JP2014504148A - T細胞をcd70陽性悪性腫瘍に仕向けるためのキメラなcd27受容体 - Google Patents
T細胞をcd70陽性悪性腫瘍に仕向けるためのキメラなcd27受容体 Download PDFInfo
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Abstract
【選択図】図1AB
Description
本発明の実施形態において、CD70の受容体と、細胞内シグナル伝達ドメインとをコードするキメラな受容体が提供される。具体的な局面において、CD70受容体は、CD70抗原を認識するポリペプチドである。具体的な局面において、CD70の受容体はCD27である。
本明細書中に記載される組成物のどれもがキットに含まれ得る。限定されない一例において、キメラな受容体の発現構築物、キメラな受容体の発現構築物を作製するための1つまたは複数の試薬、発現構築物のトランスフェクションのための細胞、および/あるいは、発現構築物のトランスフェクションのために自己由来の細胞を得るための1つまたは複数の器具(そのような器具は、シリンジ、ピペット、鉗子、および/または、いずれかのそのような医療承認された装置であるかもしれない)。
例示的な材料および方法
細胞株および腫瘍細胞
CD70特異的T細胞の作製
本発明者らは、T細胞受容体のζ鎖のシグナル伝達ドメインに融合されるCD70受容体(CD27)(CD70−CAR)をコードするSFGレトロウイルスベクターを構築した。ほとんどのナイーブなメモリーT細胞は低レベルのCD27を内因的に発現するので、IRES−tCD19発現カセットもまた、形質導入された細胞の明確な検出について可能にするためにレトロウイルスベクターに含まれた(図1A)。CD27およびtCD19は直線的な共発現パターンを示した。このことは、tCD19がCD70−CAR発現のための好適なマーカーであることを示している(図1B)。CD3/CD28活性化T細胞を、CD70−CAR−IRES−tCD19をコードするRD114偽型レトロウイルス粒子により形質導入し、形質導入後10日〜14日で、tCD19の発現をFACS分析によって求めた。平均して45%(+/−6;n=5)のT細胞がtCD19を発現し、CD4陽性細胞およびCD8陽性細胞の両方を形質導入した(図1C〜図1D)。
CD70特異的T細胞はCD70陽性腫瘍細胞への暴露の後で免疫刺激サイトカインを分泌し、増殖する
遺伝子組換えT細胞によるCD70の認識を検出するために、本発明者らは最初、CD70陰性K562細胞およびCD70遺伝子組換えK562細胞を使用した(図2)。3名のドナーのCD70特異的T細胞および非形質導入T細胞をK562またはK562.CD70により刺激し、48時間後、本発明者らはIFN−γおよびIL−2の放出を測定した(図3A、図3B)。CD70特異的T細胞は、非形質導入T細胞と比較した場合、K562.CD70にさらされた後、著量のIFN−γ(p=0.03)およびIL−2(p=0.02)を産生した。加えて、CD70陰性K562細胞はCD70特異的T細胞を活性化しなかった。このことは、サイトカインの産生には、標的細胞表面におけるCD70の発現と、T細胞表面におけるCD70−CARの存在との両方が要求されることを示している。本発明者らがこれらの培養組合せのそれぞれにおけるT細胞の増殖を比較したとき、類似した結果が認められた(図3C)。
CD70特異的T細胞はCD70陽性腫瘍細胞を殺すが、CD70陰性細胞を殺さない
本発明者らは次に、標準的な4時間の51Cr放出アッセイと、5日〜7日の共培養アッセイとの両方で、CD70特異的T細胞によるCD70陽性標的の殺傷を測定した。4時間の51Cr放出アッセイにおいて、CD70特異的T細胞はCD70陽性の標的細胞(K562.70、Daudi、U266、SNK6、SNK16)を殺したが、CD70陰性の細胞(K562)を殺さなかった。非形質導入T細胞は殺傷を全く示さず、このことから、CD70特異性が確認された(図4A、図4B)。共培養アッセイのために、CD70特異的T細胞または非形質導入T細胞をCFSEにより標識し、非標識の腫瘍細胞に2:1の比率で加えた。5日〜7日の後、腫瘍細胞の数をCD3陰性/CFSE陰性画分のFACS分析によって求めた(図4C)。CD70特異的T細胞は、試験された4つすべてのCD70陽性株(Daudi、U266、SNK6、SNK16)を排除し、一方で、コントロールT細胞はこれらを排除することができなかった(図4D)。CD3/CD28により刺激されたT細胞はCD70特異的T細胞によって殺されなかったが、MRC5細胞上のCD40リガンドにより「超生理学的に」活性化されたB細胞芽細胞はCD70特異的T細胞による殺傷に対して感受性であった(図8B)。
CD27共刺激はCD70特異的刺激の後におけるT細胞の生存のために重要である
CD70−CAR(図1A)の内部ドメイン内に位置するCD27の23アミノ酸の共刺激ドメインの役割を求めるために、本発明者らは、CD27の共刺激ドメインが欠失されたCD70−CAR(ΔCD70−CAR)を作製した。共刺激ドメインの機能的非存在を、ΔCD70−CARがTRAF2(CD27のシグナル伝達を媒介する重要なアダプタータンパク質)に結合することができないことによって確認した(図5A)。T細胞を、CD70−CAR−I−dsRedまたはΔCD70−CAR−I−dsRed(図9A)をコードするレトロウイルスベクターにより形質導入した。両方の構築物の形質導入効率は、dsRed発現によって判断されるように類似しており(65%〜90%;図9B)、細胞毒性アッセイにおいて、CD70−CAR発現T細胞およびΔCD70−CAR発現T細胞はCD70陽性の標的を同じ効率により殺した(図5B)。T細胞の活性化に対するCD27共刺激の寄与を評価するために、本発明者らは、共刺激分子を欠いているが、CD70を発現させるために遺伝子改変された自己由来の線維芽細胞(Fib.CD70)を利用した。Fib.CD70によるT細胞刺激の3日後から始まったが、活性化されたCD70−CAR T細胞の有意により大きい「凝集塊」が、ΔCD70−CAR T細胞との比較において認められた(図5C)。T細胞の増殖における差(図5D)およびIFN−γまたはIL−2の産生における差が何ら認められなかったが、ΔCD70−CAR T細胞の生存性が、CD70−CAR T細胞との比較において有意に低下した(図5D;P<0.05)。他の研究者によって報告されるように、Bcl−xl(重要な抗アポトーシスタンパク質)がCD27のシグナル伝達によって誘導される(van Oosterwijk et al., 2007)。この知見と一致して、CD70−CAR T細胞は、ΔCD70−CAR T細胞との比較においてより高レベルのBcl−xlを一貫して発現した(図5E)。これらの結果は、CD70−CAR内に位置するCD27の共刺激ドメインが共刺激シグナルを提供し、高まったT細胞生存をもたらすことを示している。したがって、すべてのその後の実験のために、本発明者らはCD70−CAR T細胞(CD70特異的T細胞)を使用した。
CD70特異的T細胞は原発性のB細胞リンパ腫およびT細胞リンパ腫の認識および殺傷を生じさせる
CD70特異的T細胞がCD70陽性のリンパ腫細胞株の認識および殺傷を生じさせることを示したので、本発明者らは次に、CD70抗原を原発性のB細胞リンパ腫およびT細胞リンパ腫の表面における標的としての妥当性について検証した。本発明者らは、原発性のCD70陽性B細胞非ホジキンリンパ腫細胞(MF1792、MF1731、MF888)およびT細胞急性リンパ芽球性白血病細胞(T007)を、健康なドナーに由来するCD70特異的T細胞と24時間にわたって共培養し、上清におけるIFN−γを測定した。コントロールのT細胞ではなく、CD70特異的T細胞が、CD70+の悪性腫瘍にさらされたとき、IFN−γの分泌をもたらした(図6A)。5日の共培養アッセイにおいて、コントロールのT細胞ではなく、CD70特異的T細胞により、原発性CD70陽性細胞が排除された(図6B、図6C)、したがって、CD70特異的T細胞は原発性CD70陽性悪性腫瘍細胞のCD70特異的様式での認識および殺傷を生じさせる。
CD70特異的T細胞を投与した後における定着リンパ腫のインビボ退行
本発明者らはCD70特異的T細胞の抗腫瘍活性を異種SCIDマウスモデルにおいて測定した。本発明者らは、亜致死的放射線照射を受けたSCIDマウスに5×105個のDaudi.FFluc細胞をi.p.注入し、腫瘍の成長をマウスの連続生物発光画像化によってモニターした。10日後、マウスは、1日離して、その後は1週間離して3回(注入0日目、注入1日目および注入7日目に)与えられる1×107個のCD70特異的T細胞の3回の注入を受けた(n=10)。腫瘍を有するマウスの第2の群には、非形質導入T細胞が注入された。非形質導入T細胞により処置されたマウスでは、腫瘍が、生物発光画像化によって判断されるように指数関数的に成長した(図7A)。対照的に、腫瘍負荷量における有意差が、T細胞注入後7日目に、CD70特異的T細胞と、非形質導入T細胞との間で認められた(p=0.002)(図7B)。成長する腫瘍を有する9匹のマウスのうちの8匹において、光子放射がCD70特異的T細胞の注入の後でベースラインに戻った。このことは、T細胞移入後の2週間超にわたって7匹のマウスにおいて持続した腫瘍退行を示している。
重症慢性活動性EBV感染を伴う原発性CD70陽性T細胞リンパ腫細胞がCD70特異的T細胞によって殺される
重症慢性活動性エプスタイン・バールウイルス感染(CAEBV)は潜在性EBV感染の希な合併症である。これは主として日本で発生するが、数例が西半球で報告されている(Kimura et al., 2003; Cohen et al., 2008)。CAEBVにおいて、ナチュラルキラー(NK)細胞、T細胞、または、希にはB細胞が感染し、患者を、命を脅かす合併症(例えば、血球貪食症候群、および、NK細胞またはT細胞のリンパ球増殖性疾患(LPD)など)に罹りやすくしている(Kimura et al,. 2001; Ishihara et al., 1997)。CAEBV関連LPDのための唯一の治癒選択肢が現在、幹細胞移植である。本実施例において、本発明者らは、攻撃的T細胞リンパ腫をCAEBVの状況で発症した患者を報告する。
本発明のある種の実施形態の重要性
本発明者らは、CD70がいくつかの血液学的悪性腫瘍およびガン腫において異常に発現されるので、CD70が、CD27をCARの一部として発現するように操作されたT細胞によって標的化され得ることを示す。CD70特異的CARを発現するT細胞はCD70陽性腫瘍細胞株および原発性腫瘍サンプルのインビトロでの認識および殺傷を生じさせ、また、ヒトCD70腫瘍をマウス異種移植において排除した。
本明細書において言及されるすべての特許および刊行物は、本発明が関連する技術分野における当業者のレベルを示すものである。すべての特許および刊行物が、それぞれの個々の刊行物が、参照によって組み込まれることが具体的かつ個々に示されていたかのように同じ程度に参照によって本明細書中に組み込まれる。
特許文献
刊行物
Claims (22)
- CD70抗原を認識し、かつ、細胞内シグナル伝達ドメインを含むキメラな抗原受容体。
- T細胞表面に存在する、請求項1に記載の受容体。
- CD70受容体を含むとしてさらに定義される、請求項1に記載の受容体。
- 前記CD70受容体がCD27である、請求項1に記載の受容体。
- 前記細胞内シグナル伝達ドメインがT細胞受容体のCD3−ζ鎖である、請求項1に記載の受容体。
- CD70抗原を有する細胞を標的化する方法であって、前記CD70抗原を有する前記細胞に、請求項1に記載される受容体を含む細胞を与える工程を含む方法。
- 前記CD70抗原を有する前記細胞が、ガン細胞、または、自己免疫疾患に関連する細胞である、請求項6に記載の方法。
- 前記ガン細胞が血液学的悪性腫瘍細胞である、請求項7に記載の方法。
- 前記ガン細胞が、リンパ腫細胞、白血病細胞、腎細胞ガン細胞、骨髄腫細胞または神経膠芽細胞腫細胞である、請求項7に記載の方法。
- 前記ガン細胞がHTLV−1関連悪性腫瘍細胞またはEBV関連悪性腫瘍細胞である、請求項7に記載の方法。
- 前記ガン細胞が固形腫瘍細胞である、請求項7に記載の方法。
- 前記固形腫瘍細胞が、腎臓(renal)ガン細胞、膵臓ガン細胞、卵巣ガン細胞、肺ガン細胞、鼻咽頭ガン細胞、胸腺ガン細胞、腎臓(kidney)ガン細胞、膵臓ガン細胞、咽頭(larynx)ガン細胞、咽頭(pharynx)ガン細胞、皮膚ガン細胞、卵巣ガン細胞、肺ガン細胞、結腸ガン細胞、乳ガン細胞または脳ガン細胞である、請求項11に記載の方法。
- 前記自己免疫疾患が、関節リウマチ、関節炎、炎症、自己免疫性脳炎、炎症性腸疾患、大腸炎または狼瘡である、請求項7に記載の方法。
- 請求項1に記載される受容体を含む前記細胞がT細胞である、請求項6に記載の方法。
- 前記T細胞がその個体から得られ、かつ、前記キメラな抗原受容体を含むために遺伝子操作される、請求項14に記載の方法。
- 前記T細胞がその個体から得られず、かつ、前記キメラな抗原受容体を含むために遺伝子操作される、請求項14に記載の方法。
- 個体におけるCD70陽性悪性腫瘍細胞を処置する方法であって、前記CD70陽性悪性腫瘍細胞を、請求項1に記載されるキメラな抗原受容体を含む腫瘍特異的T細胞により標的化する工程を含む方法。
- 請求項1に記載されるキメラな抗原受容体を保有するようにT細胞を改変する工程をさらに含む、請求項17に記載の方法。
- 前記個体がさらなる抗ガン治療を受けたことがあるか、または、さらなる抗ガン治療を受けているか、または、さらなる抗ガン治療を受ける予定である、請求項17に記載の方法。
- 前記さらなる抗ガン治療が、手術、放射線、化学療法、免疫療法またはホルモン療法を含む、請求項19に記載の方法。
- 個体をガンについて処置するためのキットであって、請求項1に記載されるキメラな受容体をコードする発現構築物を含むポリヌクレオチドを含み、前記ポリヌクレオチドが好適な容器に収容される、キット。
- T細胞をさらに含む、請求項19に記載のキット。
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JP2018505139A (ja) * | 2014-12-08 | 2018-02-22 | アメリカ合衆国 | 抗cd70キメラ抗原受容体 |
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MX2013004792A (es) | 2013-08-27 |
CN108424462A (zh) | 2018-08-21 |
JP2017123869A (ja) | 2017-07-20 |
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US20130323214A1 (en) | 2013-12-05 |
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US20180104337A1 (en) | 2018-04-19 |
NZ723974A (en) | 2017-03-31 |
CA2816379A1 (en) | 2012-05-03 |
CN103501816A (zh) | 2014-01-08 |
NZ706016A (en) | 2016-10-28 |
EP2632482A2 (en) | 2013-09-04 |
IL226018A0 (en) | 2013-06-27 |
NZ609967A (en) | 2015-04-24 |
KR20140002649A (ko) | 2014-01-08 |
NZ713462A (en) | 2017-01-27 |
JP6109741B2 (ja) | 2017-04-05 |
EP3372244A2 (en) | 2018-09-12 |
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