JP2020515581A - T細胞受容体のシグナル伝達を阻害するまたは調節することによってt細胞の疲弊を治療する方法 - Google Patents
T細胞受容体のシグナル伝達を阻害するまたは調節することによってt細胞の疲弊を治療する方法 Download PDFInfo
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Abstract
Description
本出願は、全体として参照によって本明細書に組み入れられる2017年3月31日に出願された米国仮特許出願番号62/479,930の利益を主張する。
本明細書及び添付のクレームで使用されるとき、内容が明瞭に指示しない限り、単数形態「a」、「an」及び「the」は複数の指示対象を含むことが言及されなければならない。従って、例えば、「a T細胞」への言及は2以上のT細胞、等を含む。
以下の実施例は本発明の化合物、組成物及び方法の説明に役立つものであるが、限定されない。臨床治療で通常遭遇する、且つ当業者に明白である種々の条件及びパラメーターの他の好適な修正及び適応は本発明の精神及び範囲の範囲内である。
[序論]
我々は以前、GD2−CARを発現しているT細胞が培養にて10日以内に機能的な疲弊を発生し、抑制性受容体の同時発現、腫瘍抗原に応答してサイトカインを分泌できないこと、及び異常な代謝機能を特徴とすることを報告した(Long,et.al,Nat.Med.2015)。対照培養物には、形質導入していないT細胞(偽物)及び試験管内で持続性のシグナル伝達を明示しないまたは疲弊を発生しないCD19−CARを発現しているものが含まれた。以前の研究はまた、この系では疲弊にはゼータ鎖が必要とされ、CD28のシグナル伝達は疲弊を誘導することにおけるシグナル伝達刺激の可能性を高めることを明らかにした。このモデル系を使用して、我々は今や、T細胞の疲弊を防ぐまたは元に戻すアプローチを評価するためにT細胞の疲弊の強固で操作可能で再現性のある試験管内ヒトモデルを最適化している。
我々は、その不安定性をCARに付与し、迅速なタンパク質分解を誘導するFKBP12突然変異体の不安定化ドメインに融合したGD2.28z CARを操作した。我々は、安定化するラパログshield−1(S1)を添加することまたは取り去ることによって表面発現を容易に且つ用量依存性に調節できることを観察した(図1)。CAR発現の同様の調節性は、E.coliのDHFR突然変異体(GD2.28z.DHFR、示さず)を用いても達成されたが、それは臨床で一般的に使用される抗生剤であるトリメトプリムによって調節され得る。
キメラ抗原受容体(CAR)は、細胞外腫瘍標的ドメインを、内在性のTCRシグナル伝達(例えば、CD28または4−1BBのような1〜2の共刺激ドメイン及びCD3ゼータドメイン)を模倣する細胞内ドメインと組み合わせる合成受容体である(例えば、Lim及びJune.Cell,168,724−740,(2017)を参照のこと)。CARを発現しているT細胞が抗原を発現している腫瘍細胞と遭遇すると、CAR T細胞は免疫シナプスを形成し、CARを介して下流のシグナル伝達を開始し、強力なT細胞の活性化、細胞傷害性可溶性因子の脱顆粒、サイトカイン放出、及び増殖を生じる。CAR T細胞療法は多くの血液悪性腫瘍患者で先例のない臨床的成功を示している一方で、この治療法が他の腫瘍型に拡大され、第一選択療法として提供され得る前に対処されなければならない幾つかの重要な難題がある。
この実施例は実施例IIの材料及び方法を記載する。
NALM6−GL(急性リンパ芽球性白血病株、GFP及びルシフェラーゼを安定して形質移入した)及びNALM6−GL−GD2(GD2合成酵素を過剰発現するように安定して形質移入した)の細胞株はRPMI−1640にて培養した。293T及び143Bの細胞株はDMEM(Life Technologies)にて培養した。DMEM及びRPMI−1640は10%熱非働化FBS(Gibco,Life Technologies)、10mMのHEPES、100U/mLのペニシリン、100μg/mLのストレプトマイシン、及び2mMのL−グルタミン(Gibco,Life Technologies)で補完した。
レトロウイルスの上清はすべて293GP細胞株の一時的な形質移入を介して産生された。手短には、CAR及びRD114のエンベロープタンパク質をコードするプラスミドでリポフェクトアミン2000(Life Technologies)を介して293GP細胞にトランスフェクトした。トランスフェクトの48及び72時間後に上清を回収し、等分し、−80℃で保存した。
試料はすべてLSR Fortessa(BD Bioscience)またはCytoflex(Beckman Coulter)で解析し、データはFlowJoを用いて解析した。細胞をPBSで2回洗浄し、PBSにて1×106個/mLで染色によって標識し、その後、FACS緩衝液(2%FBS及び0.4%0.5MのEDTAで補完したPBS)で2回洗浄した。GD2.CARは14g2a抗イディオタイプ抗体1A7によって検出した。CD19.CARはFMC63抗イディオタイプ抗体136.20.1によって検出した。T細胞の表現型は、CD4(OKT4、Biolegend)、CD8(SK1、Biolegend)、PD−1(eBioJ105、eBioscience)、TIM−3(F38−2E2、Biolegend)、LAG−3(3DS223H、eBioscience)、CD45RA(L48、BD Biosciences)、CCR7(150503、BD Biosciences)、CD62L(DREG−56、BD Biosciences)、CD69(FN50、Biolegend)、及びCD107a(H4A3、eBioscience)を介して評価した。CD107aを評価した共培養アッセイについては、1:1000のモネンシン(eBioscience)と抗CD107aの存在下で腫瘍細胞とCAR T細胞とを少なくとも6時間共培養した。CAR T細胞の表現型データを示すFACSのプロットすべてはCAR+細胞に予めゲートをかけた。偽物の形質導入T細胞については、解析には全T細胞集団を使用した。
96ウェルプレートの各ウェルにおけるIL−2の補完を含まない200uLの完全AimV培地にて1:8のE:T比で50,000個のNALM6−GLまたはNALM6−GL−GD2の腫瘍細胞をT細胞と共に共培養した。プレートをincucyteに装着し、2時間ごとに48〜72時間、488nmの蛍光画像を取得した。GFP+腫瘍細胞はサイズ及び蛍光強度マスクによって同定し、数えた腫瘍細胞すべての合計の総合的なGFP強度を各個々のウェルについて定量した。値をt=0に対して基準化し、データ表示のために反復ウェルを平均した。
96ウェルプレートの各ウェルにおけるIL−2の補完を含まない200uLの完全AimV培地にて1:1のE:T比で50,000個のNALM6−GL−GD2腫瘍細胞をT細胞と共に共培養した。24時間後、上清を取り出し、−20℃で保存した。IL−2及びIFNγの分泌はELISA(Biolegend)を介して評価した。
2×106個のCAR T細胞を培養物から取り出し、ペレットにし、ホスファターゼ及びプロテアーゼの阻害剤(Thermo Fisher)で補完した100uLのRIPA溶解緩衝液(10mMのTris−Cl、pH8.0、1mMのEDTA、1%のTritonX−100、0.1%のデオキシコール酸ナトリウム、0.1%のSDS、140mMのNaCl)に再浮遊させた。4℃で30分間インキュベートした後、14,000rpmでの4℃で20分間の遠心分離によって上清を透明化した。透明化した溶解物におけるタンパク質濃度は比色反応(BioRad)によって測定した。
6〜8週齢のNSGマウスに静脈注射を介して1×106個のNALM6−GL−GD2白血病細胞を生着させた。生着後4日目に、2×106個のHA−GD2.28zCAR+T細胞を静脈内に注入した。Xenogen IVIS Lumina(Caliper Life Sciences)を用いてNALM6−GL−GD2腫瘍量を評価した。先ず、マウスに3mgのD−ルシフェリン(Caliper Life Sciences)を腹腔内で注射し、次いで30秒の露出時間で4分後画像化した、または30秒がシグナル飽和を生じる場合、「自動」露出を選択した。Living Image software(Caliper Life Sciences)を用いて発光画像を解析した。
CAR配列すべてをMSGVレトロウイルスの主鎖に挿入した。各CARはシグナルペプチドと単鎖可変断片(scFv)と細胞外ヒンジ領域と膜貫通ドメインと細胞内共刺激ドメインと細胞内CD3ゼータドメインとを含む。
CD19.28z(FMC63 scFv)の核酸配列及びアミノ酸配列は図23に提供されている。
本明細書で参照されている特許文書及び科学論文のそれぞれの開示全体が目的に応じて参照によって本明細書に組み入れられる。
本発明は、その精神または本質的特徴から逸脱することなく他の特定の形態で具体化されてもよい。従って、前述の実施形態は本明細書に記載されている本発明を限定するのではなくあらゆる点で説明に役立つと見なされるべきである。従って、本発明の範囲は、前述の説明によってではなく添付の特許請求の範囲によって示され、特許請求の範囲の意味及び同等物の範囲の範囲内にある変化はすべてその中に包含されるように意図される。
Claims (57)
- 対象にてT細胞の疲弊を防ぐ及び/または元に戻す方法であって、前記方法が治療上有効な量のチロシンキナーゼ阻害剤を前記対象に投与することを含む、前記方法。
- 前記チロシンキナーゼ阻害剤がTCRのシグナル伝達及び/またはCARのシグナル伝達を阻害することができる請求項1に記載の方法。
- 前記チロシンキナーゼ阻害剤がLck阻害剤である請求項1に記載の方法。
- 前記チロシンキナーゼ阻害剤がダサチニブまたはポナチニブである請求項1に記載の方法。
- 治療が前記対象にてT細胞によるIL−2の分泌を高める請求項1に記載の方法。
- 治療が前記対象にてT細胞のアポトーシスを減少させる請求項1に記載の方法。
- 治療が、PD−1、TIM−3及びLAG−3から成る群から選択される少なくとも1つのT細胞の疲弊マーカーの発現を低下させる請求項1に記載の方法。
- 治療がCD62LまたはCCR7の発現を高める請求項1に記載の方法。
- 複数サイクルの治療が前記対象に投与される請求項1に記載の方法。
- 前記チロシンキナーゼ阻害剤が間欠的に投与される請求項7に記載の方法。
- 前記チロシンキナーゼ阻害剤が少なくとも部分的なT細胞機能を回復させるのに十分な期間投与され、その後中止される請求項1に記載の方法。
- 前記チロシンキナーゼ阻害剤が経口で投与される請求項1に記載の方法。
- 前記対象がヒトである請求項1に記載の方法。
- 前記対象が慢性感染症またはがんを有する請求項1に記載の方法。
- 治療が予防的である請求項1に記載の方法。
- 対象にて免疫系に関連する状態または疾患を治療する方法であって、
遺伝子操作したT細胞と治療上有効な量のチロシンキナーゼ阻害剤とを前記対象に投与することを含む、前記方法。 - 前記チロシンキナーゼ阻害剤がTCRのシグナル伝達及び/またはCARのシグナル伝達を阻害することができる請求項16に記載の方法。
- 前記チロシンキナーゼ阻害剤がLck阻害剤である請求項16に記載の方法。
- 前記チロシンキナーゼ阻害剤がダサチニブまたはポナチニブである請求項16に記載の方法。
- 前記チロシンキナーゼ阻害剤と前記遺伝子操作したT細胞とが同時に及び/または異なる時点で投与される請求項16に記載の方法。
- 前記免疫系に関連する状態または疾患ががんまたは自己免疫の疾患もしくは状態から選択される請求項16に記載の方法。
- 前記遺伝子操作したT細胞が、CAR T細胞、遺伝子操作したTCRを発現するT細胞、腫瘍浸潤リンパ球(TIL)療法のために構成された遺伝子操作したT細胞、形質導入T細胞療法のために構成された遺伝子操作したT細胞、及び/またはTCRもしくはCARで再操作されたウイルス特異的なT細胞から選択される請求項16に記載の方法。
- 前記対象に1以上の抗がん剤を投与することをさらに含む請求項16に記載の方法。
- 前記1以上の抗がん剤が化学療法剤及び放射線療法から選択される請求項23に記載の方法。
- 遺伝子操作したT細胞の集団を含む組成物であって、
前記遺伝子操作したT細胞の集団がチロシンキナーゼ阻害剤の存在下で増殖される、前記組成物。 - 前記チロシンキナーゼ阻害剤がTCRのシグナル伝達及び/またはCARのシグナル伝達を阻害することができる請求項25に記載の組成物。
- 前記チロシンキナーゼ阻害剤がLck阻害剤である請求項25に記載の組成物。
- 前記チロシンキナーゼ阻害剤がダサチニブまたはポナチニブである請求項25に記載の組成物。
- 前記遺伝子操作したT細胞の集団が、CAR T細胞の集団、遺伝子操作したTCRを発現するT細胞の集団、腫瘍浸潤リンパ球(TIL)療法のために構成された遺伝子操作したT細胞の集団、形質導入T細胞療法のために構成された遺伝子操作したT細胞の集団、及び/またはTCRもしくはCARで再操作されたウイルス特異的なT細胞の集団から選択される請求項25に記載の組成物。
- T細胞の疲弊に耐性を示す遺伝子操作したT細胞の集団を生成する方法であって、
チロシンキナーゼ阻害剤の存在下で遺伝子操作したT細胞の集団を増殖させることを含む、前記方法。 - 前記チロシンキナーゼ阻害剤がTCRのシグナル伝達及び/またはCARのシグナル伝達を阻害することができる請求項30に記載の方法。
- 前記チロシンキナーゼ阻害剤がLck阻害剤である請求項30に記載の方法。
- 前記チロシンキナーゼ阻害剤がダサチニブまたはポナチニブである請求項30に記載の方法。
- 前記遺伝子操作したT細胞の集団が、CAR T細胞の集団、遺伝子操作したTCRを発現するT細胞の集団、腫瘍浸潤リンパ球(TIL)療法のために構成された遺伝子操作したT細胞の集団、形質導入T細胞療法のために構成された遺伝子操作したT細胞の集団、及び/またはTCRもしくはCARで再操作されたウイルス特異的なT細胞の集団から選択される請求項30に記載の方法。
- 免疫系に関連する状態または疾患を治療する方法であって、
チロシンキナーゼ阻害剤の存在下で増殖させた遺伝子操作したT細胞の集団を前記対象に投与することを含む、前記方法。 - 前記チロシンキナーゼ阻害剤がTCRのシグナル伝達及び/またはCARのシグナル伝達を阻害することができる請求項35に記載の方法。
- 前記チロシンキナーゼ阻害剤がLck阻害剤である請求項35に記載の方法。
- 前記チロシンキナーゼ阻害剤がダサチニブまたはポナチニブである請求項35に記載の方法。
- 前記遺伝子操作したT細胞の集団が、CAR T細胞の集団、遺伝子操作したTCRを発現するT細胞の集団、腫瘍浸潤リンパ球(TIL)療法のために構成された遺伝子操作したT細胞の集団、形質導入T細胞療法のために構成された遺伝子操作したT細胞の集団、及び/またはTCRもしくはCARで再操作されたウイルス特異的なT細胞の集団から選択される請求項35に記載の方法。
- 前記対象が養子T細胞療法を受けている請求項35に記載の方法。
- 前記養子T細胞療法がCAR T細胞療法である請求項40に記載の方法。
- 前記養子T細胞療法が形質導入T細胞療法である請求項40に記載の方法。
- 前記養子T細胞療法が腫瘍浸潤リンパ球(TIL)療法である請求項40に記載の方法。
- 前記免疫系に関連する状態または疾患ががんまたは自己免疫の疾患もしくは状態から選択される請求項35に記載の方法。
- 前記対象に1以上の抗がん剤を投与することをさらに含む請求項35に記載の方法。
- 前記1以上の抗がん剤が化学療法剤及び放射線療法から選択される請求項45に記載の方法。
- 対象に投与される遺伝子操作したT細胞に関連する毒性を防ぐ及び/または元に戻す方法であって、
治療上有効な量のチロシンキナーゼ阻害剤を前記対象に投与することを含む、前記方法。 - 前記チロシンキナーゼ阻害剤がTCRのシグナル伝達及び/またはCARのシグナル伝達を阻害することができる請求項47に記載の方法。
- 前記チロシンキナーゼ阻害剤がLck阻害剤である請求項47に記載の方法。
- 前記チロシンキナーゼ阻害剤がダサチニブまたはポナチニブである請求項47に記載の方法。
- 前記遺伝子操作したT細胞が、CAR T細胞、遺伝子操作したTCRを発現するT細胞、腫瘍浸潤リンパ球(TIL)療法のために構成された遺伝子操作したT細胞、形質導入T細胞療法のために構成された遺伝子操作したT細胞、及び/またはTCRもしくはCARで再操作されたウイルス特異的なT細胞から選択される請求項33に記載の方法。
- 前記対象が養子T細胞療法を受けている請求項47に記載の方法。
- 前記養子T細胞療法がCAR T細胞療法である請求項52に記載の方法。
- 前記養子T細胞療法が形質導入T細胞療法である請求項52に記載の方法。
- 前記養子T細胞療法が腫瘍浸潤リンパ球(TIL)療法である請求項52に記載の方法。
- 対象に投与される前記遺伝子操作したT細胞に関連する毒性がサイトカイン放出症候群である請求項47に記載の方法。
- 対象に投与される前記遺伝子操作したT細胞に関連する毒性が本来の標的を含む腫瘍以外に対する毒性または標的外の腫瘍以外に対する毒性である請求項47に記載の方法。
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