JP2019520076A - 初代免疫細胞における逐次遺伝子編集 - Google Patents
初代免疫細胞における逐次遺伝子編集 Download PDFInfo
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Abstract
Description
本発明は、適応細胞免疫療法の分野に関する。本発明は、異なる遺伝子座において初代免疫細胞を遺伝子改変するためにいくつかの特異的エンドヌクレアーゼ試薬を一緒に用いる場合の、転座および細胞死の発生を減少させることを目的とする。本発明の方法によって、単一のドナーまたは患者に由来する細胞の集団または亜集団から、治療処置において後に使用するための、三重または四重遺伝子不活性化細胞などの、いくつかの遺伝子改変を有するより安全な免疫初代細胞をもたらすことが可能になる。
様々な治療法における、特に免疫細胞をエクスビボで遺伝子改変し、次いで患者に再導入することができる細胞療法の分野における、遺伝子編集の可能性が、例えばUS 8921332(特許文献1)において既に記載されているように、本出願者 (WO2004067753(特許文献2)) によって長い間想定されてきた。
・末梢血単核細胞 (PBMC) 由来などの、培養物または血液試料由来の少なくとも1つの初代免疫細胞を提供する段階;
・該細胞を遺伝子編集の段階に供する段階であって、配列特異的試薬の第1セットを該細胞に導入する段階;
・該細胞を培養して、該第1の配列特異的試薬が第1の遺伝子座においてそのゲノムを安定に改変できるようにする段階、
・該細胞を少なくとも第2の遺伝子編集段階に供して、配列特異的試薬の少なくとも第2セットを該細胞に導入する段階、および任意に
・該細胞を培養して、該第2の配列特異的試薬が該第2の遺伝子座においてそのゲノムを安定に改変できるようにする段階
のうちの1つまたはいくつかの段階を含む方法に関係する。
(a)免疫細胞を第1のエレクトロポレーションに供して、少なくとも第1の配列特異的試薬を該免疫細胞に導入する段階、
(b)該免疫細胞を培養して、該第1の配列特異的試薬が第1の遺伝子座においてそのゲノムを改変できるようにする段階、
(c)該細胞を少なくとも第2のエレクトロポレーションに移して、少なくとも第2の配列特異的試薬を該細胞に導入する段階、および任意に
(d)該免疫細胞を培養して、該第2の配列特異的試薬が該第2の遺伝子座においてそのゲノムを改変できるようにする段階
を含む。
(1)
初代免疫細胞の異なる複数の遺伝子座において遺伝子改変を導入するための方法であって、
(a)該初代免疫細胞を第1のエレクトロポレーション段階に供して、少なくとも第1の配列特異的試薬を該免疫細胞に導入する段階、
(b)該初代免疫細胞を培養し、それによって該第1の配列特異的試薬が第1の遺伝子座においてそのゲノムを改変できるようにする段階、
(c)該初代免疫を少なくとも第2のエレクトロポレーション段階に供して、少なくとも第2の配列特異的試薬を該細胞に導入する段階、
(d)該初代免疫を培養しかつ増大させ、それによって該第2の配列特異的試薬が該第2の遺伝子座においてそのゲノムを改変できるようにする段階
の逐次段階を含む、方法。
(2)
前記初代免疫細胞が、段階(b)において12〜72時間、好ましくは24〜48時間培養される、項目1記載の方法。
(3)
少なくとも前記第1の遺伝子座において改変された遺伝子の発現または欠失によって生じた産物に依存して、精製段階が、段階(b)と(c)の間に行われる、項目1記載の方法。
(4)
段階(a)〜(d)が240時間以内に、好ましくは120時間以内に、より好ましくは96時間以内に、さらにより好ましくは72時間以内に行われる、項目1〜3のいずれか一項記載の方法。
(5)
前記初代免疫細胞を第3のエレクトロポレーション段階に移して、少なくとも第3の配列特異的試薬を該細胞に導入する、少なくとも1つのさらなる段階
を含む、項目1〜4のいずれか一項記載の方法。
(6)
第1および/または第2の配列特異的試薬が、レアカットエンドヌクレアーゼ、そのサブユニットをコードするポリヌクレオチドもしくはポリペプチド、またはポリヌクレオチドおよびポリペプチドの両方の複合物である、項目1記載の方法。
(7)
第1および/または第2の配列特異的試薬が、プログラム可能なRNAもしくはDNAガイドエンドヌクレアーゼ、TALEN、ZFN、またはホーミングエンドヌクレアーゼより選択されるレアカットエンドヌクレアーゼをコードするポリヌクレオチドまたはポリペプチドである、項目2記載の方法。
(8)
第1および/または第2の配列特異的試薬が、RNAガイドとCas9またはCpf1ポリペプチドの複合物である、項目3記載の方法。
(9)
第1および/または第2の配列特異的試薬が、干渉RNA (RNAi) またはそれをコードするポリヌクレオチドである、項目1記載の方法。
(10)
形質導入段階が、レトロウイルスまたはレンチウイルスベクターと共に(b)と(c)の間に導入される、項目1記載の方法。
(11)
形質導入段階が、導入遺伝子の安定発現のための組込みレンチウイルスまたはレトロウイルスベクターを含む、項目10記載の方法。
(12)
導入遺伝子がキメラ抗原受容体 (CAR) をコードする、項目11記載の方法。
(13)
形質導入段階が非組込みウイルスベクターを含む、項目10記載の方法。
(14)
非組込みウイルスベクターが、免疫細胞のゲノム中に前記導入遺伝子を相同組換えまたはNHEJ組込みするための鋳型として用いられる、項目13記載の方法。
(15)
第1の配列特異的試薬が、形質導入段階を促進するゲノム配列に作用する、項目10記載の方法。
(16)
第1の配列特異的試薬が、段階(d)の遺伝子改変を促進するゲノム配列に作用する、項目1〜15のいずれか一項記載の方法。
(17)
段階(b)が35℃未満、好ましくは約30℃で行われる、項目1〜16のいずれか一項記載の方法。
(18)
免疫細胞がT細胞である、項目1〜17のいずれか一項記載の方法。
(19)
初代T細胞をシグナル伝達によって活性化する予備段階を含む、項目18記載の方法。
(20)
第1の配列特異的試薬が、初代T細胞によるTCRの発現を永続的に減少させるかまたは妨げる、項目18または19記載の方法。
(21)
第1または第2の配列特異的試薬が、免疫チェックポイントをコードする少なくとも1つの遺伝子の発現を永続的に減少させるかまたは妨げる、項目1〜20のいずれか一項記載の方法。
(22)
免疫チェックポイントをコードする少なくとも1つの遺伝子が、PD1、CTLA4、PPP2CA、PPP2CB、PTPN6、PTPN22、PDCD1、LAG3、HAVCR2、BTLA、CD160、TIGIT、CD96、CRTAM、LAIR1、SIGLEC7、SIGLEC9、CD244、TNFRSF10B、TNFRSF10A、CASP8、CASP10、CASP3、CASP6、CASP7、FADD、FAS、TGFBRII、TGFRBRI、SMAD2、SMAD3、SMAD4、SMAD10、SKI、SKIL、TGIF1、IL10RA、IL10RB、HMOX2、IL6R、IL6ST、EIF2AK4、CSK、PAG1、SIT1、FOXP3、PRDM1、BATF、GUCY1A2、GUCY1A3、GUCY1B2、GUCY1B3より選択される、項目21記載の方法。
(23)
第1または第2の配列特異的試薬が、薬物または免疫枯渇剤に対する前記初代免疫細胞の耐性を永続的に与える、項目1〜20のいずれか一項記載の方法。
(24)
CD52、dCK、GGH、またはHPRTを発現する遺伝子を不活性化することによって、前記耐性が与えられる、項目23記載の方法。
(25)
前記第1および/または第2および/または第3の遺伝子座において改変された1つの遺伝子の発現または欠失によって生じた少なくとも1つの産物に依存して、精製の最終段階が行われる、項目1〜24のいずれか一項記載の方法。
(26)
・TCR陰性かつPD1陰性、
・TCR陰性かつCD52陰性、
・TCR陰性かつCTLA4陰性、
・TCR陰性かつdCK陰性、
・TCR陰性かつGGH陰性、
・TCR陰性かつHPRT陰性、および
・TCR陰性かつβ2m陰性
より選択されるT細胞の少なくとも2つの亜集団を含む、項目1〜25のいずれか一項記載の方法に従って得ることができる、単一ドナーに由来する初代TCR陰性T細胞の集団。
(27)
単一ドナーに由来する初代TCR陰性T細胞の集団であって、該集団中の細胞の少なくとも20%、好ましくは30%、より好ましくは50%が、少なくとも3つの異なる遺伝子座において、配列特異的試薬を用いて改変されている、集団。
(28)
項目26または27のいずれか一項記載の初代T細胞の集団を含む、薬学的組成物。
(表2)実施例3に示されるような、本発明による様々な逐次遺伝子編集戦略の遺伝子編集効率(CD38、TCR、および/またはCD52陰性細胞の数に基づく遺伝子編集細胞の割合;D4、D5、およびD6は、凍結初代細胞を融解した後の日数である)。
(表3)実験で使用されたTALEN(登録商標)の配列。
(表4)T細胞の表面上に発現していることが見出された様々ながんの抗原マーカーの選択。特に、操作された免疫細胞に、まさにこれらの抗原を標的とするキメラ抗原受容体が付与される場合に、これらの抗原マーカーをコードする遺伝子の不活性化が、本発明による遺伝子編集段階の1つの1つの一部として提案される。
本明細書で特に定義されない限り、本明細書で用いられる専門用語および科学用語はすべて、遺伝子治療、生化学、遺伝学、および分子生物学の分野の当業者によって一般に理解されている意味と同じ意味を有する。
(a)初代免疫細胞を第1のエレクトロポレーションに供して、少なくとも第1の配列特異的試薬を該免疫細胞に導入する段階、
(b)該初代免疫細胞を培養し、それによって該第1の配列特異的試薬が第1の遺伝子座においてそのゲノムを改変できるようにする段階、
(c)該初代免疫を少なくとも第2のエレクトロポレーションに供して、少なくとも第2の配列特異的試薬を該細胞に導入する段階、
(d)該初代免疫を培養して増大させ、それによって該第2の配列特異的試薬が該第2の遺伝子座においてそのゲノムを改変できるようにする段階
を含む。
したがって本発明は、望ましくないゲノムの欠失または転座を妨げながら、哺乳動物細胞において遺伝子編集を積み重ねることを可能にする方法を提供する。
・(TNx → h → TNx) × n
・(TNx/TNx → h → TNx) × n
・(TNx → h → TNx/TNx) × n
・(TNx/TNx → h → TNx/TNx) × n
この場合、TNxは特異的エンドヌクレアーゼ試薬Nのトランスフェクション (T) であり (x≧1)、
hは時間表示による時間間隔であり、および (h≧1)、
nはその後のトランフェクションの回数である (n≧1)。
・形質導入 → h →(TNx → h →TNx) × n;
・形質導入 → h →(TNx/TNx → h → TNx) × n;
・形質導入 → h →(TNx → h → TNx/TNx) × n;
・形質導入 → h →(TNx/TNx → h → TNx/TNx) × n;
・(TNx → h → TNx) × n → h → 形質導入)× n;
・(TNx/TNx → h → TNx) × n → h → 形質導入)× n;
・(TNx → h → TNx/TNx) × n → h → 形質導入;
・(TNx/TNx → h → TNx/TNx) × n → h → 形質導入;
・(TNx → h → 形質導入 → h → TNx)× n;
・(TNx/TNx → h → 形質導入 → h → TNx)× n;
・(TNx → h → 形質導入 → h → TNx/TNx)× n;
・(TNx/TNx → h → 形質導入 → h → TNx/TNx)× n。
・前記外因性核酸配列、および標的となる内因性DNA配列と相同的な配列を含むAAVベクターを前記細胞に形質導入する段階、ならびに任意に、
・配列特異的エンドヌクレアーゼ試薬の発現を誘導して、挿入の遺伝子座において該内因性配列を切断する段階
からなる段階を含み得る。
本発明による方法は、同種治療用途のための初代免疫細胞を調製するのに特に適合している。「同種治療用途」とは、細胞が、異なるハプロタイプを有する患者に注入されることを考慮して、ドナーに由来することを意味する。実際に、本発明は、宿主-移植片の相互作用および認識に関与する様々な遺伝子座位において遺伝子編集され得る初代細胞を得るための効率的な方法を提供する。他の遺伝子座もまた、操作された初代細胞の活性、生存、または寿命を改善することを考慮して編集され得る。そのような操作された免疫細胞は、好ましくは初代T細胞である。
本発明の好ましい局面によると、遺伝子編集段階の1つは、免疫細胞阻害経路に関するタンパク質、具体的には文献中で「免疫チェックポイント」と称されるものの発現を中断させることを目的とする (Pardoll, D.M. (2012) The blockade of immune checkpoints in cancer immunotherapy, Nature Reviews Cancer, 12:252-264)。本発明の意味において、「免疫細胞阻害経路」とは、悪性細胞または感染細胞に対するリンパ球の細胞傷害活性の減少をもたらす、免疫細胞における任意の遺伝子発現を意味する。これは、例えば、T細胞に対するTregの活性(T細胞活性を緩和する)を駆動することが公知であるFOXP3の発現に関与する遺伝子であってよい。
・TCR、PD1、およびLAG3;
・TCR、PD1、およびFOXP3;
・TCR、CTLA4、およびLAG3;
・TCR、CTLA4、およびFOXP3
をコードする遺伝子への遺伝子編集を組み合わせた免疫細胞の生成、
ならびにさらにより好ましくは、少なくとも
・TCR、β2m、およびPD1
・TCR、β2m、およびCTLA4
・TCR、β2m、およびLAG3
・TCR、β2m、およびFOXP3
をコードする遺伝子への遺伝子編集段階を組み合わせた免疫細胞の生成が優先される。
本発明の別の局面によると、遺伝子編集段階は、抑制性サイトカインまたはその代謝物もしくは受容体をコードするかまたは正に調節する遺伝子、具体的にはTGFβ (Uniprot P01137)、IL10R (Uniprot Q13651および/またはQ08334)、A2aR (Uniprot P29274)、GCN2 (Uniprot P15442)、ならびにPRDM1 (Uniprot O75626) に関わる。
・TCR、PD1、およびTGFβ;
・TCR、CTLA4、およびTGFβ;
・TCR、PD1、およびIL10R;
・TCR、CTLA4、およびIL10R;
・TCR、PD1、およびTGFβ;
・TCR、CTLA4、およびTGFβ;
・TCR、PD1、およびGCN2;
・TCR、CTLA4、およびGCN2;
・TCR、PD1、およびA2aR;
・TCR、CTLA4、およびA2aR;
・TCR、PD1、およびPRDM1;
・TCR、CTLA4、およびPRDM1
をコードする遺伝子への遺伝子編集を組み合わせた免疫細胞の生成が優先される。
本方法の好ましい態様として、1つの遺伝子編集段階は、化学療法において通常用いられる薬物プリンヌクレオチド類似体 (PNA) または6-メルカプトプリン (6MP) および 6チオグアニン (6TG) などの、がんまたは感染症の標準治療処置で用いられる化合物に対する免疫細胞の感受性を担う遺伝子座について行われる。そのような化合物の作用様式に関与する遺伝子(「薬剤感作遺伝子」と称される)の減少または不活性化によって、該化合物に対する免疫細胞の耐性が改善される。
・TCR;β2m;DCK;
・TCR;PD1;DCK;
・TCR、CTLA4、DCK;
・TCR、LAG3、DCK
の発現を減少させるかまたは不活性化するために改変された遺伝子座を有する。
本発明の別の局面によると、操作免疫細胞は、グルココルチコイドまたは免疫細胞表面タンパク質に対する抗体を含むような免疫枯渇処置に対して耐性にされる。一例として、抗体アレムツズマブは、多くの事前がん処置におけるように、CD52陽性免疫細胞を枯渇するために用いられる。
前述されたように、本方法によって、免疫初代細胞のその後の増大に及ぼす遺伝子編集段階の影響を限定する時間枠内で、すなわち生成収率を顕著に減少させることなく、これらの細胞に連続的遺伝子編集改変を導入することが可能になる。
・[抗X CAR]陽性 (+またはpos) [X] 陽性 (+またはpos)
この場合、Xは、例えば表4中に列挙される抗原のいずれかであってよい。
・第1の遺伝子編集段階を行って、表面分子Xの発現を不活性化する;
・好ましくはウイルス形質導入によって、該表面分子Xを標的とするCARを発現させる;および
・第2の遺伝子編集段階を行って、TCRの発現を不活性化する;
・任意に、第3の遺伝子編集段階を行って、PD1またはCTLA4などの免疫チェックポイント遺伝子の発現を不活性化する。
遺伝子改変の前であるか後であるかにかかわらず、たとえ本発明による免疫細胞が抗原結合機構とは独立して活性化または増殖することができるとしても、それらを活性化または増大させることができる。T細胞は具体的には、例えば米国特許第6,352,694号;第6,534,055号;第6,905,680号;第6,692,964号;第5,858,358号;第6,887,466号;第6,905,681号;第7,144,575号;第7,067,318号;第7,172,869号;第7,232,566号;第7,175,843号;第5,883,223号;第6,905,874号;第6,797,514号;第6,867,041号;および米国特許出願公開第20060121005号に記載される方法を用いて、活性化および増大させることができる。T細胞は、インビトロまたはインビボで増大させることができる。T細胞は概して、CD3 TCR複合体およびT細胞の表面上にある共刺激分子を刺激してT細胞に対する活性化シグナルを生じる薬剤と接触させることによって、増大させる。例えば、カルシウムイオノフォアA23187、ホルボール12-ミリステート13-アセテート(PMA)、またはフィトヘムアグルチニン (PHA) のような***促進レクチンなどの化学物質を、T細胞に対する活性化シグナルの生成に使用することができる。
上記の本発明の方法により、操作された初代免疫細胞を、それらが特にその細胞傷害活性に関して完全な免疫治療可能性を維持するように、約15〜30日、好ましくは15〜20日、および最も好ましくは18〜20日という限定された時間枠内で生成することが可能になる。
(a) 患者の腫瘍生検試料の表面に存在する特異的抗原マーカーを決定する段階;
(b) 先に記載された本発明の方法の1つによって操作された、該特異的抗原マーカーに対するCARを発現する、操作された初代免疫細胞の集団を提供する段階;
(c) 操作された初代免疫細胞の該操作された集団を該患者に投与する段階。
本発明は、先行技術の方法によって得られ得なかった、本明細書において説明されるもののいずれをも含む、治療用途に現在利用可能である二重、三重、または四重遺伝子編集細胞の全範囲を包含する。特に、そのような細胞は、異なる遺伝子編集座位における望ましくない組換えまたは転座のリスクを減らして操作され、それらの細胞は治療用途のためにより安全なものとなる。
・TCR陰性かつPD1陰性、
・TCR陰性かつCD52陰性、
・TCR陰性かつCTLA4陰性、
・TCR陰性かつdCK陰性、
・TCR陰性かつGR陰性、
・TCR陰性かつGGH陰性、
・TCR陰性かつHPRT陰性、
・TCR陰性かつβ2m陰性
より選択され得る。
ポリペプチド配列中のアミノ酸残基は、本明細書では1文字コードに従って指定され、例えば、QはGlnまたはグルタミン残基を意味し、RはArgまたはアルギニン残基を意味し、およびDはAspまたはアスパラギン酸残基を意味する。
・ヒトTCRα鎖定常領域細胞外配列のN末端に融合されたヒトTCRα鎖可変領域配列によって構成されるαセグメント、
・ヒトTCRβ鎖定常領域細胞外配列のN末端に融合されたヒトTCRβ鎖可変領域配列によって構成されるβセグメント、および
・αセグメントのC末端をβセグメントのN末端にまたはその逆に連結するリンカー配列
を含み、αセグメントおよびβセグメントの定常領域細胞外配列はジスルフィド結合によって連結され、リンカー配列の長さおよびジスルフィド結合の位置は、αセグメントおよびβセグメントの可変領域配列が天然のαβT細胞受容体中と実質的に同様に相互に配向するような長さまたは位置である。
TALE-ヌクレアーゼ試薬の逐次エレクトロポレーションがT細胞の全体的な生存および遺伝子ノックアウト効率に及ぼす影響を解析するために、本発明者らは、以下の実験手順に従って、単一ドナー試料からの活性化初代ヒトT細胞を、TRAC遺伝子(TCRα鎖)に特異的なTALEN(登録商標)試薬(Cellectis、Paris, France)を用いることによるエレクトロポレーションに提示した。本実験で用いられる様々なTALEN(登録商標)ヘテロ二量体のアミノ酸配列を表3に示す。
Poirotら (Multiplex Genome-Edited T-cell Manufacturing Platform for “Off-the-Shelf” Adoptive T-cell Immunotherapies (2015) Cancer Res. 75: 3853-64) において、同時遺伝子ノックアウトを行うためには、2つのTALE-ヌクレアーゼヘテロ二量体の同時エレクトロポレーションが高効率であることが見出された。しかしながら、オフサイト切断または転座などの望ましくない事象が場合によって起こることが見出された。例えば、TRAC TALEN(登録商標)をコードするmRNAおよびPD1 TALEN(登録商標)をコードするmRNAの同時トランスフェクションにより、TRAC TALEN左アームとPD1 TALEN左アームとの対形成に起因して、オフサイト切断活性が生じる。オフサイト切断(およびオンサイト切断)の頻度は、エンドヌクレアーゼ切断および切断末端の忠実でない再連結の後に生成される変異配列(ヌクレオチドの欠失または付加のいずれか)の頻度によって規定される。本実験で用いられる、TRAC(SEQ ID NO.1および2)ならびにPD1(SEQ ID NO. 5および6)に関する様々なTALEN(登録商標)ヘテロ二量体をコードするアミノ酸配列を表3に示す。
逐次TALENエレクトロポレーションがT細胞の全体的な生存および遺伝子ノックアウト効率に及ぼす影響を解析するために、本発明者らは、以下の実験手順に従って、活性化ヒトT細胞に、TRAC遺伝子(TCRα鎖)、CD52、およびCD38に特異的なTALEN(アミノ酸配列を表3に示す)をトランスフェクトした。
CD22抗原に対するCARが付与された[TCR]neg[PD1]neg[B2M]neg治療用免疫細胞を生成するために、実施例1に記載されるように、T細胞をPBMCから培養し活性化した。
Claims (28)
- 初代免疫細胞の異なる複数の遺伝子座において遺伝子改変を導入するための方法であって、
(a)該初代免疫細胞を第1のエレクトロポレーション段階に供して、少なくとも第1の配列特異的試薬を該免疫細胞に導入する段階、
(b)該初代免疫細胞を培養し、それによって該第1の配列特異的試薬が第1の遺伝子座においてそのゲノムを改変できるようにする段階、
(c)該初代免疫を少なくとも第2のエレクトロポレーション段階に供して、少なくとも第2の配列特異的試薬を該細胞に導入する段階、
(d)該初代免疫を培養しかつ増大させ、それによって該第2の配列特異的試薬が該第2の遺伝子座においてそのゲノムを改変できるようにする段階
の逐次段階を含む、方法。 - 前記初代免疫細胞が、段階(b)において12〜72時間、好ましくは24〜48時間培養される、請求項1記載の方法。
- 少なくとも前記第1の遺伝子座において改変された遺伝子の発現または欠失によって生じた産物に依存して、精製段階が、段階(b)と(c)の間に行われる、請求項1記載の方法。
- 段階(a)〜(d)が240時間以内に、好ましくは120時間以内に、より好ましくは96時間以内に、さらにより好ましくは72時間以内に行われる、請求項1〜3のいずれか一項記載の方法。
- 前記初代免疫細胞を第3のエレクトロポレーション段階に移して、少なくとも第3の配列特異的試薬を該細胞に導入する、少なくとも1つのさらなる段階
を含む、請求項1〜4のいずれか一項記載の方法。 - 第1および/または第2の配列特異的試薬が、レアカットエンドヌクレアーゼ、そのサブユニットをコードするポリヌクレオチドもしくはポリペプチド、またはポリヌクレオチドおよびポリペプチドの両方の複合物である、請求項1記載の方法。
- 第1および/または第2の配列特異的試薬が、プログラム可能なRNAもしくはDNAガイドエンドヌクレアーゼ、TALEN、ZFN、megaTAL、またはホーミングエンドヌクレアーゼより選択されるレアカットエンドヌクレアーゼをコードするポリヌクレオチドまたはポリペプチドである、請求項2記載の方法。
- 第1および/または第2の配列特異的試薬が、RNAガイドとCas9またはCpf1ポリペプチドの複合物である、請求項3記載の方法。
- 第1および/または第2の配列特異的試薬が、干渉RNA (RNAi) またはそれをコードするポリヌクレオチドである、請求項1記載の方法。
- 形質導入段階が、ウイルスベクターと共に(b)と(c)の間に導入される、請求項1記載の方法。
- 形質導入段階が、導入遺伝子の安定発現のための組込みレンチウイルスまたはレトロウイルスベクターを含む、請求項10記載の方法。
- 導入遺伝子がキメラ抗原受容体 (CAR) をコードする、請求項11記載の方法。
- 形質導入段階が非組込みウイルスベクターを含む、請求項10記載の方法。
- 非組込みウイルスベクターが、免疫細胞のゲノム中に前記導入遺伝子を相同組換えまたはNHEJ組込みするための鋳型として用いられる、請求項13記載の方法。
- 第1の配列特異的試薬が、形質導入段階を促進するゲノム配列に作用する、請求項10記載の方法。
- 第1の配列特異的試薬が、段階(d)の遺伝子改変を促進するゲノム配列に作用する、請求項1〜15のいずれか一項記載の方法。
- 段階(b)が35℃未満、好ましくは約30℃で行われる、請求項1〜16のいずれか一項記載の方法。
- 免疫細胞がT細胞である、請求項1〜17のいずれか一項記載の方法。
- 初代T細胞をシグナル伝達によって活性化する予備段階を含む、請求項18記載の方法。
- 第1の配列特異的試薬が、初代T細胞によるTCRの発現を永続的に減少させるかまたは妨げる、請求項18または19記載の方法。
- 第1または第2の配列特異的試薬が、免疫チェックポイントをコードする少なくとも1つの遺伝子の発現を永続的に減少させるかまたは妨げる、請求項1〜20のいずれか一項記載の方法。
- 免疫チェックポイントをコードする少なくとも1つの遺伝子が、PD1、CTLA4、PPP2CA、PPP2CB、PTPN6、PTPN22、PDCD1、LAG3、HAVCR2、BTLA、CD160、TIGIT、CD96、CRTAM、LAIR1、SIGLEC7、SIGLEC9、CD244、TNFRSF10B、TNFRSF10A、CASP8、CASP10、CASP3、CASP6、CASP7、FADD、FAS、TGFBRII、TGFRBRI、SMAD2、SMAD3、SMAD4、SMAD10、SKI、SKIL、TGIF1、IL10RA、IL10RB、HMOX2、IL6R、IL6ST、EIF2AK4、CSK、PAG1、SIT1、FOXP3、PRDM1、BATF、GUCY1A2、GUCY1A3、GUCY1B2、GUCY1B3より選択される、請求項21記載の方法。
- 第1または第2の配列特異的試薬が、薬物または免疫枯渇剤に対する前記初代免疫細胞の耐性を永続的に与える、請求項1〜20のいずれか一項記載の方法。
- CD52、dCK、GGH、またはHPRTを発現する遺伝子を不活性化することによって、前記耐性が与えられる、請求項23記載の方法。
- 前記第1および/または第2および/または第3の遺伝子座において改変された1つの遺伝子の発現または欠失によって生じた少なくとも1つの産物に依存して、精製の最終段階が行われる、請求項1〜24のいずれか一項記載の方法。
- ・TCR陰性かつPD1陰性、
・TCR陰性かつCD52陰性、
・TCR陰性かつCTLA4陰性、
・TCR陰性かつdCK陰性、
・TCR陰性かつGGH陰性、
・TCR陰性かつHPRT陰性、および
・TCR陰性かつβ2m陰性
より選択されるT細胞の少なくとも2つの亜集団を含む、請求項1〜25のいずれか一項記載の方法に従って得ることができる、単一ドナーに由来する初代TCR陰性T細胞の集団。 - 単一ドナーに由来する初代TCR陰性T細胞の集団であって、該集団中の細胞の少なくとも20%、好ましくは30%、より好ましくは50%が、少なくとも3つの異なる遺伝子座において、配列特異的試薬を用いて改変されている、集団。
- 請求項26または27のいずれか一項記載の初代T細胞の集団を含む、薬学的組成物。
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