがそれに限定されない、免疫療法用の組成物および方法に関する。このキメラ抗原受容体には、ヒトまたはヒト化キメラ抗原受容体構築物が使用される。ヒトまたはヒト化キメラ抗原受容体は、CD8もしくはCD28膜貫通部分またはそれらの機能的等価物、および共刺激ドメインに融合されている、T細胞活性化をコントロールするシグナル伝達領域と組み合わされていてもよい。
導入遺伝子配列をコードする核酸、例えばDNAは、細胞の染色体にランダムに挿入されてもよい。ランダム組込みは、核酸、例えばDNAを細胞に導入するための任意の方法により生じ得る。例えば、その方法は、これらに限定されないが、エレクトロポレーション、ソノポレーション(sonoporation)、遺伝子銃の使用、リポトランスフェクション、リン酸カルシウムトランスフェクション、デンドリマーの使用、マイクロインジェクション、ならびにアデノウイルス、AAV、およびレトロウイルスベクターを含むウイルスベクターの使用、ならびに/またはグループIIリボザイムであってもよい。
これらに限定されないが、キメラ抗原受容体(CAR)、T細胞受容体(TCR)、もしくはB細胞受容体(BCR)、またはそれらの誘導体を含む、操作された受容体を、本明細書に記載の細胞、組成物、または方法に使用することができる。
ある特定の態様では、細胞または操作された受容体は、標的抗原に結合することができる。操作された細胞は、抗原を標的とすることができる。また、操作された細胞は、エピトープを標的とすることができる。
エピトープは、間質エピトープであってもよい。そのようなエピトープは、腫瘍微細環境の間質上にあってもよい。抗原は、間質抗原であってもよい。そのような抗原は、腫瘍微細環境の間質上にあってもよい。そうした抗原およびそうしたエピトープは、幾つか例を挙げると、例えば、腫瘍内皮細胞、腫瘍血管、腫瘍線維芽細胞、腫瘍周皮細胞、腫瘍間質、および/または腫瘍間葉細胞上に存在していてもよい。こうした抗原は、例えば、CD34、MCSP、FAP、CD31、PCNA、CD117、CD40、MMP4、および/またはテネイシンを含んでいてもよい。
ヌクレアーゼおよび転写因子、それらをコードするポリヌクレオチド、ならびに/または本明細書に記載のタンパク質および/もしくはポリヌクレオチドを含む任意の導入遺伝子ポリヌクレオチドおよび組成物は、任意の好適な手段により標的細胞に送達することができる。
細胞を増大および遺伝子改変する前に、細胞の供給源を、被験体から得ることができる。一部の場合では、T細胞を得ることができる。T細胞は、PBMC、骨髄、リンパ節組織、臍帯血、胸腺組織、および感染部位に由来する組織、腹水、胸水、脾臓組織、および腫瘍を含む、幾つかの供給源から得ることができる。
全体にわたって記載されている組成物は、医薬品に製剤化することができ、それを必要とするヒトまたは哺乳動物を処置するために、または疾患(例えば、がん)を診断するために使用することができる。そうした医薬は、1つまたは複数の化学療法剤または化学療法化合物と共に、1つまたは複数のT細胞(例えば、操作されたT細胞)により、ヒトまたは哺乳動物に同時投与することができる。
;メテレリン;メチオニナーゼ;メトクロプラミド;MIF阻害剤;ミフェプリストン;ミルテホシン;ミリモスチム;ミスマッチ二本鎖RNA;ミトグアゾン;ミトラクトール;マイトマイシン類似体;ミトナフィド;マイトトキシン線維芽細胞増殖因子−サポリン;ミトキサントロン;モファロテン;モルグラモスチム;モノクローナル抗体、ヒト絨毛性ゴナドトロピン;モノホスホリルリピドA+ミオバクテリウム(myobacterium)細胞壁sk;モピダモール;多剤耐性遺伝子阻害剤;外発性腫瘍抑制因子1に基づく療法;マスタード抗がん剤;ミカペルオキシドB;ミコバクテリア細胞壁抽出物;ミリアポロン;N−アセチルジナリン;N−置換ベンズアミド;ナファレリン;ナグレスチップ(nagrestip);ナロキソン+ペンタゾシン;ナパビン(napavin);ナフテルピン;ナルトグラスチム;ネダプラチン;ネモルビシン;ネリドロン酸(neridronic acid);中性エンドペプチダーゼ;ニルタミド;ニサマイシン;一酸化窒素調節因子;窒素酸化物抗酸化剤;ニトルリン(nitrullyn);O6−ベンジルグアニン;オクトレオチド;オキセノン;オリゴヌクレオチド;オナプリストン;オンダンセトロン;オンダンセトロン;オラシン(oracin);経口サイトカイン誘導剤;オルマプラチン;オサテロン;オキサリプラチン;オキサウノマイシン(oxaunomycin);パクリタキセル;パクリタキセル類似体;パクリタキセル誘導体;パラウアミン(palauamine);パルミトイルリゾキシン;パミドロン酸;パナキシトリオール;パノミフェン;パラバクチン;パゼリプチン;ペグアスパルガーゼ;ペルデシン;ポリ硫酸ペントサンナトリウム;ペントスタチン;ペントロゾール(pentrozole);ペルフルブロン;ペルホスファミド;ペリリルアルコール;フェナジノマイシン;フェニルアセテート;ホスファターゼ阻害剤;ピシバニール;塩酸ピロカルピン;ピラルビシン;ピリトレキシム;プラセチン(placetin)A;プラセチンB;プラスミノーゲン活性化因子阻害剤;白金錯体;白金化合物;白金−トリアミン錯体;ポルフィマーナトリウム;ポルフィロマイシン;プレドニゾン;プロピルビス−アクリドン;プロスタグランジンJ2;プロテアソーム阻害剤;プロテインAに基づく免疫調節因子;プロテインキナーゼC阻害剤;プロテインキナーゼC阻害剤、微細藻類;プロテインチロシンホスファターゼ阻害剤;プリンヌクレオシドホスホリラーゼ阻害剤;プルプリン;ピラゾロアクリジン;ピリドキシル化ヘモグロビンポリオキシエチレンコンジュゲート;rafアンタゴニスト;ラルチトレキセド;ラモセトロン;rasファルネシルタンパク質トランスフェラーゼ阻害剤;ras阻害剤;ras−GAP阻害剤;脱メチル化レテリプチン(retelliptine demethylated);レニウムRe186エチドロネート;リゾキシン;リボザイム;RIIレチンアミド;ログレチミド;ロヒツキン(rohitukine);ロムルチド;ロキニメックス;ルビギノン(rubiginone)B1;ルボキシル(ruboxyl);サフィンゴール;サイントピン(saintopin);SarCNU;サルコフィトール(sarcophytol)A;サルグラモスチム;Sdi 1模倣剤;セムスチン;セネッセンス由来阻害剤1;センスオリゴヌクレオチド;シグナル伝達阻害剤;シグナル伝達調節因子;単鎖抗原結合タンパク質;シゾフィラン;ソブゾキサン;ボロカプテイトナトリウム(sodium borocaptate);フェニル酢酸ナトリウム;ソルベロール(solverol);ソマトメジン結合タンパク質;ソネルミン;スパルホス酸(sparfosic acid);スピカマイシン(spicamycin)D;スピロムスチン;スプレノペンチン(splenopentin);スポンギスタチン1;スクアラミン;幹細胞阻害剤;幹細胞分裂阻害剤;スチピアミド(stipiamide);ストロメライシン阻害剤;スルフィノシン;超活性血管作用性腸ペプチドアンタゴニスト;スラジスタ(suradista);スラミン;スワインソニン;合成グリコサミノグリカン;タリムスチン(tallimustine);タモキシフェンメチオジド;タウロムスチン;タザロテン;テコガランナトリウム;テガフール;テルラピリリウム(tellurapyrylium);テロメラーゼ阻害剤;テモポルフィン;テモゾロミド;テニポシド;テトラクロロデカオキシド;テトラゾミン;タリブラスチン(thaliblastine);チオコラリン;トロンボポエチン;トロンボポエチン模倣体;サイマルファシン;サイモポイエチン受容体アゴニスト;チモトリナン(thymotrinan);甲状腺刺激ホルモン;エチルエチオプルプリンスズ(tin ethyl etiopurpurin);チラパザミン;二塩化チタノセン;トプセンチン;トレミフェン;全能性幹細胞因子;翻訳阻害剤;トレチノイン;トリアセチルウリジン;トリシリビン;トリメトレキセート;トリプトレリン;トロピセトロン;ツロステリド(turosteride);チロシンキナーゼ阻害剤;チルホスチン;UBC阻害剤;ウベニメクス;尿生殖洞由来成長阻害因子;ウロキナーゼ受容体アンタゴニスト;バプレオチド;バリオリン(variolin)B;ベクター系、赤血球遺伝子療法;ベラレソール;ベラミン;ベルジン;ベルテポルフィン;ビノレルビン;ビンキサルチン;ビタキシン;ボロゾール;ザノテロン;ゼニプラチン;ジラスコルブ;およびジノスタチンスチマラマーが挙げられる。一実施形態では、抗がん薬は、5−フルオロウラシル、タキソール、またはロイコボリンである。
本明細書に記載されているようなCAR T細胞免疫療法組成物を含む組成物は、医薬品に製剤化することができ、それを必要とするヒトまたは哺乳動物を処置するために、または疾患、例えば、がんを診断するために使用することができる。こうした医薬は、ヒトまたは哺乳動物に、1つまたは複数の追加のワクチンまたは他のがん療法と共に同時投与することができる。
ある特定の実施形態では、天然または操作されたNK細胞を提供して、本明細書に記載されているような細胞免疫療法と組み合わせて、それを必要とする被験体に投与してもよい。
その結果生じるCAR T細胞またはCAR NK細胞免疫療法組成物の免疫原性を増強するために、抗原特異的CAR T細胞またはCAR NK細胞の生成中に、共刺激分子を培養に組み込むことができる。また、共刺激ドメインを、キメラ抗原受容体様複合体と融合させて、操作された細胞に導入してもよい。免疫応答の開始には、APCによりナイーブT細胞を活性化するための少なくとも2つのシグナルが必要とされる(Damleら、J Immunol 148巻:1985〜92頁(1992年);Guinanら、Blood 84巻:3261〜82頁(1994年);Hellstromら、Cancer Chemother Pharmacol 38巻:S40〜44頁(1996年);Hodgeら、Cancer Res 39巻:5800〜07頁(1999年))。抗原特異的な第1のシグナルは、ペプチド/主要組織適合複合体(MHC)によりT細胞受容体(TCR)を介して送達され、T細胞の細胞周期を開始させる。サイトカインを産生および増殖させるために、第2のまたは共刺激シグナルを送達することができる。
ある特定の実施形態では、免疫経路チェックポイント阻害剤を、本明細書で開示されているようなCAR T細胞免疫療法を含む組成物と組み合わせる。ある特定の実施形態では、患者は、本明細書に記載のワクチンまたは医薬組成物と併せて、免疫経路チェックポイント阻害剤を受容した。さらなる実施形態では、組成物は、1つまたは複数の免疫経路チェックポイント調節因子と共に投与される。活性化シグナルと阻害シグナルとのバランスにより、Tリンパ球と疾患細胞との相互作用が制御され、T細胞応答は、T細胞受容体(TCR)により抗原が認識されることにより開始される。阻害経路およびシグナルは、免疫経路チェックポイントと呼ばれる。通常の状況では、免疫経路チェックポイントは、自己免疫のコントロールおよび予防に重要な役割を果たし、また、病原性感染に応答して組織損傷から保護する。
細胞は、本明細書に記載のようにヒトから抽出することができる。細胞は、ex vivoで遺伝的に変更し、それに応じて使用することができる。そうした細胞は、細胞に基づく療法に使用することができる。そうした細胞は、レシピエント(例えば、ヒト)の疾患を処置するために使用することができる。例えば、そうした細胞は、がんを処置するために使用することができる。
CEA特異的CAR T細胞の生成および機能的特徴付け
この例では、CEA特異的CARの生成およびヒトT細胞でのその機能的発現が説明される。特に、CD28/CD3ζシグナル伝達ドメインを担持するCEA特異的CARを設計し、機能性を評価するものとする。
Ad5[E1−,E2b−]−CEA.CARを発現するT細胞の機能的特徴付け
細胞内IFN−γ染色
この例では、細胞内IFN−γ染色による、Ad5[E1−,E2b−]−CEA.CARを発現するT細胞の機能的特徴付けが説明される。形質導入されたT細胞の潜在的細胞傷害性効果を評価するために、異なる細胞傷害性アッセイを実施することになる。Ad5[E1−,E2b−]−CEA.CAR発現T細胞が、ヒト結腸癌細胞を認識する能力、およびその後それらの活性化を試験した。概して、CARを発現するT細胞の活性化は、同族抗原(例えば、CEA)での刺激後に、IFN−ガンマ(または同等なサイトカイン)産生により測定することができる。1×105個のCAR形質導入T細胞を、CARの同族抗原を発現する1×105個のCEA+腫瘍細胞と共に(この例では、抗CEA特異的CARをCEA+腫瘍細胞と共に)インキュベートすることになる。1μl ml−1のGolgiplug(BD Biosciences)の存在下で37℃にて16時間インキュベーションした後、細胞を洗浄し、CD3、CD8に対する抗体(両方ともBD Biosciences)および好適な生/死色素(IR色素、Life Technologies)で染色した。その後、IFN−ガンマの細胞内レベルを、製造業者の指針に従って、Cytofix/Cytopermキット(BD Biosciences)およびIFN−ガンマに対する抗体(BD Biosciences)を使用し、フローサイトメトリーにより単一細胞ベースで決定した。IFN−ガンマ+CD8+T細胞のパーセントを、ヒトIgG1−CH2CH3断片を認識する抗体(Jackson ImmunoResearch)により測定した、Ad5[E1−,E2b−]−CEA.CAR CD8+T細胞の頻度で補正することにより、データを正規化した。
CEA特異的CAR T細胞の臨床増大
この例では、CEA特異的CAR T細胞の臨床増大を説明する。多数の形質導入されたT細胞を生成するために、迅速増大プロトコール(REP)を使用して、細胞を増殖するよう誘導する。T細胞は、REPで使用する前に、抗CD3、抗CD28、およびIL−2と共に培養を開始し、上記で詳述されているように培養を開始した後の2日目に形質導入を行うことになる。細胞を、75cm2フラスコ中で37℃および5%CO2にて培養することになる。培養物で維持することになる残りの期間にわたって2日毎に、細胞を計数し、0.5×106細胞/mLの濃度で、300IU/mLのIL−2を有する新鮮なT細胞培地に懸濁することになる。
Claims (81)
- (a)少なくとも1つの操作された受容体、および
(b)少なくとも1つの染色体外アデノウイルスゲノムを含む、
細胞であって、ここで
前記アデノウイルスゲノムが、アデノウイルス遺伝子の領域中に少なくとも1つの欠失を有し、前記操作された受容体をコードする、細胞。 - 前記操作された受容体が、キメラ抗原受容体(CAR)、T細胞受容体(TCR)、もしくはB細胞受容体(BCR)、またはそれらの誘導体である、請求項1に記載の細胞。
- 前記操作された受容体が、キメラ抗原受容体(CAR)である、請求項1および2に記載の細胞。
- 前記CARが第一世代CARである、請求項2および3に記載の細胞。
- 前記CARが第二世代CARである、請求項2および3に記載の細胞。
- 前記CARが第三世代CARである、請求項2および3に記載の細胞。
- 前記CARが、細胞外部分、膜貫通部分、および細胞内部分を含む、請求項2から6のいずれか一項に記載の細胞。
- 前記細胞内部分が、少なくとも1つのT細胞共刺激ドメインを含む、請求項7に記載の細胞。
- 前記T細胞共刺激ドメインが、CD27、CD28、TNFRS9(4−1BB)、TNFRSF4(OX40)、TNFRSF8(CD30)、CD40LG(CD40L)、ICOS、ITGB2(LFA−1)、CD2、CD7、KLRC2(NKG2C)、TNFRS18(GITR)、TNFRSF14(HVEM)、またはそれらの任意の組み合わせからなる群より選択される、請求項8に記載の細胞。
- 前記操作された受容体が標的に結合する、請求項1から9のいずれか一項に記載の細胞。
- 前記結合が、MHC非依存性である、請求項10に記載の細胞。
- 前記結合が、MHC依存性である、請求項10に記載の細胞。
- 前記結合が、疾患関連標的に特異的である、請求項10から12に記載の細胞。
- 前記疾患が、がんである、請求項13に記載の細胞。
- 前記がんが、固形腫瘍である、請求項14に記載の細胞。
- 前記がんが、液性腫瘍である、請求項14に記載の細胞。
- 前記受容体が、標的抗原に結合する、請求項1から16のいずれか一項に記載の細胞。
- 前記標的抗原が、腫瘍細胞ネオ抗原、腫瘍ネオエピトープ、腫瘍特異的抗原、腫瘍関連抗原、組織特異的抗原、細菌抗原、ウイルス抗原、酵母抗原、真菌抗原、原生動物抗原、寄生生物抗原、マイトジェン、またはそれらの組み合わせである、請求項17に記載の細胞。
- 前記標的抗原が、がん胎児抗原(CEA)、ヒト上皮増殖因子受容体1(HER1)、ヒト上皮増殖因子受容体2(HER2/neu)、ヒト上皮増殖因子受容体3(HER3)、ヒト上皮増殖因子受容体4(HER4)、ヒトパピローマウイルス(HPV)、ムチン1(MUC1)、前立腺特異的抗原(PSA)、PSMA、Brachyury、葉酸受容体アルファ、WT1、p53、MAGE−A1、MAGE−A2、MAGE−A3、MAGE−A4、MAGE−A6、MAGE−A10、MAGE−A12、BAGE、DAM−6、−10、GAGE−1、−2、−8、GAGE−3、−4、−5、−6、−7B、NA88−A、NY−ESO−1、MART−1、MC1R、Gp100、チロシナーゼ、TRP−1、TRP−2、ART−4、CAMEL、Cyp−B、BRCA1、BRACHYURY(TIVS7−2、多型)、BRACHYURY(IVS7 T/C多型)、T BRACHYURY、T、hTERT、hTRT、iCE、MUC1(VNTR多型)、MUC1c、MUC1n、MUC2、PRAME、P15、RU1、RU2、SART−1、SART−3、AFP、β−カテニン/m、カスパーゼ−8/m、CDK−4/m、ELF2M、GnT−V、G250、HSP70−2M、HST−2、KIAA0205、MUM−1、MUM−2、MUM−3、ミオシン/m、RAGE、SART−2、TRP−2/INT2、707−AP、アネキシンII、CDC27/m、TPI/mbcr−abl、ETV6/AML、LDLR/FUT、Pml/RARα、もしくはTEL/AML1、もしくはそれらの修飾バリアント、スプライスバリアント、機能的エピトープ、エピトープアゴニスト、またはそれらの組み合わせからなる群より選択される、請求項17から18のいずれか一項に記載の細胞。
- 前記受容体が、腫瘍関連細胞に結合する、請求項1から19のいずれか一項に記載の細胞。
- 前記腫瘍関連細胞が、線維芽細胞、がん幹細胞、周皮細胞、および間質細胞からなる群より選択される、請求項20に記載の細胞。
- 二次受容体をさらに含む、請求項1から21のいずれか一項に記載の細胞。
- 前記二次受容体が、コクサッキーアデノウイルス受容体である、請求項22に記載の細胞。
- 前記染色体外アデノウイルスゲノムが、アデノウイルス血清型5(Ad5)である、請求項1から23のいずれか一項に記載の細胞。
- アデノウイルス遺伝子の領域中の前記欠失が、初期領域1(E1)遺伝子の領域中の欠失、初期領域2b(E2b)遺伝子中の欠失、初期領域3(E3)遺伝子中の欠失、またはそれらの組み合わせである、請求項1から24のいずれか一項に記載の細胞。
- アデノウイルス遺伝子の領域中の前記欠失が、初期領域2b(E2b)遺伝子の領域中の欠失である、請求項1から25のいずれか一項に記載の細胞。
- アデノウイルス遺伝子の領域中の前記欠失が、初期領域1(E1)遺伝子、初期領域2b(E2b)遺伝子、および初期領域3(E3)遺伝子中の欠失である、請求項1から26のいずれか一項に記載の細胞。
- 外因性遺伝子をさらに含む、請求項1から27のいずれか一項に記載の細胞。
- 前記外因性遺伝子が、自殺遺伝子、サイトカイン遺伝子、抗血管新生遺伝子、代謝遺伝子、または低酸素遺伝子を含むリストから選択される、請求項28に記載の細胞。
- 内因性遺伝子欠失をさらに含む、請求項1から29のいずれか一項に記載の細胞。
- 免疫細胞である、請求項1から30のいずれか一項に記載の細胞。
- 前記免疫細胞がT細胞である、請求項31に記載の細胞。
- 前記T細胞が、エフェクター(TEFF)細胞、エフェクターメモリー(TEM)細胞、セントラルメモリー(TCM)、Tメモリー幹(TSCM)、ナイーブ(TN)、またはCD4+もしくはCD8+である、請求項32に記載の細胞。
- 霊長類細胞である、請求項1から33のいずれか一項に記載の細胞。
- ヒト細胞である、請求項1から34のいずれか一項に記載の細胞。
- ex vivoで増大される、請求項1から35のいずれか一項に記載の細胞。
- 医薬組成物に製剤化される、請求項1から36のいずれか一項に記載の細胞。
- それを必要とする被験体を処置するための併用療法の一部である、請求項1から37のいずれか一項に記載の細胞。
- 前記操作された受容体が、それを必要とする前記被験体のゲノムに組み込まれている、請求項1から38のいずれか一項に記載の細胞。
- 細胞を調製する方法であって、細胞を、少なくとも1つの外因性受容体配列を含む少なくとも1つの操作された染色体外ベクターとex vivoで接触させるステップを含む、方法。
- 前記染色体外ベクターが、アデノウイルスベクターである、請求項40に記載の方法。
- 前記アデノウイルスベクターが、アデノウイルス血清型5(Ad5)である、請求項41に記載の方法。
- 前記ベクターが、少なくとも1つの遺伝子欠失を有する、請求項40から42のいずれか一項に記載の方法。
- 前記欠失が、初期領域1(E1)遺伝子および初期領域3(E3)遺伝子の領域中の欠失である、請求項43に記載の方法。
- 前記欠失が、初期領域2b(E2b)遺伝子中の欠失、初期領域3(E3)遺伝子中の欠失、またはそれらの組み合わせである、請求項43に記載の方法。
- 前記ベクターが、初期領域1(E1)遺伝子、初期領域2b(E2b)遺伝子、および初期領域3(E3)遺伝子中の欠失を含有する、請求項40から45のいずれか一項に記載の方法。
- 前記ベクターが、中空ベクターではない、請求項40から46のいずれか一項に記載の方法。
- 前記外因性受容体の前に、少なくとも1つの二次受容体を導入するステップをさらに含む、請求項40から47のいずれか一項に記載の方法。
- 前記二次受容体が、コクサッキーアデノウイルス受容体である、請求項48に記載の方法。
- 前記外因性受容体配列が、キメラ抗原受容体(CAR)、T細胞受容体(TCR)、もしくはB細胞受容体(BCR)、またはそれらの誘導体を含むリストから選択される、請求項40から49のいずれか一項に記載の方法。
- 前記外因性受容体配列が、キメラ抗原受容体(CAR)をコードする、請求項50に記載の方法。
- 前記ベクターが、第2の外因性遺伝子配列をさらに含む、請求項40から51のいずれか一項に記載の方法。
- 前記外因性遺伝子配列が、自殺遺伝子、サイトカイン遺伝子、抗血管新生遺伝子、代謝遺伝子、および低酸素遺伝子からなる群より選択される、請求項52に記載の方法。
- 前記第2の外因性遺伝子配列が、誘導可能な自殺遺伝子配列を含む、請求項40から53のいずれか一項に記載の方法。
- 前記誘導可能な自殺遺伝子配列が、誘導可能なカスパーゼ9遺伝子配列、またはEGF受容体R配列の部分である、請求項54に記載の方法。
- 前記外因性受容体配列が、少なくとも1つのベクターを用いて前記細胞内に導入される、請求項40から55のいずれか一項に記載の方法。
- 前記細胞が、ex vivoで活性化されている、請求項40から56のいずれか一項に記載の方法。
- 前記活性化が、前記外因性受容体配列が導入される前に生じる、請求項57に記載の方法。
- 前記活性化が、抗CD3(OKT3)、抗CD28、少なくとも1つのサイトカイン、またはそれらの任意の組み合わせで実施される、請求項57から58のいずれか一項に記載の方法。
- 前記サイトカインが、インターロイキン−2(IL−2)、インターロイキン−7(IL−7)、インターロイキン−15(IL−15)、インターロイキン−21(IL−21)、またはそれらの任意の組み合わせを含む、請求項59に記載の方法。
- 前記細胞を増大させるステップをさらに含む、請求項40から60に記載の方法。
- 前記細胞が、それを必要とする被験体に対して自系である、請求項40から61のいずれか一項に記載の方法。
- 前記細胞が、それを必要とする被験体に対して同種異系である、請求項40から61のいずれか一項に記載の方法。
- それを必要とする前記被験体が、前記アデノウイルスベクターに対して既存免疫を有する、請求項62から63のいずれか一項に記載の方法。
- 前記細胞が、医薬品および医薬部外品の製造管理および品質管理規則(GMP)準拠の試薬である、請求項40から64のいずれか一項に記載の方法。
- 前記試薬が、がんを処置するための併用療法の一部である、請求項65に記載の方法。
- 請求項1から39のいずれか一項に記載の細胞、または請求項40から66のいずれか一項により調製された細胞を含む医薬組成物。
- 状態の処置を必要とする被験体において状態を処置する方法であって、治療有効量の請求項67に記載の医薬組成物を被験体に投与するステップを含む、方法。
- 前記医薬組成物が、静脈内投与される、請求項68に記載の方法。
- 前記医薬組成物が、腫瘍に局所投与される、請求項68に記載の方法。
- 1つもしくは複数の追加の治療剤を投与するステップ、または1つもしくは複数の追加の療法で前記被験体を処置するステップをさらに含む、請求項68から70のいずれか一項に記載の方法。
- 1つまたは複数の追加の療法での前記被験体の処置が、移植を含む、請求項71に記載の方法。
- 1つまたは複数の追加の療法での前記被験体の処置が、免疫療法を含む、請求項72に記載の方法。
- 前記医薬組成物が、前記被験体に対して自系である、請求項68から73のいずれか一項に記載の方法。
- 前記医薬組成物が、前記被験体に対して同種異系である、請求項68から74のいずれか一項に記載の方法。
- 操作されたナチュラルキラー(NK)細胞の集団を含む医薬組成物を、前記被験体に投与するステップをさらに含む、請求項68から75のいずれかに記載の方法。
- 前記操作されたNK細胞が、KIR(キラー細胞阻害受容体)の発現を本質的に欠如するように改変されている1つまたは複数のNK細胞、高親和性CD16バリアントを発現するように改変されている1つまたは複数のNK細胞、および1つまたは複数のCAR(キメラ抗原受容体)を発現するように改変されている1つまたは複数のNK細胞、またはそれらの任意の組み合わせを含む、請求項76に記載の方法。
- 前記操作されたNK細胞が、前記KIRの発現を本質的に欠如するように改変されている1つまたは複数のNK細胞を含む、請求項77に記載の方法。
- 前記操作されたNK細胞が、高親和性CD16バリアントを発現するように改変されている1つまたは複数のNK細胞を含む、請求項77に記載の方法。
- 前記操作されたNK細胞が、1つまたは複数のCARを発現するように改変されている1つまたは複数のNK細胞を含む、請求項77に記載の方法。
- 前記CARが、腫瘍ネオ抗原、腫瘍ネオエピトープ、HPV、PSA、PSMA、WT1、p53、MAGE−A1、MAGE−A2、MAGE−A3、MAGE−A4、MAGE−A6、MAGE−A10、MAGE−A12、BAGE、DAM−6、DAM−10、葉酸受容体アルファ、GAGE−1、GAGE−2、GAGE−8、GAGE−3、GAGE−4、GAGE−5、GAGE−6、GAGE−7B、NA88−A、NY−ESO−1、MART−1、MC1R、Gp100、チロシナーゼ、TRP−1、TRP−2、ART−4、CAMEL、CEA、Cyp−B、HER1、HER2/neu、HER3、HER4、BRCA1、Brachyury、Brachyury(TIVS7−2、多型)、Brachyury(IVS7 T/C多型)、T Brachyury、T、hTERT、hTRT、iCE、MUC1、MUC1(VNTR多型)、MUC1c、MUC1n、MUC2、PRAME、P15、RU1、RU2、SART−1、SART−3、AFP、β−カテニン/m、カスパーゼ−8/m、CDK−4/m、ELF2M、GnT−V、G250、HSP70−2M、HST−2、KIAA0205、MUM−1、MUM−2、MUM−3、ミオシン/m、RAGE、SART−2、TRP−2/INT2、707−AP、アネキシンII、CDC27/m、TPl/mbcr−abl、ETV6/AML、LDLR/FUT、Pml/RARα、TEL/AML1、またはそれらの任意の組み合わせに対するCARである、請求項77または80に記載の方法。
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EP3402495A4 (en) | 2019-06-19 |
TW201740958A (zh) | 2017-12-01 |
CN109715174A (zh) | 2019-05-03 |
KR20180101540A (ko) | 2018-09-12 |
CA3010869A1 (en) | 2017-07-20 |
AU2017207936A1 (en) | 2018-07-26 |
EP3402495A1 (en) | 2018-11-21 |
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