JP2020528885A - 養子免疫療法における免疫細胞調節のための組成物および方法 - Google Patents
養子免疫療法における免疫細胞調節のための組成物および方法 Download PDFInfo
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Abstract
Description
本願は、2017年7月19日に出願された米国仮特許出願第62/534,537号、および2018年2月9日に出願された同第62/628,733号に基づく優先権を主張するものであり、これらの開示の全体が参照によって本明細書に援用される。
本開示は、広くは養子免疫細胞療法の分野に関する。より具体的には、本開示は、養子細胞療法に適した免疫細胞を調節するための小分子の使用に関する。
本発明は、いくつかの実施形態において、養子細胞をベースとした治療法に好適な免疫細胞(例えば、調節された免疫細胞)の1または複数の特性(例えば、治療的有効性)を改善するのに十分な量の1または複数の調節薬を含む組成物を提供する。いくつかの態様では、治療的有効性が改善された免疫細胞は、前記1または複数の調節薬を含まない条件(例えば類似条件)下で、発生したまたは維持された細胞と比較して、増殖の改善、残留性の改善、細胞毒性の改善、および/または細胞リコール/記憶の改善を示す。いくつかの実施形態では、前記薬剤、または前記調節薬を含む組成物を用いた免疫細胞の調節によって、得られた免疫細胞は、1または複数のそのような改善(例えば、少なくとも1つの特性の改善)を含む。いくつかの態様では、前記少なくとも1つの特性は、以下を包含するが、これらに限定はされず、且つ/または、以下のうちの少なくとも1または複数を含む:表現型の傾き(skewing)(例えば、TeffもしくはTemからTn、Tcm、および/もしくはTscmへの傾き、並びに/または、1または複数の他のT細胞亜集団と比較した場合の、ナイーブT細胞、セントラルメモリーT細胞および/またはステムセントラルメモリーT細胞の相対数の増加);細胞増殖の増加、細胞生存率の増加;並びに/または、腫瘍除去能および残留性の増加。いくつかの実施形態では、養子細胞ベースの治療法に好適な免疫細胞などの免疫細胞は、その標的によって分類される1または複数のクラスの調節薬と接触されるか、それで処理されるか、それで調節される。いくつかの実施形態では、前記組成物または調節薬または薬剤の存在下で実行される方法、少なくとも1または複数の工程を通じて、細胞は操作される。上記のように、少なくとも1つの生物学的特性において免疫細胞の治療的有効性を改善できる調節薬のクラスとしては、BET阻害剤、CDK阻害剤、CRACチャネル阻害剤、Cox阻害剤、ドパミン拮抗剤、ERK5阻害剤、グルココルチコイド、IGF−1R阻害剤、IKK阻害剤、JAK阻害剤、Lck阻害剤、PDK1阻害剤、Raf阻害剤、およびSyk阻害剤が挙げられる。上記の調節薬の各クラスについて、非限定的且つ例示的な化合物を表1にいくつか列挙する。
本発明は、免疫細胞の治療的有効性を改善するのに十分な量の、BET阻害剤、CDK阻害剤、CRACチャネル阻害剤、Cox阻害剤、ドパミン拮抗剤、ERK5阻害剤、グルココルチコイド、IGF−1R阻害剤、IKK阻害剤、JAK阻害剤、Lck阻害剤、PDK1阻害剤、Raf阻害剤、またはSyk阻害剤を少なくとも含む1または複数の調節薬と接触させることにより調節された、調節された免疫細胞の集団または亜集団を提供する。
本発明は、いくつかの実施形態において、養子細胞をベースとした治療法に好適な免疫細胞集団または免疫細胞亜集団を調節する方法を提供し、前記方法は、前記免疫細胞を、BET阻害剤、CDK阻害剤、CRACチャネル阻害剤、Cox阻害剤、ドパミン拮抗剤、ERK5阻害剤、グルココルチコイド、IGF−1R阻害剤、IKK阻害剤、JAK阻害剤、Lck阻害剤、PDK1阻害剤、Raf阻害剤、またはSyk阻害剤を少なくとも含む1または複数の調節薬を含む組成物と接触させることを含み、1または複数の前記薬剤と接触させられた前記免疫細胞集団または免疫細胞亜集団は、前記調節を受けていない細胞と比較して、治療的有効性が改善される。1または複数の前記薬剤による前記調節は、細胞増殖を改善し、細胞毒性を改善し、残留性を改善し、且つ/または、細胞療法における再発率を減少させるように、免疫細胞の生物学的特性を調節し得る。いくつかの実施形態では、前記1または複数の調節薬の組成物は、少なくとも1つの、表1から選択される化合物、およびその誘導体または類似体を含む。いくつかの実施形態では、前記1または複数の調節薬の組成物は、BET阻害剤、IKK阻害剤、JAK阻害剤、PDK1阻害剤、Raf阻害剤、またはSyk阻害剤を含む。いくつかの実施形態では、前記1または複数の調節薬の組成物は、PDK1阻害剤を少なくとも含む。いくつかの他の実施形態では、前記1または複数の調節薬の組成物は、Raf阻害剤を少なくとも含む。いくつかの他の実施形態では、前記1または複数の調節薬の組成物は、Syk阻害剤を少なくとも含む。さらに別の実施形態では、前記1または複数の調節薬の組成物は、GSK2334470、AZ628、GDC−0879、ダブラフェニブ、R788、パクリチニブ、バルドキソロンメチル、およびPRT062607のうちの少なくとも1つを含む。1つの実施形態では、前記1または複数の調節薬の組成物は、GSK2334470を含む。別の実施形態では、前記1または複数の調節薬の組成物は、AZ628を含む。さらに別の実施形態では、前記1または複数の調節薬の組成物は、R788を含む。いくつかの他の実施形態では、前記1または複数の調節薬の組成物は、バルドキソロンメチルを含む。
表1の化合物群の、免疫療法におけるT細胞に影響を与える能力を評価するために、いくつかのインビトロ系およびインビボモデルを用いてデータ解析を行った。個々の化合物の、ナイーブT細胞、幹細胞様メモリーT細胞、またはセントラルメモリーT細胞に対する影響を、追加のドナーから得られた細胞で評価した。表1の各化合物が、以下の側面の少なくとも1つにおいて、処理されたT細胞に正の影響を与えることが示された:(1)表現型から同定されたナイーブT細胞、幹細胞様メモリーT細胞、またはセントラルメモリーT細胞の割合を高くする、またはその絶対数を多くする;(2)標的細胞の殺滅能を改善する;(3)細胞生存および増殖を増加させる;(4)サイトカイン産生を増加させる;並びに、(5)腫瘍除去能の増加、インビボにおける移植後の細胞残留性の改善、腫瘍量を減少させる能力の増加、または高腫瘍線量に暴露後の動物の生存を促進する能力の増加を含む、インビボにおける有効性を有する。
新鮮なリューコパック(leukopak)(オールセルズ社(AllCells)、カリフォルニア州アラメダ;キーバイオロジクス社(Key Biologics)、テネシー州メンフィス)を健常ドナーから採取して、そのリューコパックから、例えば、EasySep Human T Cell Enrichment Kit(ステム・セル・テクノロジーズ社(Stem Cell Technologies)、バンクーバー、カナダ)を用いて、T細胞をネガティブセレクションにかけた。新鮮な単離されたT細胞を分注して凍結保存した。アッセイ開始日に、T細胞を解凍し、IL−2およびペニシリン/ストレプトマイシンをはじめとする添加剤を含むX−Vivo15で洗浄した。細胞を、平底384ウェルプレートに、5×105細胞/mlで、抗CD3/抗CD28ビーズと共に播種した。個々の化合物を、10μM〜10nMの範囲に亘る最終濃度で、各プレートのカラム3からカラム22までの各ウェルに添加した。陽性対照および陰性対照を追加のウェルに添加した。細胞を約6日間、37℃、5%CO2でインキュベートした。
T細胞サブセットは、Tcm、ナイーブT細胞(Tn)、エフェクターメモリーT細胞(Tem)、およびCD45RA+エフェクターメモリーT細胞(Temra)を含む。Tn細胞およびTcm細胞は分化度が最低限であるため増殖能が最も大きいが、Temra細胞は完全分化度が最も大きいため増殖能が乏しいが、強力なエフェクター機能を有する(D’Asaro et al. 2006)。非ヒト霊長類およびNOD/Scid IL−2RγCヌル(NSG)マウスの両モデルにおける試験で、セントラルメモリー(Tcm)表現型のT細胞の、養子移入後の残留性が向上していたことが示された(Berger et al. 2008; Wang et al. 2011)。加えて、CAR発現CD4セントラルメモリーT細胞(Tcm)およびCAR発現CD8セントラルメモリーT細胞(Tcm)のサブセットを、造血系幹細胞移植後の非ホジキンリンパ腫患者に投与したところ、Tcmから派生したCAR−T細胞が増殖の改善を示したことから、Tcmがヒトのがんの治療において治療上の利点を有し得ることが示された。
スコア=溶媒に対しての正規化標準偏差×有意性(−log10(p値))+1
この図の他のグラフのスコアも同じ式を用いている。
(試験値−最小値)/(最大値−最小値)×10
T細胞が種々の刺激に応答できることはT細胞の機能において重要である。T細胞の非特異的刺激に応答して複数のサイトカインを産生する能力は、T細胞の「多機能性」の尺度となる。処理された細胞に対する表現型を偏らせる効果の点から、選択された化合物がこの「多機能的」応答に影響を与えるかどうかを評価するため、処理された細胞の、刺激後にインターフェロン−γ(IFNγ)、IL−2およびTNFαを産生する能力を測定した。CD8+T細胞を表1の化合物で処理した後、細胞をPMA/イオノマイシン混合物で4時間刺激した。刺激後、種々のフルオロフォアと結合した、これらのサイトカインを認識する、蛍光を発する抗体を用いる細胞内サイトカイン染色により、サイトカイン産生を測定した。蛍光はフローサイトメトリーを用いて測定した。3種類のうち少なくとも2種のサイトカインを産生していた場合に、細胞を多機能的と定義した。
インビトロにおける連続的な殺滅/再刺激アッセイは、複数回にわたり、インビトロにおけるCAR−T細胞の腫瘍細胞を「除去」する能力を試験するアッセイであり、CARに認識される抗原を発現する腫瘍細胞の存在下での、CAR−T増殖を評価するためのモデルとして用いることができる。
細胞は通常、解糖および酸化的リン酸化という、2つの主要なエネルギー経路を利用する。ストレスまたは仕事の増加に応答してエネルギーを生産する細胞で臨時の能力として利用される、ミトコンドリアの予備呼吸能(spare respiratory capacity)(SRC)は、メモリーT細胞では増加しているが、TemraなどのエフェクターT細胞では増加していないことが示されている(van der Windt and Pearce 2012)。しかし、SRCの増加と、酸化的リン酸化への依存が、CD8+メモリーT細胞にとって必須ではない場合もある(Phan et al. 2016)。Van der Windt and PearceとPhan et al.とによる発表には相違が認められるが、これらの発表から、また本明細書における所見から、T細胞代謝の変化がT細胞機能と関連があることは明らかである。
CAR−T細胞のインビボにおける機能性を調べるために設計されたCD19+異種移植モデルを用いて、選択された化合物で処理後の細胞の腫瘍除去能を特徴付けした。簡潔に説明すると、最適以下の治療量の化合物で処理されたCD19標的化CAR−T細胞を、Nalm−6−luc CD19+播種性腫瘍を担持するNSGマウスに投与した。このストレス試験(すなわち、腫瘍の制御または除去に失敗するであろう最適量以下のCAR−T細胞を用いた試験)によって、化合物処理の結果としてCAR−T細胞が獲得したあらゆる優位性の検知が可能となる。CD4+T細胞およびCD8+T細胞にCARを導入し、抗CD3/抗CD28ビーズで活性化した。これらのCD4+CAR−T細胞およびCD8+CAR−T細胞を、溶媒または表1の化合物と共に培養した。6日間の処理が完了した後、これらのCD4+CAR−T細胞およびCD8+CAR−T細胞を凍結保存した。処理されたT細胞を解凍後、CD4+T細胞とCD8+T細胞とを1:1比で混合し、約2.5×105細胞の投与量でマウスに投与した。Nalm−6−luc CD19+腫瘍細胞が発現するルシフェラーゼの量に基づいて各マウスにおける総輝度(total radiance)を測定する、IVIS Lumina Series IIIイメージングシステム(マサチューセッツ州ウォルサム)を用いて、腫瘍量を測定した。
Claims (96)
- 免疫細胞集団と、BET阻害剤、CDK阻害剤、CRACチャネル阻害剤、Cox阻害剤、ドパミン拮抗剤、ERK5阻害剤、グルココルチコイド、IGF−1R阻害剤、IKK阻害剤、JAK阻害剤、Lck阻害剤、PDK1阻害剤、Raf阻害剤、またはSyk阻害剤を少なくとも含む1または複数の調節薬と、を含み、前記1または複数の調節薬が接触の直後または後に免疫細胞の治療的有効性を改善する、組成物。
- 前記1または複数の調節薬が、
(a)細胞の増殖、維持、分化、脱分化、および/もしくは生存率を改善する;
(b)細胞増殖、細胞毒性、残留性、サイトカイン応答、サイトカイン分泌、および/もしくは細胞リコールを改善する;並びに/または
(c)前記免疫細胞集団中の1もしくは複数の目的の免疫細胞亜集団の数もしくは相対比を増加させる、
請求項1に記載の組成物。 - 前記免疫細胞がT細胞、NKT細胞、および/またはNK細胞を含む、請求項1に記載の組成物。
- 数または相対比の増加が起こる前記1または複数の目的の免疫細胞亜集団が、
(a)ナイーブT細胞、幹細胞様メモリーT細胞、および/もしくはセントラルメモリーT細胞;
(b)I型NKT細胞;または
(c)獲得NK細胞(adaptive NK cell)、
を含む、請求項2に記載の組成物。 - 前記免疫細胞が、末梢血、骨髄、リンパ節組織、臍帯血、胸腺組織、感染部位由来組織、腹水、胸水、脾臓組織、または腫瘍から単離された免疫細胞である、またはそれに含まれた免疫細胞である、請求項1に記載の組成物。
- 前記免疫細胞が、
(a)健常な対象;
(b)自己免疫疾患、造血器悪性腫瘍、ウイルス感染症、もしくは固形腫瘍を有する対象;
(c)遺伝子改変免疫細胞を以前に投与された対象;または
(d)サイトメガロウイルス(CMV)血清陽性の対象、
から単離された免疫細胞である、請求項1に記載の組成物。 - 前記単離された免疫細胞が、
(a)ゲノム操作されており、挿入、欠失、または核酸置換(nucleic acid replacement)を含む;または、
(b)少なくとも1種の遺伝子改変されたモダリティを含む、
請求項5または請求項6に記載の組成物。 - 前記免疫細胞が、
(a)幹細胞、造血幹細胞、造血前駆細胞、もしくは前駆細胞からインビトロで分化された;または
(b)造血系もしくは非造血系の非多能性細胞からインビトロで分化転換された、
免疫細胞である、請求項1に記載の組成物。 - 前記幹細胞が誘導多能性幹細胞(iPSC)または胚性幹細胞(ESC)を含む、請求項8に記載の組成物。
- 前記前駆細胞がCD34+造血性内皮細胞、多分化能前駆細胞、T細胞前駆細胞、NK前駆細胞、またはNKT前駆細胞である、請求項8に記載の組成物。
- 前記幹細胞、造血幹細胞、造血前駆細胞、または前駆細胞が、
(a)ゲノム操作されており、挿入、欠失、または核酸置換を含む;または、
(b)少なくとも1種の遺伝子改変されたモダリティを含む、
幹細胞、造血幹細胞、造血前駆細胞、または前駆細胞である、請求項8に記載の組成物。 - 前記遺伝子改変されたモダリティが、セーフティ・スイッチタンパク質、標的化モダリティ、受容体、シグナル伝達分子、転写因子、薬剤的に活性なタンパク質およびペプチド、薬物標的候補;または、前記免疫細胞の移植、輸送、ホーミング、生存能、自己複製、残留性、免疫応答の制御および調節、並びに/もしくは生存を促進するタンパク質、のうちの少なくとも1つを含む、請求項7または請求項11に記載の組成物。
- 前記遺伝子改変されたモダリティが、(i)B2M、TAP1、TAP2、タパシン、NLRC5、PD1、LAG3、TIM3、RFXANK、CIITA、RFX5、またはRFXAP、および染色体6p21領域内のあらゆる遺伝子の発現の欠失または減少;並びに、(ii)HLA−E、HLA−G、HACD16、hnCD16、41BBL、CD3、CD4、CD8、CD47、CD113、CD131、CD137、CD80、PDL1、A2AR、Fc受容体、または、二重特異性エンゲージャー、多重特異性エンゲージャー、もしくは汎用エンゲージャーとの結合のための表面上トリガー受容体の発現の導入または増加、のうちの1または複数を含む、請求項12に記載の組成物。
- 前記単離された免疫細胞が、T細胞受容体(TCR)および/またはキメラ抗原受容体(CAR)をコードする外来性核酸を含む、請求項7に記載の組成物。
- 前記幹細胞、造血幹細胞、造血前駆細胞、または前駆細胞が、T細胞受容体(TCR)および/またはキメラ抗原受容体(CAR)を含むタンパク質をコードする外来性核酸を含む、請求項11に記載の組成物。
- 前記1または複数の調節薬が、
(a)表1の化合物のうちの少なくとも1つ、またはその塩、エステル、エーテル、溶媒和物、水和物、立体異性体、もしくはプロドラッグを含む;
(b)BET阻害剤、IKK阻害剤、JAK阻害剤、PDK1阻害剤、Raf阻害剤、またはSyk阻害剤を少なくとも含む;
(c)PDK1阻害剤を少なくとも含む;
(d)Raf阻害剤を少なくとも含む;
(e)Syk阻害剤を少なくとも含む;
(f)GSK2334470、AZ628、GDC−0879、ダブラフェニブ、R788、パクリチニブ、バルドキソロンメチル、およびPRT062607のうちの少なくとも1種を含む;
(g)GSK2334470を少なくとも含む;
(h)バルドキソロンメチルを少なくとも含む;または
(i)AZ628を少なくとも含む、
請求項1〜15のいずれか一項に記載の組成物。 - ペプチド、抗体、抗体フラグメント、サイトカイン、マイトジェン、増殖因子、スモールRNA、dsRNA、単核血液細胞、フィーダー細胞、フィーダー細胞の成分または代替要素、1または複数の目的のポリ核酸を含むベクター、化学療法剤または放射性部分、および免疫調節薬(IMiD)、からなる群から選択される1または複数の添加剤をさらに含む、請求項1〜16のいずれか一項に記載の組成物。
- ジメチルスルホキシド(DMSO)、N,N−ジメチルホルムアミド(DMF)、ジメトキシエタン(DME)、ジメチルアセトアミド、エタノールおよびこれらの組み合わせ、からなる群から選択される少なくとも1種の有機溶剤をさらに含む、請求項1に記載の組成物。
- T細胞を含む、請求項1に記載の組成物。
- 前記T細胞がCAR−T細胞を含む、請求項19に記載の組成物。
- 養子細胞をベースとした治療法に好適な免疫細胞の治療的有効性を改善するための組成物であって、
BET阻害剤、CDK阻害剤、CRACチャネル阻害剤、Cox阻害剤、ドパミン拮抗剤、ERK5阻害剤、グルココルチコイド、IGF−1R阻害剤、IKK阻害剤、JAK阻害剤、Lck阻害剤、PDK1阻害剤、Raf阻害剤、およびSyk阻害剤からなる群から選択される少なくとも1種の調節薬を含み;
前記調節薬が接触後に免疫細胞の治療的有効性を改善する、
前記組成物。 - 前記薬剤が、免疫細胞の、
(a)細胞増殖、維持および/もしくは分化を調節する、
(b)細胞増殖、細胞毒性、サイトカイン応答、サイトカイン分泌、リコール、および/もしくは残留性を改善する;
(c)細胞生存率を改善する;並びに/または
(d)1もしくは複数の目的の細胞亜集団の数もしくは相対比を増加させる、
請求項21に記載の組成物。 - 前記免疫細胞がT細胞、NKT細胞、および/またはNK細胞を含む、請求項21または請求項22に記載の組成物。
- 数または相対比の増加が起こる前記1または複数の目的の細胞亜集団が、
(a)ナイーブT細胞、幹細胞様メモリーT細胞、および/もしくはセントラルメモリーT細胞;
(b)I型NKT細胞;または
(c)獲得NK細胞、
を含む、請求項22に記載の組成物。 - 前記免疫細胞が、末梢血、骨髄、リンパ節組織、臍帯血、胸腺組織、感染部位由来組織、腹水、胸水、脾臓組織、または腫瘍から単離された免疫細胞である、またはそれに含まれた免疫細胞である、請求項21に記載の組成物。
- 前記免疫細胞が、
(a)健常な対象;
(b)自己免疫疾患、造血器悪性腫瘍、ウイルス感染症、もしくは固形腫瘍を有する対象;
(c)遺伝子改変免疫細胞を以前に投与された対象;または
(d)CMV血清陽性の対象、
から単離された免疫細胞である、請求項21に記載の組成物。 - 前記免疫細胞が、
(a)ゲノム操作されており、挿入、欠失、または核酸置換を含む;または
(b)少なくとも1種の遺伝子改変されたモダリティを含む、
免疫細胞である、請求項21に記載の組成物。 - 前記免疫細胞が、
(a)幹細胞、造血幹細胞、造血前駆細胞、もしくは前駆細胞からインビトロで分化された;または
(b)造血系もしくは非造血系の非多能性細胞からインビトロで分化転換された、
免疫細胞である、請求項21に記載の組成物。 - 前記幹細胞が誘導多能性幹細胞(iPSC)または胚性幹細胞(ESC)を含む、請求項28に記載の組成物。
- 前記前駆細胞がCD34+造血性内皮細胞、多分化能前駆細胞、T細胞前駆細胞、NK前駆細胞、またはNKT前駆細胞である、請求項28に記載の組成物。
- 前記幹細胞、造血幹細胞、造血前駆細胞、または前駆細胞が、
(a)ゲノム操作されており、挿入、欠失、もしくは核酸置換を含む、または
(b)少なくとも1種の遺伝子改変されたモダリティを含む、
請求項28に記載の組成物。 - 前記遺伝子改変されたモダリティが、セーフティ・スイッチタンパク質、標的化モダリティ、受容体、シグナル伝達分子、転写因子、薬剤的に活性なタンパク質およびペプチド、薬物標的候補;または、前記免疫細胞の移植、輸送、ホーミング、生存能、自己複製、残留性、免疫応答の制御および調節、並びに/もしくは生存を促進するタンパク質、のうちの少なくとも1つを含む、請求項27または請求項31に記載の組成物。
- 前記遺伝子改変されたモダリティが、(i)B2M、TAP1、TAP2、タパシン、NLRC5、PD1、LAG3、TIM3、RFXANK、CIITA、RFX5、またはRFXAP、および染色体6p21領域内のあらゆる遺伝子の発現の欠失または減少;並びに、(ii)HLA−E、HLA−G、HACD16、hnCD16、41BBL、CD3、CD4、CD8、CD47、CD113、CD131、CD137、CD80、PDL1、A2AR、Fc受容体、または、二重特異性エンゲージャー、多重特異性エンゲージャー、もしくは汎用エンゲージャーとの結合のための表面上トリガー受容体の発現の導入または増加、のうちの1または複数を含む、請求項32に記載の組成物。
- 前記単離された免疫細胞が、T細胞受容体(TCR)および/またはキメラ抗原受容体(CAR)をコードする外来性核酸を含む、請求項21に記載の組成物。
- 前記幹細胞、造血幹細胞、造血前駆細胞、または前駆細胞が、T細胞受容体(TCR)および/またはキメラ抗原受容体(CAR)を含むタンパク質をコードする外来性核酸を含む、請求項28に記載の組成物。
- (a)表1の化合物のうちの少なくとも1つ、またはその塩、エステル、エーテル、溶媒和物、水和物、立体異性体、もしくはプロドラッグを含む;
(b)BET阻害剤、IKK阻害剤、JAK阻害剤、PDK1阻害剤、Raf阻害剤、またはSyk阻害剤を少なくとも含む;
(c)PDK1阻害剤を少なくとも含む;
(d)Raf阻害剤を少なくとも含む;
(e)Syk阻害剤を少なくとも含む;
(f)GSK2334470、AZ628、GDC−0879、ダブラフェニブ、R788、パクリチニブ、バルドキソロンメチル、およびPRT062607のうちの少なくとも1種を含む;
(g)GSK2334470を少なくとも含む;
(h)バルドキソロンメチルを少なくとも含む;または
(i)AZ628を少なくとも含む、
請求項21に記載の組成物。 - ペプチド、抗体、抗体フラグメント、サイトカイン、マイトジェン、増殖因子、スモールRNA、dsRNA、単核血液細胞、フィーダー細胞、フィーダー細胞の成分または代替要素、1または複数の目的のポリ核酸を含むベクター、化学療法剤または放射性部分、および免疫調節薬(IMiD)、からなる群から選択される1または複数の添加剤をさらに含む、請求項21に記載の組成物。
- ジメチルスルホキシド(DMSO)、N,N−ジメチルホルムアミド(DMF)、ジメトキシエタン(DME)、ジメチルアセトアミド、エタノールおよびこれらの組み合わせ、からなる群から選択される少なくとも1種の有機溶剤をさらに含む、請求項21に記載の組成物。
- 単離された免疫細胞と、BET阻害剤、CDK阻害剤、CRACチャネル阻害剤、Cox阻害剤、ドパミン拮抗剤、ERK5阻害剤、グルココルチコイド、IGF−1R阻害剤、IKK阻害剤、JAK阻害剤、Lck阻害剤、PDK1阻害剤、Raf阻害剤、およびSyk阻害剤からなる群から選択される1もしくは複数の調節薬を含む組成物と、の接触から得られる調節された免疫細胞を含む、且つ/または、調節された免疫細胞が、BET、CDK、CRACチャネル、Cox、IKK、JAK、LCK、PDK1、Raf、および/もしくはSykの発現もしくは活性が途絶もしくは低減した細胞を含む、組成物であって;前記調節された免疫細胞が、調節されていない免疫細胞との比較で養子免疫療法においての治療的有効性が改善した免疫細胞亜集団を少なくとも含む、前記組成物。
- 前記調節された免疫細胞またはその亜集団の、
(a)細胞の増殖、維持、分化、脱分化、および/もしくは生存率が改善した;
(b)細胞増殖、細胞毒性、残留性、サイトカイン応答、サイトカイン分泌、および/もしくは細胞リコールが改善した;且つ/または
(c)1もしくは複数の目的の免疫細胞亜集団の数もしくは相対比が増加した、
請求項39に記載の組成物。 - 前記調節された免疫細胞がT細胞、NKT細胞、および/またはNK細胞を含む、請求項40に記載の組成物。
- 数または相対比の増加が起こる前記1または複数の目的の免疫細胞亜集団が、
を含む、請求項40に記載の組成物。
(a)ナイーブT細胞、幹細胞様メモリーT細胞、および/もしくはセントラルメモリーT細胞;
(b)I型NKT細胞;または
(c)獲得NK細胞、 - 前記単離された免疫細胞が、末梢血、骨髄、リンパ節組織、臍帯血、胸腺組織、感染部位由来組織、腹水、胸水、脾臓組織、または腫瘍から得られた免疫細胞である、請求項39に記載の組成物。
- 前記単離された免疫細胞が、
(a)健常な対象;
(b)自己免疫疾患、造血器悪性腫瘍、ウイルス感染症、もしくは固形腫瘍を有する対象;
(c)遺伝子改変免疫細胞を以前に投与された対象;または
(d)CMV血清陽性の対象、
から得られた免疫細胞である、請求項39に記載の組成物。 - 前記単離された免疫細胞が、
(a)ゲノム操作されており、挿入、欠失、もしくは核酸置換を含む;または
(b)少なくとも1種の遺伝子改変されたモダリティを含む、
請求項39に記載の組成物。 - 前記単離された免疫細胞が、
(a)幹細胞、造血幹細胞、造血前駆細胞、もしくは前駆細胞からインビトロで分化された;または
(b)造血系もしくは非造血系の非多能性細胞からインビトロで分化転換された、
免疫細胞である、請求項39に記載の組成物。 - 前記幹細胞が誘導多能性幹細胞(iPSC)または胚性幹細胞(ESC)を含む、請求項46に記載の組成物。
- 前記前駆細胞がCD34+造血性内皮細胞、多分化能前駆細胞、T細胞前駆細胞、NK前駆細胞、またはNKT前駆細胞である、請求項46に記載の組成物。
- 前記幹細胞、造血幹細胞、造血前駆細胞、または前駆細胞が、
(a)ゲノム操作されており、挿入、欠失、もしくは核酸置換を含む、または
(b)少なくとも1種の遺伝子改変されたモダリティを含む、
請求項46に記載の組成物。 - 前記遺伝子改変されたモダリティが、セーフティ・スイッチタンパク質、標的化モダリティ、受容体、シグナル伝達分子、転写因子、薬剤的に活性なタンパク質およびペプチド、薬物標的候補;または、前記免疫細胞の移植、輸送、ホーミング、生存能、自己複製、残留性、免疫応答の制御および調節、並びに/もしくは生存を促進するタンパク質、のうちの少なくとも1つを含む、請求項45または請求項49に記載の組成物。
- 前記遺伝子改変されたモダリティが、(i)B2M、TAP1、TAP2、タパシン、NLRC5、PD1、LAG3、TIM3、RFXANK、CIITA、RFX5、またはRFXAP、および染色体6p21領域内のあらゆる遺伝子の発現の欠失または減少;並びに、(ii)HLA−E、HLA−G、HACD16、hnCD16、41BBL、CD3、CD4、CD8、CD47、CD113、CD131、CD137、CD80、PDL1、A2AR、Fc受容体、または、二重特異性エンゲージャー、多重特異性エンゲージャー、もしくは汎用エンゲージャーとの結合のための表面上トリガー受容体の発現の導入または増加、のうちの1または複数を含む、請求項50に記載の組成物。
- 前記単離された免疫細胞が、T細胞受容体(TCR)および/またはキメラ抗原受容体(CAR)をコードする外来性核酸を含む、請求項39に記載の組成物。
- 前記幹細胞、造血幹細胞、造血前駆細胞、または前駆細胞が、T細胞受容体(TCR)および/またはキメラ抗原受容体(CAR)を含むタンパク質をコードする外来性核酸を含む、請求項49に記載の組成物。
- 前記1または複数の調節薬が、
(a)表1の化合物のうちの少なくとも1つ、またはその塩、エステル、エーテル、溶媒和物、水和物、立体異性体、もしくはプロドラッグ;
(b)BET阻害剤、IKK阻害剤、JAK阻害剤、PDK1阻害剤、Raf阻害剤、またはSyk阻害剤を少なくとも含む;
(c)PDK1阻害剤を少なくとも含む;
(d)Raf阻害剤を少なくとも含む;
(e)Syk阻害剤を少なくとも含む;
(f)GSK2334470、AZ628、GDC−0879、ダブラフェニブ、R788、パクリチニブ、バルドキソロンメチル、およびPRT062607のうちの少なくとも1種を含む;
(g)GSK2334470を少なくとも含む;
(h)バルドキソロンメチルを少なくとも含む;または
(i)AZ628を少なくとも含む、
請求項39に記載の組成物。 - ペプチド、抗体、抗体フラグメント、サイトカイン、マイトジェン、増殖因子、スモールRNA、dsRNA、単核血液細胞、フィーダー細胞、フィーダー細胞の成分または代替要素、1または複数の目的のポリ核酸を含むベクター、化学療法剤または放射性部分、および免疫調節薬(IMiD)、からなる群から選択される1または複数の添加剤をさらに含む、請求項39に記載の組成物。
- ジメチルスルホキシド(DMSO)、N,N−ジメチルホルムアミド(DMF)、ジメトキシエタン(DME)、ジメチルアセトアミド、エタノールおよびこれらの組み合わせ、からなる群から選択される少なくとも1種の有機溶剤をさらに含む、請求項39に記載の組成物。
- 前記調節された免疫細胞集団が、前記調節薬のうちの1または複数を含む組成物による調節を受けていない免疫細胞集団と比較した場合に、
(a)CD27、CCR7、CD62L、TCF7、LEF1、BLIMP−1、ALDOC、およびENO2のうちの少なくとも1つの遺伝子発現の増加;
(b)PD−1およびTim−3のうちの少なくとも1つの遺伝子発現の減少;
(c)セントラルメモリーT細胞亜集団の増加;
(d)エフェクターメモリーT細胞亜集団および/またはエフェクターT細胞亜集団の減少;
(e)増殖および生存能の改善;並びに
(f)腫瘍除去能および残留性の改善、
のうちの少なくとも1つが生じたT細胞を含む、請求項39に記載の組成物。 - 前記T細胞がCAR−T細胞である、請求項57に記載の組成物。
- 調節されていないT細胞集団と比較した場合に、
(a)CD27、CCR7、CD62L、TCF7、LEF1、BLIMP−1、ALDOC、およびENO2のうちの少なくとも1つの遺伝子発現の増加;
(b)PD−1およびTim−3のうちの少なくとも1つの遺伝子発現の減少;
(c)セントラルメモリーT細胞亜集団の増加;並びに
(d)エフェクターメモリーT細胞亜集団および/またはエフェクターT細胞亜集団の減少;
のうちの少なくとも1つが生じた、調節されたT細胞集団を含む組成物。 - 前記T細胞集団がCAR−T細胞を含む、請求項59に記載の組成物。
- 前記T細胞集団が、
増殖および生存能の改善;並びに/または
腫瘍除去能および残留性の改善、
を生じた、請求項59に記載の組成物。 - 免疫細胞を調節する方法であって、
免疫細胞集団と、BET阻害剤、CDK阻害剤、CRACチャネル阻害剤、Cox阻害剤、ドパミン拮抗剤、ERK5阻害剤、グルココルチコイド、IGF−1R阻害剤、IKK阻害剤、JAK阻害剤、Lck阻害剤、PDK1阻害剤、Raf阻害剤、およびSyk阻害剤からなる群から選択される1または複数の調節薬とを、調節されていない免疫細胞と比較して、および/または接触直前の前記細胞集団と比較して、治療的有効性が改善した、且つ/または、養子免疫療法においての治療的有効性を示す1もしくは複数の特性が増加した、調節された免疫細胞を得るのに十分な時間、接触させること、
を含む、前記方法。 - 前記調節された免疫細胞が、前記1または複数の調節薬と接触させていない免疫細胞と比較した場合に、
(a)増殖、細胞毒性、サイトカイン応答、サイトカイン放出、細胞リコール、および/もしくは残留性の改善;
(b)細胞増殖、維持、分化、脱分化、および/もしくは生存率の改善;または
(c)1もしくは複数の目的の免疫細胞亜集団の数もしくは相対比の増加、
を生じた細胞を含む、請求項62に記載の方法。
- 前記免疫細胞集団がT細胞、NKT細胞、および/またはNK細胞を含む、請求項62に記載の方法。
- 前記1または複数の目的の亜集団を前記調節された免疫細胞から単離すること、
をさらに含む、請求項62に記載の方法。 - 前記1または複数の目的の亜集団が、
(a)ナイーブT細胞、幹細胞様メモリーT細胞、および/もしくはセントラルメモリーT細胞;
(b)I型NKT細胞;または
(c)獲得NK細胞、
を含む、請求項65に記載の方法。 - 前記単離された免疫細胞が、末梢血、骨髄、リンパ節組織、臍帯血、胸腺組織、感染部位由来組織、腹水、胸水、脾臓組織、または腫瘍から得られた免疫細胞である、またはそれに含まれた免疫細胞である、請求項62に記載の方法。
- 前記単離された免疫細胞が、
(a)健常な対象;
(b)自己免疫疾患、造血器悪性腫瘍、ウイルス感染症、もしくは固形腫瘍を有する対象;
(c)遺伝子改変免疫細胞を以前に投与された対象;または
(d)CMV血清陽性の対象、
から得られた免疫細胞である、請求項62に記載の方法。 - 前記単離された免疫細胞が、
(a)ゲノム操作されており、挿入、欠失、もしくは核酸置換を含む;または
(b)少なくとも1種の遺伝子改変されたモダリティを含む、
免疫細胞である、請求項62に記載の方法。 - 前記単離された免疫細胞が、
(a)幹細胞、造血幹細胞、造血前駆細胞、もしくは前駆細胞からインビトロで分化された;または
(b)造血系もしくは非造血系の非多能性細胞からインビトロで分化転換された、
免疫細胞である、請求項62に記載の方法。 - 前記幹細胞が誘導多能性幹細胞(iPSC)または胚性幹細胞(ESC)を含む、請求項70に記載の方法。
- 前記前駆細胞がCD34+造血性内皮細胞、多分化能前駆細胞、T細胞前駆細胞、NK前駆細胞、またはNKT前駆細胞である、請求項70に記載の方法。
- 前記幹細胞、造血幹細胞、造血前駆細胞、または前駆細胞が、
(a)ゲノム操作されており、挿入、欠失、もしくは核酸置換を含む、または
(b)少なくとも1種の遺伝子改変されたモダリティを含む、
請求項70に記載の方法。 - 前記遺伝子改変されたモダリティが、セーフティ・スイッチタンパク質、標的化モダリティ、受容体、シグナル伝達分子、転写因子、薬剤的に活性なタンパク質およびペプチド、薬物標的候補;または、前記免疫細胞の移植、輸送、ホーミング、生存能、自己複製、残留性、免疫応答の制御および調節、並びに/もしくは生存を促進するタンパク質、のうちの少なくとも1つを含む、請求項69または請求項73に記載の方法。
- 前記遺伝子改変されたモダリティが、(i)B2M、TAP1、TAP2、タパシン、NLRC5、PD1、LAG3、TIM3、RFXANK、CIITA、RFX5、またはRFXAP、および染色体6p21領域内のあらゆる遺伝子の発現の欠失または減少;並びに、(ii)HLA−E、HLA−G、HACD16、hnCD16、41BBL、CD3、CD4、CD8、CD47、CD113、CD131、CD137、CD80、PDL1、A2AR、Fc受容体、または、二重特異性エンゲージャー、多重特異性エンゲージャー、もしくは汎用エンゲージャーとの結合のための表面上トリガー受容体の発現の導入または増加、のうちの1または複数を含む、請求項74に記載の方法。
- 前記単離された免疫細胞が、T細胞受容体(TCR)および/またはキメラ抗原受容体(CAR)をコードする外来性核酸を含む、請求項62に記載の方法。
- 前記幹細胞、造血幹細胞、造血前駆細胞、または前駆細胞が、T細胞受容体(TCR)および/またはキメラ抗原受容体(CAR)を含むタンパク質をコードする外来性核酸を含む、請求項70に記載の方法。
- 前記1または複数の調節薬が、
(a)表1の化合物、およびその塩、エステル、エーテル、溶媒和物、水和物、立体異性体、もしくはプロドラッグ、のうちの少なくとも1つを含む;
(b)BET阻害剤、IKK阻害剤、JAK阻害剤、PDK1阻害剤、Raf阻害剤、またはSyk阻害剤を少なくとも含む;
(c)PDK1阻害剤を少なくとも含む;
(d)Raf阻害剤を少なくとも含む;
(e)Syk阻害剤を少なくとも含む;
(f)GSK2334470、AZ628、GDC−0879、ダブラフェニブ、R788、パクリチニブ、バルドキソロンメチル、およびPRT062607のうちの少なくとも1種を含む;
(g)GSK2334470を少なくとも含む;
(h)バルドキソロンメチルを少なくとも含む;または
(i)AZ628を少なくとも含む、
請求項62に記載の方法。 - 前記単離された免疫細胞集団がT細胞を含む、請求項62に記載の方法。
- 前記調節された免疫細胞集団が、前記1または複数の調節薬と接触させていないT細胞を含む免疫細胞集団と比較した場合に、
(a)CD27、CCR7、CD62L、TCF7、LEF1、BLIMP−1、ALDOC、およびENO2のうちの少なくとも1つの遺伝子発現の増加;
(b)PD−1およびTim−3のうちの少なくとも1つの遺伝子発現の減少;
(c)セントラルメモリーT細胞亜集団の増加;
(d)エフェクターメモリーT細胞亜集団および/またはエフェクターT細胞亜集団の減少;
(e)増殖および生存能の改善;並びに
(f)腫瘍除去能および残留性の改善、
のうちの少なくとも1つが生じたT細胞を含む、請求項62に記載の方法。 - 前記T細胞がCAR−T細胞である、請求項79に記載の方法。
- 請求項62〜81に記載のT細胞を調節する方法。
- 請求項62〜82のいずれか一項に記載の細胞療法用のT細胞、NK細胞、またはNKT細胞を含む調節された免疫細胞を含む治療用組成物を作製する方法。
- 請求項62〜82のいずれか一項において作製された、調節された免疫細胞集団。
- 請求項62〜83において作製された、調節されたT細胞集団。
- 調節されていないT細胞集団と比較した場合に、
(a)CD27、CCR7、CD62L、TCF7、LEF1、BLIMP−1、ALDOC、およびENO2のうちの少なくとも1つの遺伝子発現の増加;
(b)PD−1およびTim−3のうちの少なくとも1つの遺伝子発現の減少;
(c)セントラルメモリーT細胞亜集団の増加;並びに
(d)エフェクターメモリーT細胞亜集団および/またはエフェクターT細胞亜集団の減少;
のうちの少なくとも1つが生じた、調節されたT細胞集団。 - 請求項62〜83のいずれか一項において作製された前記調節された免疫細胞と、治療上許容できる培地と、を含む治療用組成物。
- ペプチド、サイトカイン、マイトジェン、増殖因子、スモールRNA、dsRNA(二本鎖RNA)、単核血液細胞、フィーダー細胞、フィーダー細胞の成分または代替要素、1または複数の目的のポリ核酸を含むベクター、抗体、化学療法剤または放射性部分、および免疫調節薬(IMiD)からなる群から選択される1または複数の追加の添加剤をさらに含む、請求項87に記載の治療用組成物。
- 治療に十分な量の請求項87または請求項88に記載の治療用組成物を、養子免疫療法を必要とする対象に投与することにより、前記対象を治療する方法であって、自家細胞療法であっても他家細胞療法であってもよく、前記対象が自己免疫障害、造血器腫瘍、固形腫瘍、またはHIV、RSV、EBV、CMV、アデノウイルス、もしくはBKポリオーマウイルスが関連した感染症を有する、前記方法。
- 抗体療法、化学療法、または放射線療法と組み合わせて、治療に十分な量の請求項87に記載の治療用組成物を投与することにより対象を治療する方法であって、前記抗体療法、化学療法、または放射線療法が前記治療用組成物の投与前、投与と同時、投与後である、前記方法。
- 請求項62〜83のいずれか一項に記載の方法に従った細胞療法用の治療用組成物を製造するための混合物の使用であって、前記混合物が
(a)単離された免疫細胞集団と、
(b)BET阻害剤、CDK阻害剤、CRACチャネル阻害剤、Cox阻害剤、ドパミン拮抗剤、ERK5阻害剤、グルココルチコイド、IGF−1R阻害剤、IKK阻害剤、JAK阻害剤、Lck阻害剤、PDK1阻害剤、Raf阻害剤、およびSyk阻害剤からなる群から選択される1または複数の調節薬を含む組成物と、
前記(b)の組成物が接触後に前記(a)の細胞の治療的有効性を改善することが可能な、前記使用。 - 前記1または複数の調節薬が、
(a)表1の化合物、およびその塩、エステル、エーテル、溶媒和物、水和物、立体異性体、もしくはプロドラッグ、のうちの少なくとも1つを含む;
(b)BET阻害剤、IKK阻害剤、JAK阻害剤、PDK1阻害剤、Raf阻害剤、またはSyk阻害剤を少なくとも含む;
(c)PDK1阻害剤を少なくとも含む;
(d)Raf阻害剤を少なくとも含む;
(e)Syk阻害剤を少なくとも含む;
(f)GSK2334470、AZ628、GDC−0879、ダブラフェニブ、R788、パクリチニブ、バルドキソロンメチル、およびPRT062607のうちの少なくとも1種を含む;
(g)GSK2334470を少なくとも含む;
(h)バルドキソロンメチルを少なくとも含む;または
(i)AZ628を少なくとも含む、
請求項91に記載の使用。 - 前記単離された免疫細胞集団がT細胞を含む、請求項91に記載の使用。
- 調節されていない、T細胞を含む免疫細胞集団と比較した場合に、前記単離された免疫細胞集団が、接触後に、
(a)CD27、CCR7、CD62L、TCF7、LEF1、BLIMP−1、ALDOC、およびENO2のうちの少なくとも1つの遺伝子発現の増加;
(b)PD−1およびTim−3のうちの少なくとも1つの遺伝子発現の減少;
(c)セントラルメモリーT細胞亜集団の増加;
(d)エフェクターメモリーT細胞亜集団および/またはエフェクターT細胞亜集団の減少;
(e)増殖および生存能の改善;並びに
(f)腫瘍除去能および残留性の改善、
のうちの少なくとも1つが生じたT細胞を含む、請求項91に記載の使用。 - 前記T細胞がCAR−T細胞である、請求項93または請求項94に記載の使用。
- 請求項62〜83のいずれか一項に記載の免疫細胞を製造する方法。
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ES2898329T3 (es) | 2016-01-12 | 2022-03-07 | Oncotracker Inc | Métodos mejorados para supervisar el estado inmunitario de un sujeto |
WO2018231944A1 (en) | 2017-06-13 | 2018-12-20 | Berenson James R | Diagnostic, prognostic, and monitoring methods for solid tumor cancers |
MX2021001523A (es) | 2018-08-09 | 2021-05-27 | Juno Therapeutics Inc | Procesos para generar células modificadas y composiciones de las mismas. |
KR20210098450A (ko) | 2018-10-31 | 2021-08-10 | 주노 테라퓨틱스 게엠베하 | 세포의 선택 및 자극을 위한 방법 및 이를 위한 장치 |
WO2020092792A2 (en) * | 2018-10-31 | 2020-05-07 | Oncotracker, Inc. | Method of enhancing immune-based therapy |
MA55562A (fr) * | 2019-04-05 | 2022-02-09 | 2Seventy Bio Inc | Production de cellules car-t anti-bcma |
GB201909573D0 (en) * | 2019-07-03 | 2019-08-14 | Cancer Research Tech Ltd | Modulation of T cell cytotoxicity and related therapy |
GB201911958D0 (en) * | 2019-08-20 | 2019-10-02 | Adaptimmune Ltd | Methods of t cell production |
US20230016034A1 (en) * | 2019-12-06 | 2023-01-19 | Fate Therapeutics, Inc. | ENHANCEMENT OF iPSC-DERIVED EFFECTOR IMMUNE CELL USING SMALL COMPOUNDS |
FR3108501A1 (fr) * | 2020-03-27 | 2021-10-01 | Universite De Paris | « Nouvelles cibles thérapeutiques à effet anti-inflammatoire et anti-interféron ». |
CN111454903B (zh) * | 2020-05-06 | 2023-10-20 | 青岛瑞思德生物科技有限公司 | 免疫细胞体外培养、诱导、激活、冻存方法及其细胞库建立 |
KR102594083B1 (ko) | 2020-07-07 | 2023-10-25 | 칸큐어 엘엘씨 | Mic 항체 및 결합제 및 이의 사용 방법 |
WO2022120247A1 (en) * | 2020-12-04 | 2022-06-09 | Fate Therapeutics, Inc. | Off-the-shelf ipsc-derived nk cell therapy for hematological cancer treatment |
WO2022183056A1 (en) * | 2021-02-26 | 2022-09-01 | Salk Institute For Biological Studies | Modulating regulatory t cell function in autoimmune disease and cancer |
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