JP2019519246A - 免疫療法向けのt細胞組成物 - Google Patents
免疫療法向けのt細胞組成物 Download PDFInfo
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Abstract
Description
(a)T細胞を含む初期細胞集団を得ることと、
(b)細胞集団を1つ以上の標的抗原及びサイトカインに曝露することにより、T細胞を刺激することと、
(c)細胞集団をサイトカインを含む培地中で培養することと、
(d)細胞集団の抗原特異的反応性を試験することと、
(e)得られたT細胞を含む組成物を採取することと
を含む、方法を提供する。
本発明の諸実施形態において、上記の方法は、ステップ(b)を繰り返すことをさらに含む。諸実施形態において、上記の方法は、細胞集団中のT細胞のポリクローナル刺激をさらに含む。一実施形態において、ポリクローナル刺激は、ステップ(c)の後に、細胞集団をCD3、CD28、及びCD2に結合する四量体抗体に曝露することを含む。
(a)T細胞を含む初期細胞集団を得ることと、
(b)T細胞活性化マーカーの発現に基づいてT細胞を選別することと、
(d)T細胞のポリクローナル刺激と、
(e)得られたT細胞を含む組成物を採取することと
を含む、方法を提供する。
(a)T細胞を含む初期細胞集団を得ることと、
(b)細胞集団を1つ以上の標的抗原及びサイトカインに曝露することにより、T細胞を刺激することと、
(c)細胞集団をサイトカインを含む培地中で培養することと、
(d)細胞集団の抗原特異的反応性を試験することと、
(e)得られたT細胞を含む組成物を採取することと
を含む、方法を提供する。
(a)T細胞を含む初期細胞集団を得ることと、
(b)T細胞活性化マーカーの発現に基づいてT細胞を選択することと、
(c)T細胞のポリクローナル刺激と、
(d)得られたT細胞を含む組成物を採取することと
を含む、方法を提供する。
・PepMix EBV(LMP1):潜伏型膜タンパク1(Latent membrane protein 1)に由来する94ペプチドのプール、Swiss−Prot ID:エプスタイン・バーウイルス(HHV4)のP03230。
・PepMix EBV(LMP2):潜伏型膜タンパク2に由来する122ペプチドのプール、Swiss−Prot ID:エプスタイン・バーウイルス(HHV4)のP13285。
・PepMix EBV(EBNA1):エプスタイン・バー核内抗原1に由来する158ペプチドのプール、Swiss−Prot ID:エプスタイン・バーウイルス(HHV4)のP03211。
・PepMix HCMVA(pp65):65kDaのリンタンパク質に由来する138ペプチドのプール、Swiss−Prot ID:ヒトサイトメガロウイルス(HHV−5)のP06725。
Claims (42)
- T細胞を含む組成物を作製する方法であって、以下ステップ:
(a)T細胞を含む初期細胞集団を得ることと、
(b)前記細胞集団を1つ以上の標的抗原及びサイトカインに曝露することにより、T細胞を刺激することと、
(c)前記細胞集団をサイトカインを含む培地中で培養することと、
(d)前記細胞集団の抗原特異的反応性を試験することと、
(e)前記得られたT細胞を含む組成物を採取することと
を含む、前記方法。 - 前記初期細胞集団において、総T細胞(CD3+)、CD8+、及びCD4+ T細胞、単球、B細胞、ならびにNK細胞の量を試験することをさらに含む、請求項1に記載の方法。
- 前記細胞集団の抗原特異的反応性を試験することが、フローサイトメトリーによる活性化マーカーの検出、細胞内サイトカイン染色による抗原誘導サイトカイン産生量の測定、ELISA、またはELISPOTを含む、請求項1に記載の方法。
- ステップ(b)及び(c)における前記サイトカインが、個別に、IL−2、IL−7、IL−15、及びIL−21のうちの1つ以上を含む、請求項1に記載の方法。
- ステップ(b)及び(c)における前記サイトカインが、個別に、IL−7及びIL−15を含む、請求項1に記載の方法。
- 前記方法が、ステップ(b)を繰り返すことをさらに含む、請求項1〜5のいずれか1項に記載の方法。
- 前記方法が、前記細胞集団中の前記T細胞のポリクローナル刺激をさらに含む、請求項1〜6のいずれか1項に記載の方法。
- 前記ポリクローナル刺激が、ステップ(c)の後に、前記細胞集団をCD3、CD28、及びCD2に結合する四量体抗体に曝露することを含む、請求項7に記載の方法。
- 前記細胞集団が複数のサブ集団に分割され、その各々が異なる標的抗原への曝露により刺激される、請求項1〜8のいずれか1項に記載の方法。
- 前記複数のサブ集団が、ステップ(c)の前に組み合わされる、請求項9に記載の方法。
- 前記複数のサブ集団が、ステップ(e)の前に組み合わされる、請求項9に記載の方法。
- 前記1つ以上の標的抗原が、前記1つ以上の標的抗原に由来する複数の重複ペプチドを含む、請求項1〜11のいずれか1項に記載の方法。
- 前記1つ以上の標的抗原が、1つ以上のサブドミナント抗原に由来するポリペプチドを含む、請求項12に記載の方法。
- 前記1つ以上の標的抗原が、1つ以上のネオ抗原に由来するポリペプチドを含む、請求項12に記載の方法。
- 前記1つ以上の標的抗原が、ウイルス抗原に由来するポリペプチドを含む、請求項12に記載の方法。
- 前記1つ以上の標的抗原が、サイトメガロウイルス、エプスタイン・バーウイルス、B型肝炎ウイルス、ヒトパピローマウイルス、アデノウイルス、ヘルペスウイルス、ヒト免疫不全ウイルス、インフルエンザウイルス、ヒトRSウイルス、ワクシニアウイルス、水痘帯状疱疹ウイルス、黄熱病ウイルス、エボラウイルス、及びジカウイルスのうちの1つ以上からのウイルス抗原に由来するポリペプチドを含む、請求項15に記載の方法。
- 前記1つ以上の標的抗原が、前記エプスタイン・バーウイルス抗原、LMP1、LMP2、及びEBNA1のうちの1つ以上に由来するポリペプチドを含む、請求項16に記載の方法。
- 前記1つ以上の標的抗原が、サイトメガロウイルス抗原、pp65、がん/精巣抗原1(NY−ESO−1)、及びサバイビンのうちの1つ以上に由来するポリペプチドを含む、請求項16に記載の方法。
- 前記方法から得られた前記T細胞組成物が、主としてCD8+対CD4+ T細胞を含む70%超のCD3+ T細胞を含む、請求項1〜18のいずれか1項に記載の方法。
- 前記方法から得られた前記T細胞組成物が、総CD3+細胞の約1%超が、前記抗原(1つまたは複数)に対し反応性である、請求項1〜18のいずれか1項に記載の方法。
- 前記方法から得られた前記T細胞組成物が、CD62L、CCR7、またはCXCR3の表面発現上昇と、1つ以上の活性化/疲弊マーカーLAG3、CD244(2B4)、CD160、TIM−3、CTLA−4の表面発現低下とを有するT細胞を含む、請求項1〜18のいずれか1項に記載の方法。
- T細胞を含む組成物を作製する方法であって、以下ステップ:
(a)T細胞を含む初期細胞集団を得ることと、
(b)T細胞活性化マーカーの発現に基づいてT細胞を選択することと、
(c)T細胞のポリクローナル刺激と、
(d)前記得られたT細胞を含む組成物を採取することと
を含む、前記方法。 - 前記方法が、ステップ(b)の前に、前記細胞集団を1つ以上の標的抗原及びサイトカインに曝露することにより、前記T細胞を刺激することをさらに含む、請求項22に記載の方法。
- ステップ(b)が前記初期細胞集団に対し実施される、請求項22または23に記載の方法。
- ステップ(b)が、前記細胞集団を1つ以上の標的抗原及びサイトカインに曝露することにより前記T細胞を刺激することの約7日後に実施される、請求項22または23に記載の方法。
- 前記サイトカインが、IL−2、IL−7、IL−15、及びIL−21のうちの1つ以上を含む、請求項23に記載の方法。
- 前記サイトカインがIL−7及びIL−15を含む、請求項23に記載の方法。
- ステップ(b)の前記T細胞活性化マーカーが、CD69、CD279(PD−1)、CD223(LAG3)、CD134(OX40)、CD183(CXCR3)、CD27(IL−7Ra)、CD137(4−1BB)、CD366(TIM3)、CD25(IL−2Ra)、CD80、CD152(CTLA−4)、CD28、CD278(IOS)、CD154(CD40L)、及びCD45ROのうちの1つ以上を含む、請求項22または23に記載の方法。
- 前記ポリクローナル刺激が、ステップ(b)の後に、前記細胞集団をCD3、CD28、及びCD2に結合する四量体抗体に曝露することを含む、請求項22または23に記載の方法。
- 前記1つ以上の標的抗原が、前記1つ以上の標的抗原に由来する複数の重複ペプチドを含む、請求項23に記載の方法。
- 前記1つ以上の標的抗原が、1つ以上のサブドミナント抗原に由来するポリペプチドを含む、請求項30に記載の方法。
- 前記1つ以上の標的抗原が、1つ以上のネオ抗原に由来するポリペプチドを含む、請求項30に記載の方法。
- 前記1つ以上の標的抗原が、ウイルス抗原に由来するポリペプチドを含む、請求項30に記載の方法。
- 前記1つ以上の標的抗原が、サイトメガロウイルス、エプスタイン・バーウイルス、B型肝炎ウイルス、ヒトパピローマウイルス、アデノウイルス、ヘルペスウイルス、ヒト免疫不全ウイルス、インフルエンザウイルス、ヒトRSウイルス、ワクシニアウイルス、水痘帯状疱疹ウイルス、黄熱病ウイルス、エボラウイルス、及びジカウイルスのうちの1つ以上からのウイルス抗原に由来するポリペプチドを含む、請求項33に記載の方法。
- 前記1つ以上の標的抗原が、前記エプスタイン・バーウイルス抗原、LMP1、LMP2、及びEBNA1のうちの1つ以上に由来するポリペプチドを含む、請求項34に記載の方法。
- 前記1つ以上の標的抗原が、サイトメガロウイルス抗原、pp65、がん/精巣抗原1(NY−ESO−1)、及びサバイビンのうちの1つ以上に由来するポリペプチドを含む、請求項34に記載の方法。
- 前記方法から得られた前記T細胞組成物が、主としてCD8+対CD4+ T細胞を含む70%超のCD3+ T細胞を含む、請求項1〜18のいずれか1項に記載の方法。
- 免疫療法の方法であって、免疫療法を必要とする患者にT細胞を含む組成物を投与することを含み、前記組成物が、請求項1〜29のいずれか1項に記載の方法により作製される、前記方法。
- 処置を必要とする患者に、1つ以上のEBV抗原に対し反応性のT細胞が豊富化されたT細胞組成物を投与することにより、非ホジキンリンパ腫、胃癌、または上咽頭癌を処置する方法であって、前記T細胞組成物が、請求項1〜17及び22〜35のいずれか1項に記載の方法により作製される、前記方法。
- 処置を必要とする患者に、pp65、がん/精巣抗原1(NY−ESO−1)、及びサバイビンのうちの1つ以上に対し反応性のT細胞が豊富化されたT細胞組成物を投与することにより、神経膠芽細胞腫を処置する方法であって、前記T細胞組成物が、請求項1〜16、18、22〜34、及び36のいずれか1項に記載の方法により作製される、前記方法。
- 免疫療法向けのT細胞を含む組成物であって、前記組成物が50万個超のCD3+細胞を含み、生細胞が70%超のCD3+ T細胞を含み、前記T細胞が、主としてCD8+対CD4+ T細胞であり、かつ主としてエフェクターメモリーT細胞である、前記組成物。
- 前記組成物中の前記T細胞が、最小限の疲弊マーカー、高発現レベルのリンパ球ホーミング及び輸送マーカー、ならびに高い抗原反応性を示す、請求項41に記載の組成物。
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