JP2021530999A - 免疫改変多能性幹細胞由来のキメラ抗原受容体t細胞 - Google Patents
免疫改変多能性幹細胞由来のキメラ抗原受容体t細胞 Download PDFInfo
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Abstract
Description
本願は、その全体において本明細書中で参照により組み込まれる2018年7月17日提出の第62/698,941号明細書に対する優先権を主張する。
本発明は、本明細書中で概説するようないくつかの遺伝子操作ゆえに宿主免疫反応を回避する低免疫原性多能性(「HIP」)細胞を提供する。本細胞は、免疫応答を惹起する主要免疫抗原を欠き、食作用を回避するように改変される。これにより、特異的な組織及び臓器を生成させるための「容易に入手可能な」細胞生成物の誘導が可能になる。ヒト患者においてヒト同種HIP細胞派生物を使用可能であることの利点により、一般に同種移植で見られる長期の補助免疫抑制療法及び薬物使用を回避することができるようになることを含め、顕著な有益性が得られる。細胞療法は、各患者に対する個々の処置を必要とせずに使用し得るので、コストも顕著に削減される。近年、自己細胞源から作製された細胞生成物が、僅か数個又はさらには1個の抗原性突然変異で免疫拒絶に対する対象になり得ることが示された。従って、自己細胞生成物は本質的に非免疫原性ではない。また、細胞改変及び品質管理は非常に重労働でコスト集約的であり、自己細胞は急性治療の選択肢としては利用可能ではない。免疫ハードルが克服され得る場合、同種細胞生成物のみが、より大きい患者集団に対して使用可能である。HIP細胞は、普遍的に許容可能な派生物の作製のための普遍的な細胞供給源となる。
「多能性細胞」という用語は、未分化状態に留まりながら自己更新及び増殖し得、適正な条件下で特別な細胞タイプに分化するように誘導され得る細胞を指す。「多能性細胞」という用語は、本明細書中で使用される場合、胚性幹細胞及び、胎児、羊膜又は体細胞の幹細胞を含め、他のタイプの幹細胞を包含する。代表的なヒト幹細胞株はH9ヒト胚性幹細胞株を含む。さらなる代表的な幹細胞株は、National Institutes of Health Human Embryonic Stem Cell Registry and the Howard Hughes Medical Institute HUES collection(その全体において本明細書中で参照により組み込まれるCowan,C.A.et.al,New England J.Med.350:13.(2004)に記載のとおり)を通じて利用可能にされるものを含む。
本発明は、HIP細胞を作製し、野生型細胞を用いて開始し、それらを多能性にし(例えば誘導多能性幹細胞又はiPSCを作製)、次いでiPSC集団からHIP細胞を作製するための、組成物及び方法を提供する。
本発明は、多能性細胞及びHIP細胞の両方を作製するために細胞内又は無細胞条件下で核酸配列を修飾する方法を含む。代表的な技術としては、相同組み換え、ノックイン、ZFN(ジンクフィンガーヌクレアーゼ)、TALEN(転写活性化因子様エフェクターヌクレアーゼ)、メガヌクレアーゼ(例えばホーミングエンドヌクレアーゼ)、CRISPR(クラスター化された規則的配置の短回文配列リピート(clustered regularly interspaced short palindromic repeats))/Cas9及び他の部位特異的なヌクレアーゼ技術が挙げられる。これらの技術により、所望の遺伝子座部位での2本鎖DNA破壊が可能になる。これらの制御された2本鎖破壊は、特異的な遺伝子座部位で相同組み換えを促進する。この工程は、配列を認識し結合するエンドヌクレアーゼでの、染色体など、核酸分子の特異的な配列を標的とすることに焦点を当て、核酸分子での2本鎖破壊を誘導する。2本鎖破壊は、エラープローン非相同末端結合(NHEJ)又は相同組み換え(HR)の何れかにより修復される。
一実施形態では、当技術分野で公知のように、クラスター化された規則的配置の短回文配列リピート(Clustered regularly interspaced short palindromic repeats)/Cas(「CRISPR」)技術を使用して、細胞を操作する。開始iPSCを作製するため又はiPSCからHIP細胞を作製するために、CRISPR/Casを使用し得る。CRISPR/Casに基づく多数の技術があり、例えば参照により本明細書によって組み込まれるDoudna and Charpentier,Science doi:10.1126/science.1258096を参照。CRISPR技術及びキットは市販されている。
一部の実施形態では、本発明のHIP細胞は、転写活性化因子様エフェクターヌクレアーゼ(TALEN)法を使用して作製される。TALENは、実際に何らかの所望のDNA配列に結合し、切断するように改変され得るヌクレアーゼと組み合わせられた制限酵素である。TALENキットは市販されている。
一実施形態では、Znフィンガーヌクレアーゼ技術を使用して細胞を操作する。Znフィンガーヌクレアーゼは、ジンクフィンガーDNA結合ドメインをDNA切断ドメインに融合させることにより作製される人工的制限酵素である。ジンクフィンガードメインは特異的な所望のDNA配列を標的とするために改変され得、これにより、ジンクフィンガーヌクレアーゼが複雑なゲノム内でユニークな配列を標的とすることが可能になる。内在性DNA修復機構の長所により、CRISPR及びTALENと同様に、より高等な生物のゲノムを適正に改変するためにこれらの試薬を使用し得る。
レトロウイルスベクター、レンチウイルスベクター、アデノウイルスベクター及びセンダイウイルスベクターの使用を含むが限定されない、本発明のHIP細胞を作製するために(並びにiPSCのオリジナル作製(original generation)のため)使用し得る多岐にわたるウイルス技術がある。iPSCの作製において使用されるエピソームベクターを下で記載する。
他の実施形態では、HLA分子で使用されるタンパク質をコードする遺伝子は、RNA干渉(RNAi)技術により下方制御される。RNAiは、しばしば特異的なmRNA分子の分解を引き起こすことにより、RNA分子が遺伝子発現を阻害する過程を指す。2つのタイプのRNA分子−マイクロRNA(miRNA)及び低分子干渉RNA(siRNA)−がRNA干渉のために使用され得る。これらは、標的mRNA分子に結合し、それらの活性を上昇又は低下させる。RNAiは、ウイルス及びトランスポゾン由来のものなどの寄生性の核酸に対する細胞防御を助ける。RNAiは発生にも影響を与える。
本発明は、多能性細胞から非免疫原性多能性細胞を作製する方法を提供する。従って、第1段階は多能性幹細胞を提供することである。
本発明は、本明細書中で定められるように、患者への低免疫原性細胞の作製、操作、増殖及び移植を対象とする。多能性細胞からのHIP細胞の作製は3個という少ない遺伝子変化により行われ、その結果、細胞活性の破壊が最小限となるが、細胞に対して免疫サイレンシングを与える。
本発明のHIP細胞は、MHCI機能(細胞がヒト細胞由来である場合はHLA I)の低下を含む。
一実施形態では、多能性幹細胞、本明細書中で開示されるヒト配列、におけるHLA−I活性の低下は、β−2ミクログロブリン遺伝子の発現を破壊することにより行われる。この変化は一般に本明細書中で、遺伝子「ノックアウト」と呼び、本発明のHIP細胞において、これは宿主細胞において両アレル上で行われる。一般に、両破壊を行うための技術は同じである。
HLA Iの低下に加えて、本発明のHIP細胞は、MHC II機能(細胞がヒト由来の場合はHLA II)も欠く。
一実施形態では、HLA−II活性の低下は、多能性幹細胞においてCIITA遺伝子の発現を破壊することにより行われ、そのヒト配列は本明細書中で示す。この変化は一般に、本明細書中で遺伝子「ノックアウト」と呼ばれ、本発明のHIP細胞において、宿主細胞中の両アレル上で行われる。
HLA I及びII(又はMHC I及びII)の減少に加えて、一般的にはB2M及びCIITAノックアウトを使用して、本発明のHIP細胞は、マクロファージ食作用及びNK細胞殺傷に対する感受性が低下している。得られたHIP細胞は、1つ以上のCD47トランス遺伝子の発現により、免疫マクロファージ及び自然経路を「回避する」。
一部の実施形態では、マクロファージ食作用及びNK細胞殺傷感受性の低下は、HIP細胞表面上でのCD47上昇によるものである。これは、「ノックイン」又はトランスジェニック技術を使用して当業者により認められるように、いくつかの方法で行われる。一部の例では、CD47発現上昇は、1つ以上のCD47導入遺伝子によるものである。
一部の実施形態では、本発明は、「自殺遺伝子」又は「自殺スイッチ」を含む低免疫原性多能性細胞を提供する。これらは、望ましくない方式で増殖し、***する場合に低免疫原性多能性細胞の死を引き起こし得る「安全スイッチ」として機能するように組み込まれる。「自殺遺伝子」消失アプローチは、特異的な化合物により活性化された場合のみ細胞死滅を引き起こすタンパク質をコードする遺伝子移入ベクターにおいて自殺遺伝子を含む。自殺遺伝子は、選択的に無毒性化合物を強毒性代謝産物に変換する酵素をコードし得る。この結果は、酵素を発現する細胞を特異的に除去している。一部の実施形態では、自殺遺伝子はヘルペスウイルスチミジンキナーゼ(HSV−tk)遺伝子であり、トリガーはガンシクロビルである。他の実施形態では、自殺遺伝子はエシェリキア・コリ(Escherichia coli)シトシンデアミナーゼ(EC−CD)遺伝子であり、トリガーは5−フルオロシトシン(5−FC)である(両者ともそれらの全体において参照により本明細書中で組み込まれる、Barese et al.,Mol.Therap.20(10):1932−1943(2012),Xu et al.,Cell Res.8:73−8(1998))。
HIP細胞が作製されたら、一般に本明細書中に及び実施例に記載のように、これらをそれらの低免疫原性及び/又は多能性保持についてアッセイし得る。
HIP細胞として又はHIP細胞の分化産物としての何れかでヒト患者などの同種宿主に移植された場合に多能性を示すが宿主免疫応答を生じさせない低免疫原性多能性幹細胞(「HIP細胞」)が本明細書中で提供される。
作製されたら、iPSCの維持のために知られているようにHIP細胞を未分化状態に維持し得る。例えば分化を防ぎ、多能性を維持する培地を使用してマトリゲル上でHIP細胞を培養する。
本明細書中に記載のHIP細胞を様々な細胞タイプに分化させ得る。HIPの多能性は、細胞を内胚葉、中胚葉及び外胚葉細胞タイプに分化させることにより評価され得る。一部の例では、HIP細胞は奇形腫形成により評価される。
本発明は、抗原結合ドメイン、膜貫通ドメイン及び細胞内シグナル伝達ドメインを含むCARをコードする核酸を含むHIP細胞から分化させられた改変T細胞を提供する。一部の実施形態では、CARは、抗原結合ドメイン、膜貫通ドメイン及び同時刺激ドメインの細胞内シグナル伝達ドメインを含む。本発明の別の態様では、抗原結合ドメイン、膜貫通ドメイン及び細胞内シグナル伝達ドメインを含むCARをコードする核酸を含む低免疫原性多能性細胞が本明細書中で提供される。低免疫原性CAR−T(HI−CAR−T)細胞を作製するために、このような低免疫原性多能性細胞をインビトロでT細胞に分化させ得る。
様々な実施形態では、本抗原結合ドメインは、標的細胞、例えば癌細胞上の抗原に結合する。抗原結合ドメイン(細胞外ドメインとも呼ばれる)は、当技術分野で公知のように抗原に結合し得る。一部の実施形態では、抗原結合ドメインは、モノクローナル抗体、ポリクローナル抗体、合成抗体、ヒト抗体、ヒト化抗体、非ヒト抗体、ナノボディ、1本鎖可変断片(scFv)、F(ab’)2、Fab’、Fab、Fvなどを含む。
当業者により認識される何れかの方法を使用して、CARをコードする核酸を含むHIP細胞をCAR T細胞などのCAR発現免疫細胞に分化させ得る。
一部の態様では、治療的有効量のHIP細胞由来CAR−T細胞を投与することにより、患者、例えばヒト患者における癌を処置する方法が本明細書中で提供される。一部の例では、HIP細胞由来CAR−T細胞は、治療的に有効な担体とともに投与される。
一部の実施形態では、本発明のマウス低免疫原性多能性幹(マウスHIP)細胞は、B2M活性を排除するゲノム修飾、CIITA活性を排除するゲノム修飾、CD47をコードする外因性核酸配列及びCARコンストラクトをコードする外因性核酸配列を含む。他の実施形態では、マウス低免疫原性多能性幹細胞は誘導性自殺遺伝子も含む。
実施例1:マウス誘導多能性幹細胞の作製
本明細書中に記載の方法の出典はDiecke et al.,Sci Rep,2015,8081である。
Gibco(商標)ヒトエピソームiPSC株(カタログ番号A18945、ThermoFisher)は、3プラスミド、7因子(SOKMNLT;SOX2、OCT4(POU5F1)、KLF4、MYC、NANOG、LIN28及びSV40L T抗原)EBNAに基づくエピソーム系を使用して、CD34+臍帯血から得た。このiPSC株は、初期化事象からのゲノムへの組み込みがなかったので、ゼロフットプリント(zero foot−print)であるとみなされる。全ての初期化遺伝子不含であることが示された。ヒトiPSCを凍結融解し、培養し、継代するためのプロトコールは製品マニュアルで提供される。
低免疫原性多能性細胞(例えばマウスb2m−/−ciita−/−CD47tg iPSC及びヒトB2M−/−CIITA−/−CD47tg iPSC)の能力及び免疫自然応答経路を逃れるための能力を評価するために、実施例を行った。
この実施例は、CD8+低、CD8+高、CD4+、CD4+/CD8+高及びCD4+/CD8+低T細胞を含むT細胞にHIP細胞(例えばマウスHIP細胞及びヒトHIP細胞)を分化させたことを示す。この実施例はまた、分化を様々なT細胞サブタイプに向けるために刺激性シグナル及びサイトカインを使用したことも示す。ナイーブCD4+T細胞の数を増加させ、セントラルメモリーCD4+T細胞の数を減少させるために、HIP由来EPCなどの内皮祖先細胞(EPC)を使用したことが示された。この実施例はまた、擬似微小重力(sμg)刺激のみ又はサイトカイン(例えばIL−2、IL−7又はIL−2及びIL−2の組み合わせ)との組み合わせがセントラルメモリーCD8+T細胞へのHIP由来T細胞の分化を誘導したことも示す。
Claims (58)
- キメラ抗原受容体(CAR)をコードする核酸を含む単離低免疫原性誘導多能性幹(HIP)細胞であって、
内在性β−2ミクログロブリン(B2M)遺伝子活性及び内在性クラスIIトランス活性化因子(CIITA)遺伝子活性が排除され、CD47発現が上昇している、単離低免疫原性誘導多能性幹(HIP)細胞。 - 前記CARが細胞外ドメイン、膜貫通ドメイン及び細胞内シグナル伝達ドメインを含む、請求項1に記載の単離HIP細胞。
- 前記細胞外ドメインが、CD19、CD20、CD22、CD38、CD123、CD171、CS1、BCMA、MUC16、ROR1及びWT1からなる群から選択される抗原に結合する、請求項2に記載の単離HIP細胞。
- 前記細胞外ドメインが1本鎖可変断片(scFv)を含む、請求項2又は3に記載の単離HIP細胞。
- 前記膜貫通ドメインが、CD3ζ、CD4、CD8α、CD28、4−1BB、OX40、ICOS、CTLA−4、PD−1、LAG−3及びBTLAを含む、請求項2〜4の何れか1項に記載の単離HIP細胞。
- 前記細胞内シグナル伝達ドメインが、CD3ζ、CD28、4−1BB、OX40、ICOS、CTLA−4、PD−1、LAG−3及びBTLAを含む、請求項2〜5の何れか1項に記載の単離HIP細胞。
- B2M遺伝子活性及びCIITA遺伝子が排除され、CD47発現が上昇した後、前記CARをコードする核酸がiPSCに導入される、請求項2〜6の何れか1項に記載の単離HIP細胞。
- 前記HIP細胞がヒト誘導多能性幹細胞であり、前記B2M遺伝子がヒトB2M遺伝子であり、前記CIITA遺伝子がヒトB2M遺伝子であり、前記CD47発現上昇が、プロモーターの制御下でヒトCD47遺伝子の少なくとも1コピーを前記iPSCに導入した結果である、請求項1〜7の何れか1項に記載の単離HIP細胞。
- 前記HIP細胞がマウス誘導多能性幹細胞であり、前記B2M遺伝子がマウスB2M遺伝子であり、前記CIITA遺伝子がマウスB2M遺伝子であり、前記CD47発現上昇が、プロモーターの制御下でマウスCD47遺伝子の少なくとも1コピーを前記iPSCに導入した結果である、請求項1〜7の何れか1項に記載の単離HIP細胞。
- 前記プロモーターが構成的プロモーターである、請求項8又は9に記載の単離HIP細胞。
- B2M遺伝子活性の前記排除が、前記B2M遺伝子の両アレルを破壊するクラスター化された規則的配置の短回文配列リピート(CRISPR)/Cas9反応の結果である、請求項1〜10の何れか1項に記載の単離HIP細胞。
- CIITA遺伝子活性の前記排除が、前記CIITA遺伝子の両アレルを破壊するCRISPR/Cas9反応の結果である、請求項1〜11の何れか1項に記載の単離HIP細胞。
- 前記低免疫原性多能性細胞を死に誘導するトリガー物質により活性化される自殺遺伝子をさらに含む、請求項1〜12の何れか1項に記載の単離HIP細胞。
- 前記自殺遺伝子が単純ヘルペスウイルスチミジンキナーゼ(HSV−tk)遺伝子であり、前記トリガー物質がガンシクロビルである、請求項13に記載の単離HIP細胞。
- 前記HSV−tk遺伝子が、配列番号4に対して少なくとも90%の配列同一性を含むタンパク質をコードする、請求項14に記載の単離HIP細胞。
- 前記HSV−tk遺伝子が、配列番号4のアミノ酸配列を含むタンパク質をコードする、請求項14に記載の単離HIP細胞。
- 前記自殺遺伝子がエシェリキア・コリ(Escherichia coli)シトシンデアミナーゼ(CD)遺伝子であり、前記トリガー物質が5−フルオロシトシン(5−FC)である、請求項13に記載の単離HIP細胞。
- 前記CD遺伝子が、配列番号5に対して少なくとも90%の配列同一性を含むタンパク質をコードする、請求項17に記載の単離HIP細胞。
- 前記CD遺伝子が、配列番号5のアミノ酸配列を含むタンパク質をコードする、請求項17に記載の単離HIP細胞。
- 前記自殺遺伝子が誘導型カスパーゼ9タンパク質をコードし、前記トリガー物質が二量体誘導化合物(CID)である、請求項13に記載の単離HIP細胞。
- 前記誘導型カスパーゼ9タンパク質が、配列番号6に対して少なくとも90%の配列同一性を含む、請求項20に記載の単離HIP細胞。
- 前記誘導型カスパーゼ9タンパク質が、配列番号6のアミノ酸配列を含む、請求項20に記載の単離HIP細胞。
- 前記CIDが化合物AP1903である、請求項20〜22の何れか1項に記載の単離HIP細胞。
- 請求項1〜23の何れか1項に記載のHIP細胞のインビトロ分化により作製される単離低免疫CAR−T細胞。
- 前記CAR−T細胞が低免疫細胞傷害性CAR−T細胞である、請求項24に記載の単離低免疫CAR−T細胞。
- 前記インビトロ分化が、bFGF、EPO、Flt3L、IGF、IL−2、IL−3、IL−6、IL−7、IL−15、GM−CSF、SCF及びVEGFからなる群から選択される1つ以上の増殖因子又はサイトカインを含む培地中で前記HIP細胞を培養することを含む、請求項24又は25に記載の単離低免疫CAR−T細胞。
- 前記培地が、BMP活性化因子、GSK3阻害剤、ROCK阻害剤、TGFβ受容体/ALK阻害剤及びNOTCH活性化因子からなる群から選択される1つ以上をさらに含む、請求項24〜26の何れか1項に記載の単離低免疫CAR−T細胞。
- 前記インビトロ分化が、前記HIP細胞をフィーダー細胞上で培養することを含む、請求項24〜27の何れか1項に記載の単離低免疫CAR−T細胞。
- 前記インビトロ分化が、擬似微小重力中で培養することを含む、請求項24〜28の何れか1項に記載の単離低免疫CAR−T細胞。
- 擬似微小重力中での前記培養が少なくとも72時間にわたる、請求項29に記載の単離低免疫CAR−T細胞。
- 癌の処置としての使用のための、請求項24〜30の何れか1項に記載の単離低免疫CAR−T細胞。
- 請求項24〜27の何れか1項に記載の単離低免疫CAR−T細胞の治療的有効量を含む組成物を投与することによって癌患者を処置する方法。
- 前記組成物が治療的に有効な担体をさらに含む、請求項32に記載の方法。
- 前記投与が、静脈内投与、皮下投与、リンパ節内投与、腫瘍内投与、くも膜下腔内投与、胸膜内投与及び腹腔内投与を含む、請求項32又は33に記載の方法。
- 前記投与が、ボーラス又は連続点滴によるものをさらに含む、請求項32〜34の何れか1項に記載の方法。
- 前記癌が、白血病、リンパ腫及び骨髄腫からなる群から選択される血液癌である、請求項32〜35の何れか1項に記載の方法。
- 前記癌が、固形腫瘍癌又は液性腫瘍癌である、請求項32〜35の何れか1項に記載の方法。
- インビトロ分化を含む方法による単離HIP細胞集団由来の低免疫CAR−T細胞の純粋集団であって、
前記単離HIP細胞が、キメラ抗原受容体(CAR)をコードする核酸及び前記HIP細胞を死に誘導し得るトリガー物質により活性化される自殺遺伝子を含み、
前記HIP細胞において、内在性β−2ミクログロブリン(B2M)遺伝子活性及び内在性クラスIIトランス活性化因子(CIITA)遺伝子活性が排除され、CD47発現が上昇している、低免疫CAR−T細胞の純粋集団。 - 前記自殺遺伝子が単純ヘルペスウイルスチミジンキナーゼ(HSV−tk)遺伝子であり、前記トリガー物質がガンシクロビルであるか、前記自殺遺伝子がエスケリキア・コリ(Escherichia coli)シトシンデアミナーゼ(CD)遺伝子であり、前記トリガー物質が5−フルオロシトシン(5−FC)であるか又は前記自殺遺伝子が誘導性カスパーゼ9タンパク質であり、前記トリガー物質が二量体誘導化合物(CID)である、請求項38に記載の単離低免疫CAR−T細胞の純粋集団。
- 前記CAR−T細胞が低免疫細胞傷害性CAR−T細胞である、請求項38又は39に記載の単離低免疫CAR−T細胞の純粋集団。
- 前記インビトロ分化が、bFGF、EPO、Flt3L、IGF、IL−2、IL−3、IL−6、IL−7、IL−15、GM−CSF、SCF及びVEGFからなる群から選択される1つ以上の増殖因子又はサイトカインを含む培地中で前記HIP細胞を培養することを含む、請求項38〜40の何れか1項に記載の単離低免疫CAR−T細胞の純粋集団。
- 前記培地が、BMP活性化因子、GSK3阻害剤、ROCK阻害剤、TGFβ受容体/ALK阻害剤及びNOTCH活性化因子からなる群から選択される1つ以上をさらに含む、請求項38〜41の何れか1項に記載の単離低免疫CAR−T細胞の純粋集団。
- 前記インビトロ分化が、フィーダー細胞上で前記HIP細胞を培養することを含む、請求項38〜42の何れか1項に記載の単離低免疫CAR−T細胞の純粋集団。
- 前記インビトロ分化が、擬似微小重力中で培養することを含む、請求項38〜43の何れか1項に記載の単離低免疫CAR−T細胞の純粋集団。
- 擬似微小重力中での前記培養が少なくとも72時間にわたる、請求項44に記載の単離低免疫CAR−T細胞の純粋集団。
- 前記方法が、前記HIP細胞を死に誘導するために前記トリガー物質を含む負の選択培地中で前記低免疫CAR−T細胞を培養し、それによって、実質的に低免疫原性iPSC不含であるか又は低免疫原性iPSC不含である単離低免疫CAR−T細胞集団を作製することをさらに含む、請求項38〜42の何れか1項に記載の単離低免疫CAR−T細胞の純粋集団。
- 請求項38〜46の何れか1項に記載の単離低免疫CAR−T細胞の純粋集団の治療的有効量を含む組成物を投与することによって癌患者を処置する方法。
- 前記組成物が、治療的に有効な担体をさらに含む、請求項47に記載の方法。
- 前記投与が、静脈内投与、皮下投与、リンパ節内投与、腫瘍内投与、くも膜下腔内投与、胸膜内投与及び腹腔内投与を含む、請求項47又は48に記載の方法。
- 前記投与がボーラス又は連続点滴によるものをさらに含む、請求項47〜49の何れか1項に記載の方法。
- 前記癌が、白血病、リンパ腫及び骨髄腫からなる群から選択される血液癌である、請求項47〜50の何れか1項に記載の方法。
- 前記癌が固形腫瘍癌又は液性腫瘍癌である、請求項47〜50の何れか1項に記載の方法。
- 請求項1〜23の何れか1項に記載のHIP細胞の何れか1つのインビトロ分化を含む請求項24〜27の何れか1項に記載の単離低免疫CAR−T細胞を作製する方法であって、インビトロ分化が、bFGF、EPO、Flt3L、IGF、IL−2、IL−3、IL−6、IL−7、IL−15、GM−CSF、SCF及びVEGFからなる群から選択される1つ以上の増殖因子又はサイトカインを含む培地中で前記HIP細胞を培養することを含む、方法。
- 前記培地が、BMP活性化因子、GSK3阻害剤、ROCK阻害剤、TGFβ受容体/ALK阻害剤及びNOTCH活性化因子からなる群から選択される1つ以上をさらに含む、請求項53に記載の方法。
- 前記インビトロ分化が、フィーダー細胞上で前記HIP細胞を培養することを含む、請求項53又は54に記載の方法。
- 前記インビトロ分化が、フィーダー細胞上で前記HIP細胞を培養することを含む、請求項53〜55の何れか1項に記載の方法。
- 前記インビトロ分化が、擬似微小重力中で培養することを含む、請求項53〜56の何れか1項に記載の方法。
- 擬似微小重力中での前記培養が少なくとも72時間にわたる、請求項57に記載の方法。
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CN112639081A (zh) | 2021-04-09 |
IL279854A (en) | 2021-03-01 |
EP3824075A1 (en) | 2021-05-26 |
EP3824075A4 (en) | 2022-04-20 |
WO2020018620A1 (en) | 2020-01-23 |
KR20210032449A (ko) | 2021-03-24 |
US20210308183A1 (en) | 2021-10-07 |
BR112021000639A2 (pt) | 2021-04-13 |
MX2021000607A (es) | 2021-06-23 |
AU2019305586A1 (en) | 2021-01-28 |
EA202190295A1 (ru) | 2021-06-11 |
CA3106022A1 (en) | 2020-01-23 |
SG11202100156UA (en) | 2021-02-25 |
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