TW201900870A - 製備和使用胚胎間充質先驅細胞的方法 - Google Patents
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Abstract
本揭示案提供了一種產生非聚集幹細胞的方法。中胚層分化之前的集群破壞增加hEMP和T細胞分化的產量和效率。因此,該方法允許開發改進的hEMP和T細胞分化方法。
Description
本發明係關於製備和使用胚胎間充質先驅細胞的方法。
人類癌症就其本質而言由正常細胞組成,這些細胞經歷了遺傳或表觀遺傳轉化而成為異常癌細胞。在此過程中,癌細胞開始表達與正常細胞表達的蛋白質和其他抗原不同的蛋白質和其他抗原。這些異常的腫瘤抗原可被人體免疫系統用於特異性靶向和殺死癌細胞。然而,癌細胞採用各種機制來阻止免疫細胞如T和B淋巴細胞成功靶向癌細胞。
目前的T細胞治療依賴於富集或修飾的人T細胞靶向並殺死患者的癌細胞。由於缺乏自我更新,患者或正常供體來源的T細胞本質上是有限的。從幹細胞源得到T細胞將提供用於治療用途的可能無限量的細胞來源。存在對於使多能幹細胞分化成胚胎中胚層先驅細胞和成熟T細胞的有效活體外方法的需要。
本發明尤其藉由提供產生人胚胎間充質先驅(hEMP)細胞、其衍生細胞以及使用該等細胞、衍生細胞來有效產生T細胞的改進方法來滿足這種需求。
在一個態樣,本揭示案提供了產生人胚胎間充質先驅(hEMP)細胞的方法,該方法包括以下步驟:以限定的單細胞密度使非聚集幹細胞與基質接觸;在促進細胞生長的培養條件下培養幹細胞至所需匯合;並修飾培養條件以誘導幹細胞分化成hEMP細胞達所需的溫育時間;從而產生hEMP細胞。
在一些實施例中,非聚集幹細胞是人胚胎幹(ES)細胞或誘導多能幹(iPS)細胞。在一些實施例中,ES或iPS細胞來源於人。
在一些實施例中,ES或iPS細胞是H1細胞、H9細胞、HES3細胞、HSF1細胞、HSF6細胞、ESI-017細胞、CS02iCTR-NTn1細胞、CS03iCTR-NTn1細胞、CS80iCTR-Tn3細胞、CS179iCTR-NTn1細胞、CS201iCTR-NTn4細胞、CS202iCTR-NTn2細胞或CS206iCTR-Tn5細胞。
在一些實施例中,限定的單細胞密度在約1.5×105
至約8×105
個細胞/cm2
之間。在某些實施例中,限定的單細胞密度為約1.89×105
個細胞/cm2
,約3.2×105
個細胞/cm2
,約3.4×105
個細胞/cm2
,約3.6×105
個細胞/cm2
,約3.79×105
個細胞/cm2
,約7.2×105
個細胞/cm2
或約7.58×105
個細胞/cm2
。
在一些實施例中,基質用Matrigel®
或重組人類玻連蛋白但不用小鼠胚胎纖維母細胞(MEF)包被。在一些實施例中,基質是孔板,細胞培養皿,膜,袋,培養瓶,反蛋白石,聚合物晶格,靜態細胞懸浮液,攪動的細胞懸浮液或血漿處理的聚合物。在一些實施例中,基質包含膜。
在一些實施例中,促進細胞生長的培養條件包括在mTeSR1培養基中培養幹細胞。在一些實施例中,mTeSR1培養基還包含ROCK抑制劑。在某些實施例中,mTeSR1培養基還包含ROCK抑制劑Y27632。
在一些實施例中,細胞生長至約20%至約80%之間的期望匯合。在一些實施例中,匯合為約20%,約30%,約40%,約50%,約60%,約70%或約80%。
在一些實施例中,修飾培養條件的步驟包括在X-VIVOTM
15培養基中培養細胞。
在一些實施例中,溫育時間在約2天和約4天之間。在一些實施例中,溫育時間為約2.0,約2.5,約3.0,約3.5或約4.0天。在某些實施例中,溫育時間為約3.5天。
在一些實施例中,該方法還包括將hEMP細胞分化成T細胞的步驟。
在一些實施例中,該方法還包括破壞幹細胞集群以產生非聚集幹細胞的步驟。在一些實施例中,幹細胞集群藉由機械或化學破壞來破壞。在一些實施例中,化學破壞包括與胰蛋白酶樣酶(TrypLE)一起溫育。在某些實施例中,胰蛋白酶樣酶為胰蛋白酶,TrypLE Express,TrypLE Select,膠原酶,分散酶或胰蛋白酶-EDTA。
在一些實施例中,根據本文所述的方法產生人胚胎間充質先驅(hEMP)細胞。
在一個態樣,本揭示案提供了包含根據本文所述的方法產生的人胚胎間充質先驅(hEMP)細胞群的組成物。
在一個態樣,本揭示案提供了產生T細胞的方法,所述方法包括以下步驟:以限定的單細胞密度使非聚集幹細胞與基質接觸,其中該等幹細胞不包含小鼠胚胎纖維母細胞(MEF);在促進細胞生長的培養條件下培養幹細胞至所需匯合;並修飾培養條件以誘導幹細胞分化成T細胞達所需的溫育時間;由此從幹細胞產生T細胞。
在一些實施例中,幹細胞是人胚胎幹(ES)細胞或誘導多能幹(iPS)細胞。在一些實施例中,ES或iPS細胞來源於人。
在一些實施例中,ES或iPS細胞是H1細胞,H9細胞,HES3細胞,HSF1細胞,HSF6細胞,ESI-017細胞,CS02iCTR-NTn1細胞,CS03iCTR-NTn1細胞,CS80iCTR-Tn3細胞,CS179iCTR-NTn1細胞,CS201iCTR-NTn4細胞,CS202iCTR-NTn2細胞或CS206iCTR-Tn5細胞。
在一些實施例中,限定的單細胞密度在約1.5×105
至約8×105
個細胞/cm2
之間。在某些實施例中,限定的單細胞密度為約1.89×105
個細胞/cm2
,約3.2×105
個細胞/cm2
,約3.4×105
個細胞/cm2
,約3.6×105
個細胞/cm2
,約3.79×105
個細胞/cm2
,約7.2×105
個細胞/cm2
或約7.58×105
個細胞/cm2
。
在一些實施例中,基質用Matrigel®
或重組人類玻連蛋白但不用小鼠胚胎纖維母細胞(MEF)包被。在一些實施例中,基質是孔板,細胞培養皿,膜,袋,培養瓶,反蛋白石,聚合物晶格,靜態細胞懸浮液,攪動的細胞懸浮液或血漿處理的聚合物。在一些實施例中,基質包含膜。
在一些實施例中,促進細胞生長的培養條件包括在mTeSR1培養基中培養幹細胞。在一些實施例中,mTeSR1培養基還包含ROCK抑制劑。在某些實施例中,mTeSR1培養基還包含ROCK抑制劑Y27632。
在一些實施例中,細胞生長至約20%至約80%之間的期望匯合。在一些實施例中,匯合為約20%,約30%,約40%,約50%,約60%,約70%或約80%。
在一些實施例中,修飾培養條件的步驟包括在X-VIVOTM
15培養基中培養細胞。
在一些實施例中,溫育時間在約2天和約4天之間。在一些實施例中,溫育時間為約2.0,約2.5,約3.0,約3.5或約4.0天。在某些實施例中,溫育時間為約3.5天。
在一個態樣,本揭示案提供了根據本文描述的方法產生的T細胞。
在一個態樣,本揭示案提供了包含根據本文所述的方法產生的T細胞群的組成物。
本文描述的任何態樣或實施例可以與本文揭示的任何其他態樣或實施例組合。儘管已經結合其詳細描述來描述了本揭示案,但是前述描述旨在說明而不是限制由所附申請專利範圍的範疇限定的本揭示案的範疇。其他態樣、優點和修改在以下申請專利範圍的範疇內。
本文提到的專利和科學文獻確立了熟習此項技術者可用的知識。本文引用的所有美國專利案和公佈的或未公開的美國專利申請案以引用之方式併入本文中。本文引用的所有公佈的外國專利案和專利申請案以引用之方式併入本文中。本文引用的所有其他出版的參考文獻、詞典、文獻、手稿和科學文獻以引用之方式併入本文中。
本揭示案的其它特徵和優點將從圖式和以下詳細描述(包括實例)和申請專利範圍書中顯而易見。
相關申請案之交互參照
本申請案要求於2017年5月26日提交的美國臨時申請案62/511,907和於2017年6月2日提交的美國臨時申請案62/514,467的優先權,這兩個申請案以全文引用之方式併入本文中。定義
為了使本發明更容易理解,首先在下文定義某些術語。以下術語及其他術語之其他定義在說明書中闡明。
如本說明書及隨附申請專利範圍中所使用,單數形式「一」及「該」包括複數提及物,除非上下文另外清楚地指定。
除非特別說明或從上下文中明顯看出,否則如本文所使用的術語「或」應理解為是包含性的並且涵蓋「或」和「及」兩者。
此外,「及/或」在本文中使用時應視為對兩個指定特徵或組分中之各者在存在或不存在另一者之情況下的具體揭示。因此,如本文中諸如「A及/或B」之片語中所使用之術語「及/或」意欲包括A及B、A或B、A(單獨)及B(單獨)。同樣,如諸如「A、B及/或C」之片語中使用之術語「及/或」意欲涵蓋以下態樣中之各者:A、B及C;A、B或C;A或C;A或B;B或C;A及C;A及B;B及C;A(單獨);B(單獨);及C(單獨)。
本文使用的術語「例如」和「亦即」僅僅是作為示例而使用的,不意欲限制,並且不應該被解釋為僅僅涉及說明書中明確列舉的那些項目。
術語「或多個」、「至少」、「多於」等等,例如「至少一個」應理解為包括但不限於至少1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19 20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50、51、52、53、54、55、56、57、58、59、60、61、62、63、64、65、66、67、68、69、70、71、72、73、74、75、76、77、78、79、80、81、82、83、84、85、86、87、88、89、90、91、92、93、94、95、96、97、98、99、100、101、102、103、104、105、106、107、108、109、110、111、112、113、114、115、116、117、118、119、120、121、122、123、124、125、126、127、128、129、130、131、132、133、134、135、136、137、138、139、140、141、142、143、144、145、146、147、148、149或150、200、300、400、500、600、700、800、900、1000、2000、3000、4000、5000個或超過所述值。還包括之間的任何更大的數字或分數。
相反,術語「不超過」包括小於所述值的每個值。例如,「不超過100個核苷酸」包括100、99、98、97、96、95、94、93、92、91、90、89、88、87、86、85、84、83、82、81、80、79、78、77、76、75、74、73、72、71、70、69、68、67、66、65、64、63、62、61、60、59、58、57、56、55、54、53、52、51、50、49、48、47、46、45、44、43、42、41、40、39、38、37、36、35、34、33、32、31、30、29、28、27、26、25、24、23、22、21、20、19、18、17、16、15、14、13、12、11、10、9、8、7、6、5、4、3、2、1及0個核苷酸。還包括之間的任何更小的數字或分數。
術語「複數個」、「至少兩個」、「兩個或更多個」、「至少第二個」等等應理解為包括但不限於至少2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19 20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50、51、52、53、54、55、56、57、58、59、60、61、62、63、64、65、66、67、68、69、70、71、72、73、74、75、76、77、78、79、80、81、82、83、84、85、86、87、88、89、90、91、92、93、94、95、96、97、98、99、100、101、102、103、104、105、106、107、108、109、110、111、112、113、114、115、116、117、118、119、120、121、122、123、124、125、126、127、128、129、130、131、132、133、134、135、136、137、138、139、140、141、142、143、144、145、146、147、148、149或150、200、300、400、500、600、700、800、900、1000、2000、3000、4000、5000或更多個。還包括之間的任何更大的數字或分數。
在整個說明書中,詞語「包含(comprising)」或者諸如「包含(comprises)」或者「包含(comprising)」的變化形式將被理解為暗示包括所陳述的要素、整數或者步驟,或者要素、整數或者步驟的組,但是不排除任何其他要素、整數或步驟,或者要素、整數或步驟的組。應理解,當在本文中用語言「包含」描述各態樣時,亦提供以「由...組成」及/或「實質上由...組成」之術語描述之其他相似態樣。
除非特別說明或從上下文中明顯看出,否則如本文所用,術語「約」是指在由一般技術人員確定的特定值或組成物的可接受誤差範圍內的值或組成物,其將部分地取決於如何量測或確定該值或組成物,亦即量測系統的局限性。例如,「約」或「基本上包含」可意指根據此項技術的實務在一個或多於一個標準偏差內。「約」或「基本上包含」可以表示高達10%(亦即,±10%)的範圍。因此,「約」可以理解為在大於或小於所述值的10%、9%、8%、7%、6%、5%、4%、3%、2%、1%、0.5%、0.1%、0.05%、0.01%或者0.001%。例如,約5 mg可以包括4.5 mg和5.5 mg之間的任何量。此外,特別是在生物系統或過程方面,這些術語可能意味著高達一個數量級或高達5倍的數值。當在本揭示案中提供特定值或組成物時,除非另有說明,否則「約」或「基本上包含」的含義應被假定為在該特定值或組成物的可接受的誤差範圍內。
除非另外指示,否則如本文所述之任何濃度範圍、百分率範圍、比率範圍或整數範圍均應理解為包括在所陳述之範圍內的任何整數值且當適當時,包括其分數(諸如整數之十分之一及一百分之一)。
單位、前置語及符號皆以其國際單位制(Système International de Unites (SI))可接受之形式給出。數字範圍包括界定該範圍之數字在內。
除非另外定義,否則本文所使用之所有技術及科學術語皆具有與本發明所屬領域之一般技術人員通常所理解相同的含義。例如,Juo,「The Concise Dictionary of Biomedicine and Molecular Biology」,第2版,(2001),CRC Press;「The Dictionary of Cell&Molecular Biology」,第5版,(2013),Academic Press;和「The Oxford Dictionary of Biochemistry and Molecular Biology」,Cammack等人編(2006),牛津大學出版社,為熟習此項技術者提供本揭示案中使用的許多術語的通用字典。
「投與」是指使用熟習此項技術者已知的各種方法和遞送系統中之任一者將藥劑實體引入至受試者體內。本文揭示的製劑的示例性投與途徑包括靜脈內,肌肉內,皮下,腹膜內,脊髓或其他腸胃外投與途徑,例如藉由注射或輸注。如本文所用,片語「非經腸投藥」意謂除腸內及局部投藥外之投藥模式,通常藉由注射投予,且包括(不限於)靜脈內、肌內、動脈內、鞘內、病灶內、囊內、眶內、心內、皮內、腹膜內、經氣管、皮下、表皮下、關節內、囊下、蛛網膜下、脊椎內、硬膜外及胸骨內注射及輸注,以及活體內電穿孔。在一些實施例中,製劑藉由非腸胃外途徑給藥,例如口服給藥。其他非腸胃外途徑包括局部、表皮或黏膜投與途徑,例如鼻內、陰道、直腸、舌下或局部。還可以例如一次、多次和/或在一個或多個延長的時間段內執行投藥。
如本文所使用的,如果抗原與第一結合分子、抗體或其抗原結合分子之間的相互作用阻斷、限制、抑制或以其他方式降低參考結合分子、參考抗體或其抗原結合分子與抗原相互作用的能力,則抗原結合分子、抗體或其抗原結合分子與參考抗體或其抗原結合分子「交叉競爭」。交叉競爭可以是完全的,例如,結合分子與抗原的結合完全阻斷了參考結合分子結合抗原的能力,或者其可以是部分的,例如結合分子與抗原的結合降低參考結合分子結合抗原的能力。在某些實施例中,與參考抗原結合分子交叉競爭的抗原結合分子與參考抗原結合分子結合相同或重疊的表位。在其他實施例中,與參考抗原結合分子交叉競爭的抗原結合分子與參考抗原結合分子結合不同的表位。許多類型的競爭性結合分析可用於確定一個抗原結合分子是否與另一個抗原結合分子競爭,例如:固相直接或間接放射免疫分析(RIA)、固相直接或間接酶免疫分析(EIA)、夾心競爭分析(Stahli等人, 1983, Methods in Enzymology 9:242-253);固相直接生物素-抗生物素蛋白EIA (Kirkland等人, 1986, J. Immunol. 137:3614-3619)、固相直接標記分析、固相直接標記夾心分析(Harlow及Lane, 1988, Antibodies, A Laboratory Manual, Cold Spring Harbor Press);使用1-125標記的固相直接標記RIA (Morel等人, 1988, Molec. Immunol. 25:7-15);固相直接生物素-抗生物素蛋白EIA (Cheung等人, 1990, Virology 176:546-552);及直接標記RIA (Moldenhauer等人, 1990, Scand. J. Immunol. 32:77-82)。
「抗原」是指引起免疫應答或能夠被抗體或抗原結合分子結合的任何分子。免疫應答可能涉及抗體產生或特定的免疫活性細胞的活化或兩者。熟習此項技術者將容易理解,任何大分子,包括幾乎所有的蛋白質或肽,都可以用作抗原。抗原可以被內源表達,亦即由基因組DNA表達,或者可以被重組表達。抗原可以對某些組織如癌細胞具有特異性,或者可以廣泛表達。另外,較大分子的片段可以充當抗原。在一個實施例中,抗原是腫瘤抗原。
術語「同種異體」是指來源於一個個體的任何物質,然後將其引入同一物種的另一個個體,例如同種異體T細胞移植。
術語「轉導(transduction)」和「轉導(transduced)」是指藉由病毒載體將外來DNA引入細胞的過程(參見Jones等人,「Genetics: principles and analysis,」 Boston: Jones & Bartlett Publ. (1998))。在一些實施例中,載體是逆轉錄病毒載體,DNA載體,RNA載體,腺病毒載體,桿狀病毒載體,Epstein Barr病毒載體,乳多空病毒載體,牛痘病毒載體,單純皰疹病毒載體,腺病毒相關的載體,慢病毒載體或其任何組合。
「癌症」是指一組涵蓋較廣的以體內異常細胞的不受控制的生長為特徵的各種疾病。不受調控的細胞分裂和生長導致侵入鄰近組織的惡性腫瘤的形成,並可能藉由淋巴系統或血流轉移至身體的遠端部位。「癌症」或「癌症組織」可以包括腫瘤。可以藉由本揭示案的方法治療的癌症的實例包括但不限於免疫系統的癌症,包括淋巴瘤、白血病、骨髓瘤和其他白血球惡性腫瘤。在一些實施例中,本揭示案的方法可以用於減小源自以下癌症的腫瘤的腫瘤大小,例如骨癌,胰腺癌,皮膚癌,頭或頸部癌,皮膚或眼內惡性黑素瘤,子宮癌,卵巢癌,直腸癌,肛門區癌症,胃癌,睾丸癌,子宮癌,輸卵管癌,子宮內膜癌,宮頸癌,陰道癌,外陰癌,多發性骨髓瘤,霍奇金氏病,非霍奇金淋巴瘤(NHL),原發性縱隔大B細胞淋巴瘤(PMBC),彌漫性大B細胞淋巴瘤(DLBCL),濾泡性淋巴瘤(FL),轉化的濾泡性淋巴瘤,脾邊緣區淋巴瘤(SMZL),食道癌,小腸癌,內分泌系統癌,甲狀腺癌,甲狀旁腺癌,腎上腺癌,軟組織肉瘤,尿道癌,陰莖癌,慢性或急性白血病,急性骨髓性白血病,慢性骨髓性白血病,急性淋巴母細胞性白血病(ALL)(包括非T細胞ALL),慢性淋巴細胞白血病(CLL),兒童時期的實體瘤,淋巴細胞性淋巴瘤,膀胱癌,腎或輸尿管癌,腎盂癌,中樞神經系統(CNS)腫瘤,原發性CNS淋巴瘤,腫瘤血管產生,脊柱軸腫瘤,腦幹膠質瘤,垂體腺瘤,卡波西肉瘤,表皮樣癌,鱗狀細胞癌,T細胞淋巴瘤,環境誘導的癌症包括由石棉誘導的癌症,其他B細胞惡性腫瘤和該等癌症的組合。在一個具體的實施例中,該癌症為多發性骨髓瘤。特定的癌症可能對化療或放射療法有反應,或者癌症可能是難治的。難治性癌症是指不受手術干預影響的癌症,並且癌症最初對化學療法或放射療法無響應或隨著時間的推移癌症變得無響應。
本文所用的「抗腫瘤作用」是指可表現為腫瘤體積減小,腫瘤細胞數量減少,腫瘤細胞增殖減少,轉移瘤數量減少,總體或無進展生存期的增加,預期壽命的增加或與腫瘤相關的各種生理症狀的改善的生物學作用。抗腫瘤作用也可以指防止腫瘤發生,例如疫苗。
如本文所用,「細胞介素」是指由一種細胞響應於與特定抗原接觸而釋放的非抗體蛋白,其中細胞介素與第二細胞相互作用以介導第二細胞中的應答。細胞介素可以由細胞內源性表達或投與受試者。細胞介素可以藉由免疫細胞,包括巨噬細胞、B細胞、T細胞和肥大細胞來釋放以傳播免疫應答。細胞介素可以在受體細胞中誘導各種應答。細胞介素可以包括穩態細胞介素、趨化介素、促炎細胞介素、效應物和急性期蛋白。例如,穩態細胞介素(包括白細胞介素(IL)7和IL-15)促進免疫細胞存活和增殖,並且促炎細胞介素可促進炎症反應。穩態細胞介素的實例包括但不限於IL-2,IL-4,IL-5,IL-7,IL-10,IL-12p40,IL-12p70,IL-15和干擾素(IFN)γ。促炎細胞介素的實例包括但不限於IL-1a,IL-1b,IL-6,IL-13,IL-17a,腫瘤壞死因子(TNF)-α,TNF-β,纖維母細胞生長因子(FGF)2,粒細胞巨噬細胞集落刺激因子(GM-CSF),可溶性細胞間黏附分子1(sICAM-1),可溶性血管黏附分子1(sVCAM-1),血管內皮生長因子(VEGF),VEGF-C,VEGF-D和胎盤生長因子(PLGF)。效應物的實例包括但不限於顆粒酶A,顆粒酶B,可溶性Fas配位體(sFasL)和穿孔蛋白。急性期蛋白的實例包括但不限於C-反應蛋白(CRP)和血清澱粉樣蛋白A(SAA)。
「趨化介素」是介導細胞趨化性或定向運動的一類細胞介素。趨化介素的實例包括但不限於IL-8,IL-16,伊紅趨素,伊紅趨素-3,巨噬細胞源趨化介素(MDC或CCL22),單核細胞趨化蛋白1(MCP-1或CCL2),MCP-4,巨噬細胞炎症蛋白1α(MIP-1α,MIP-1a),MIP-1β(MIP-1b),γ誘導蛋白10(IP-10)以及胸腺和活化調節趨化介素(TARC或CCL17)。
治療劑(例如工程CAR T細胞)的「治療有效量」,「有效劑量」,「有效量」或「治療有效劑量」是當單獨使用或與另一種治療劑組合使用時,可以保護受試者免於疾病發作或促進疾病消退的任何量,藉由疾病症狀的嚴重程度的減輕、無疾病症狀期的頻率和持續時間的增加,或者預防疾病所致的損傷或失能來證明。治療劑促進疾病消退的能力可使用熟習此項技術者已知的多種方法來評估,例如在臨床試驗過程中的人受試者中,在預測人體中之功效的動物模型系統中,或藉由在活體外測定中測定試劑之活性。
如本文所用,術語「淋巴細胞」包括自然殺傷(NK)細胞、T細胞或B細胞。NK細胞是一類細胞毒性(細胞中毒)淋巴細胞,代表了固有免疫系統的主要成分。NK細胞排斥腫瘤和病毒感染的細胞。它藉由凋亡或程式性細胞死亡的過程起作用。它們被稱為「自然殺手」,因為它們不需要激活以殺死細胞。T細胞在細胞介導的免疫中起主要作用(沒有抗體參與)。它的T細胞受體(TCR)將它們自己與其他淋巴細胞類型區分開來。胸腺是免疫系統的專門器官,主要負責T細胞的成熟。有六種類型的T細胞,即:輔助性T細胞(例如CD4+細胞),細胞毒性T細胞(也稱為TC,細胞毒性T淋巴細胞,CTL,T-殺傷細胞,細胞溶解性T細胞,CD8+ T-細胞或殺傷T細胞),記憶T細胞((i)幹記憶TSCM細胞,如同原初細胞,是CD45RO-,CCR7+,CD45RA+,CD62L+(L-選擇蛋白),CD27+,CD28+和IL-7Rα+,但是它們也表達大量的CD95,IL-2Rβ,CXCR3和LFA-1,並且顯示許多與記憶細胞不同的功能屬性);(ii)中央記憶性TCM細胞表達L-選擇蛋白和CCR7,它們分泌IL-2但不分泌IFNγ或IL-4,然而(iii)效應記憶性TEM細胞不表達L-選擇蛋白或CCR7,但產生效應細胞介素如IFNγ和IL-4),調節性T細胞(Tregs,抑制性T細胞或CD4+CD25+調節性T細胞),天然殺傷T細胞(NKT)和γδT細胞。另一方面,B細胞在體液免疫中發揮主要作用(抗體參與)。它們製造抗體和抗原,發揮抗原呈遞細胞(APC)的作用,並在抗原相互作用激活後變成記憶B細胞。在哺乳動物中,未成熟的B細胞在骨髓中形成。
術語「基因工程」,「工程化」或「修飾」是指修飾細胞的方法,包括但不限於藉由刪除編碼或非編碼區或其部分而在基因中產生缺陷或藉由反義技術,或增加引入編碼區或其部分的蛋白質的表達。在一些實施例中,被修飾的細胞是幹細胞(例如造血幹細胞(HSC),胚胎幹細胞(ES),誘導多能幹(iPS)細胞),淋巴細胞(例如T細胞),其可以從患者或供體獲得。
「免疫應答」是指免疫系統的細胞(例如T淋巴細胞,B淋巴細胞,自然殺傷(NK)細胞,巨噬細胞,嗜酸性白血球,肥大細胞,樹突細胞和嗜中性白血球)以及由這些細胞中之任一者或肝臟產生的可溶性大分子(包括Ab、細胞介素和補體)的作用,該作用導致對於以下各者的選擇性靶向、結合、損傷、破壞和/或從脊椎動物體內消除:入侵的病原體,感染病原體的細胞或組織,癌症或其他異常細胞,或在自身免疫或病理性炎症的情況下,正常人類細胞或組織。
術語「免疫療法」是指藉由包括誘導,增強,抑制或以其他方式修飾免疫應答的方法來治療罹患疾病或有感染疾病或遭受疾病復發之風險的受試者。免疫療法的實例包括但不限於T細胞療法。T細胞療法可以包括過繼性T細胞療法,腫瘤浸潤淋巴細胞(TIL)免疫療法,自體細胞療法,工程化自體細胞療法(eACTTM
)和同種異體T細胞移植。然而,熟習此項技術者將認識到,本文揭示的調理方法將增強任何移植T細胞療法的有效性。T細胞治療的實例在美國專利公開案第2014/0154228號和第2002/0006409號,美國專利案第5,728,388號和國際公開案第WO 2008/081035號中有所描述。
免疫療法的T細胞可以來自此項技術已知的任何來源。例如,T細胞可以在活體外從造血幹細胞群、誘導的多能幹細胞(iPS)、胚胎幹細胞(ES)分化或T細胞可以從受試者獲得。T細胞可獲自例如周邊血單核球(PBMC)、骨髓、淋巴結組織、臍帶血、胸腺組織、來自感染部位之組織、腹水、胸膜滲出液、脾組織、及腫瘤。另外,T細胞可以來源於此項技術中可用的一種或多種T細胞系。還可以使用熟習此項技術者已知的許多技術,例如FICOLLTM
分離和/或血球分離,從由受試者採集的血液單位獲得T細胞。美國專利公開案第2013/0287748號中揭示了分離T細胞用於T細胞療法的另外的方法,其以全文引用之方式併入本文中。
術語「工程化的自體細胞療法」,可簡稱為「eACT™」,也稱為過繼性細胞轉移,是一種過程,藉由該過程收集患者自身的T細胞並隨後基因改變以識別和靶向在一種或多種特定腫瘤細胞或惡性腫瘤的細胞表面上表達的一種或多種抗原。本文使用的「患者」包括患有癌症(例如,淋巴瘤或白血病)的任何人。「受試者」及「患者」等詞在本文中可互換使用。
如本文所用,術語「活體外細胞」是指離體培養的任何細胞。具體而言,活體外細胞可以包含T細胞。
術語「肽」、「多肽」及「蛋白質」在本文中互換使用並且指包含藉由肽鍵來共價連接之胺基酸殘基的化合物。蛋白質或肽含有至少兩個胺基酸,並且對可包含蛋白質或肽序列的胺基酸的最大數目沒有限制。多肽包括包含藉由肽鍵彼此連接的兩個或更多個胺基酸的任何肽或蛋白質。如本文所用,該術語是指短鏈,其在此項技術中通常也稱為肽、寡肽和寡聚物,並且也指較長的鏈,其在此項技術通常稱為蛋白質,存在很多種類之蛋白質。「多肽」包括例如生物活性片段、基本上同源的多肽、寡肽、同二聚體、異二聚體、多肽變體、修飾的多肽、衍生物、類似物、融合蛋白等等。多肽包括天然肽、重組肽、合成肽或其組合。
如本文所用,「刺激」是指由刺激分子與其同源配位體結合誘導的原初應答,其中該結合介導信號轉導事件。「刺激分子」是T細胞上的分子,例如T細胞受體(TCR)/ CD3複合物,其與存在於抗原呈遞細胞上的同源刺激配位體特異性結合。「刺激性配位體」是當存在於抗原呈遞細胞(例如,APC、樹突細胞、B細胞等)上時可以與T細胞上的刺激分子特異性結合從而介導T細胞的原初應答的配位體,包括但不限於激活、免疫應答的啟動、增殖等。刺激性配位體包括但不限於抗CD3抗體、負載有肽的MHC I類分子、超級促效抗CD2抗體和超級促效抗CD28抗體。
如本文所用,「共刺激信號」是指與原初信號例如TCR/CD3連接反應組合來導致T細胞應答的信號,該應答例如但不限於增殖和/或上調或下調關鍵分子。
如本文所用,「共刺激配位體」包括特異性結合T細胞上的同源共刺激分子的抗原呈遞細胞上的分子。共刺激配位體的結合提供介導T細胞應答的信號,包括但不限於增殖、激活、分化等。例如,藉由T細胞受體(TCR)/ CD3複合物與負載有肽的主要組織相容性複合物(MHC)分子的結合,共刺激配位體誘導除了由刺激分子提供的原初信號之外的信號。共刺激配位體可以包括但不限於3/TR6,4-1BB配位體,結合Toll配位體受體的促效劑或抗體,B7-1(CD80),B7-2(CD86),CD30配位體,CD40,CD7,CD70,CD83,皰疹病毒進入介質(HVEM),人類白血球抗原G(HLA-G),ILT4,免疫球蛋白樣轉錄物(ILT)3,誘導型共刺激配位體(ICOS-L),細胞間黏附分子(ICAM),與B7-H3特異性結合的配位體,淋巴毒素β受體,MHC I類鏈相關蛋白A(MICA),MHC I類鏈相關蛋白B(MICB),OX40配位體,PD-L2或程式性死亡(PD)L1。共刺激配位體包括但不限於與存在於T細胞上的共刺激分子特異性結合的抗體,例如但不限於4-1BB,B7-H3,CD2,CD27,CD28,CD30,CD40,CD7,ICOS,與CD83特異性結合的配位體,淋巴細胞功能相關抗原-1(LFA-1),天然殺傷細胞受體C(NKG2C),OX40,PD-1或腫瘤壞死因子超家族成員14(TNFSF14或LIGHT)。
「共刺激分子」是T細胞上的同源結合配偶體,其與共刺激配位體特異性結合,從而介導T細胞的共刺激反應,例如但不限於增殖。共刺激分子包括但不限於:「共刺激分子」是T細胞上的同源結合配偶體,其與共刺激配位體特異性結合,從而介導T細胞的共刺激反應,例如但不限於增殖。共刺激分子包括但不限於4-1BB/CD137,B7-H3,BAFFR,BLAME(SLAMF8),BTLA,CD 33,CD 45,CD100(SEMA4D),CD103,CD134,CD137,CD154,CD16,CD160(BY55),CD18,CD19,CD19a,CD2,CD22,CD247,CD27,CD276(B7-H3),CD28,CD29,CD3(α;β;δ;ε;γ;ζ),CD30,CD37,CD4,CD4,CD40,CD49a,CD49D,CD49f,CD5,CD64,CD69,CD7,CD80,CD83配位體,CD84,CD86,CD8α,CD8β,CD9,CD96(Tactile),CD1-1a,CD1-1b,CD1-1c,CD1-1d,CDS,CEACAM1,CRT AM,DAP-10,DNAM1(CD226),Fcγ受體,GADS,GITR,HVEM(LIGHTR),IA4,ICAM-1,ICAM-1,ICOS,Igα(CD79a),IL2Rβ,IL2Rγ,IL7Rα,整聯蛋白,ITGA4,ITGA4,ITGA6,ITGAD,ITGAE,ITGAL,ITGAM,ITGAX,ITGB2,ITGB7,ITGBl,KIRDS2,LAT,LFA-1,LFA-1,LIGHT,LIGHT(腫瘤壞死因子超家族成員14;TNFSF14),LTBR,Ly9(CD229),淋巴細胞功能相關抗原-1(LFA-1(CD11a / CD18),MHC I類分子,NKG2C,NKG2D,NKp30,NKp44,NKp46,NKp80(KLRF1),OX40,PAG/Cbp,PD-1,PSGL1,SELPLG(CD162),信號轉導淋巴細胞激活分子,SLAM(SLAMF1;CD150;IPO-3),SLAMF4(CD244;2B4),SLAMF6(NTB-A;Lyl08),SLAMF7,SLP-76,TNF,TNFr,TNFR2,Toll配位體受體,TRANCE/RANKL,VLA1或VLA-6,或其片段、截斷或組合。
術語「減少」和「降低」在本文中可互換使用,並表示任何小於原始的變化。「減少」和「降低」是相對術語,需要在量測前和量測後進行比較「減少」和「降低」包括完全消耗。
受試者的「治療(Treatment)」或「治療(treating)」是指對於受試者進行的任何類型的干預或過程或投與活性劑,目的是逆轉、減輕、改善、抑制、減緩或預防症狀、併發症或病症的發作、進展、發展、嚴重性或復發,或與疾病相關的生化指標。在一個實施例中,「治療(treatment)」或「治療(treating)」包括部分緩解。在另一個實施例中,「治療(treatment)」或「治療(treating)」包括完全緩解。
為了計算一致性百分比,所比較之序列通常係以得到序列之間最大匹配的方式比對。可用於確定一致性百分比的電腦程式的一個實例是GCG程式包,其包括GAP(Devereux等,1984, Nucl. Acid Res. 12:387; Genetics Computer Group, University of Wisconsin, Madison, Wis.)。計算機演算法GAP用於比對欲確定序列一致性百分比的兩種多肽或多核苷酸。該等序列經比對以用於其各自胺基酸或核苷酸之最佳匹配(「匹配跨度」,如藉由演算法所確定)。在某些實施例中,演算法亦使用標準比較矩陣(參見,針對PAM 250比較矩陣,Dayhoff等人, 1978, Atlas of Protein Sequence and Structure 5:345-352;針對BLOSUM 62比較矩陣,Henikoff等人, 1992, Proc. Natl. Acad. Sci. U.S.A. 89:10915-10919)。
如本文所用,術語「破壞(disruption)」或「破壞(disrupt)」是指聚集細胞的機械、化學和/或酶解離。如本文所用,經破壞的細胞保持完整但是鬆散的細胞-細胞黏附接觸以及膜黏附性質。
如本文所用,術語「培養」或語法等同物是指將細胞維持在有利於生長、存活或分化的條件下的過程。術語「培養」和「細胞培養物」或任何同義詞在本申請案中可互換地使用。
如本文所用,術語「細胞密度」或「單細胞密度」是指體積或表面積中細胞的量。在一些實施例中,細胞密度以六孔板的細胞/孔來表示。根據本揭示案,標準六孔板具有約9.5cm2
的表面積。在一些實施例中,細胞密度表示為細胞/cm2
。
如本文所用,術語「培養容器」是指可以提供用於培養細胞的無菌環境的任何容器。示例性培養容器包括但不限於玻璃、塑膠或金屬容器。
本發明之多個態樣更詳細地描述於以下各小節中。詳細描述
根據本揭示案,HSC或其他幹細胞(胚胎幹細胞(ES)或誘導多能幹細胞(iPS))可用於產生大量,可能無限數量的具有所需譜系的工程化T細胞。本揭示案尤其提供了用於將人胚胎幹(ES)或誘導性多能幹(iPS)細胞分化成胚胎中胚層先驅(hEMP)細胞和/或T細胞的高效方法,以及包含其的組成物。
不希望受任何具體理論的束縛,預期如果在前面進行稱為「中胚層推動」或hEMP誘導的誘導步驟,從ES或iPS細胞產生T細胞更有效。簡而言之,將ES或iPS細胞培養、傳代並生長直至達到理想的匯合。隨後,培養條件改變為hEMP誘導培養基。在一些實施例中,培養ES或iPS細胞的方法是在Matrigel®或重組人玻連蛋白上無飼養細胞(亦即無MEF)。令人驚訝的是,本發明人發現如果非聚集細胞培養物用於「中胚層推動」或hEMP誘導,可以更有效地產生hEMP。例如,可以將非聚集幹細胞以限定的單細胞密度接種在基質上並誘導。其結果是有效且可重複的中胚層推動。來自中胚層推動的高產量hEMP細胞允許在下游應用中有效、快速和穩健的T細胞分化。 多能幹細胞
各種多能幹細胞可用於實踐本揭示案。例如,骨髓(另外臍帶血或外周血)中的造血幹細胞(HSC)除了產生所有其他成熟的血細胞外,還會產生定型胸腺先驅細胞。這些胸腺先驅細胞進入胸腺,它們在胸腺中開始發育至成熟的T細胞。Notch受體藉由它們的配位體Delta和Jagged,特別是胸腺中的Notch1和δ樣4的信號傳導驅動轉錄級聯(亦即Tcf7、Gata3、Bcl11b等),其導致TCR基因座藉由重組酶活化基因RAG1和RAG2的重排。首先,生產性TCRb重排(亦即產生TCR蛋白質)將產生與pTa配對並流向表面的蛋白質。這種表面運輸向該細胞傳遞了一個信號,使其能夠進一步發育。如在成熟TCR中發生的,表面pTa-TCRb不需要與MHC相互作用 - 存活信號可以不依賴於肽:MHC。隨後細胞繼續將TCRα重排,在成為成熟初始T細胞並循環至周邊之前,對成功的α/β配對和自身肽:MHC的弱識別(亦即陽性和陰性選擇或中樞耐受)進行詳細檢查。
在一些實施例中,可以使用胚胎幹(ES)或誘導性多能幹(iPS)幹(iPS)細胞。
幹細胞可以從此項技術已知的任何來源獲得。例如,誘導性多能幹細胞(iPS)或胚胎幹細胞(ES)可以從商業來源獲得。合適的HSC、ES細胞、iPS細胞和其他幹細胞也可以是培養的永生細胞系或直接從患者分離。用於分離、發育和/或培養幹細胞的各種方法在此項技術中是已知的並且可以用於實踐本揭示案。 產生非聚集的幹細胞
如本文所述,在中胚層誘導之前培養懸浮的非聚集單細胞幹細胞導致幹細胞分化的效率提高。可以使用各種方法來產生非聚集幹細胞培養物。例如,ES或iPS細胞可以首先在小鼠胚胎纖維母細胞(MEF)、Matrigel®或玻連蛋白上以集群形式進行培養,並以集群形式在Matrigel®或玻連蛋白包被的板上傳代。在一些實施例中,為了產生懸浮的單細胞,藉由用胰蛋白酶、胰蛋白酶樣酶或此項技術已知的其他細胞-細胞黏附破壞劑消化來將集群以化學方式破壞。在一些實施例中,藉由均化(例如再懸浮、機械攪拌、培養基洗滌、緩衝液洗滌、細胞解離器(例如Miltenyi GentleMACS)或渦旋)來將集群以機械方式破碎以產生懸浮液中的單細胞。
在一些實施例中,培養條件適於促進單細胞生長,使得幹細胞不形成集群。例如,幹細胞可以在懸浮液中生長。 基質
根據本揭示案,將非聚集幹細胞以限定的單細胞密度接種在基質上以進行生長。如本文所用,術語「基質」是指任何固體或半固體表面或載體。例如,合適的基質可以是層、微珠、孔板、細胞培養皿、膜、袋、培養瓶、容器、反蛋白石、聚合物晶格、凝膠或聚合物。
在一些實施例中,可以用期望的塗層來處理合適的基質。例如,合適的基質可以用Matrigel®
或玻連蛋白塗覆。在一些實施例中,用膠原蛋白(例如膠原蛋白I、II、II或IV),明膠,纖連蛋白,層黏連蛋白,玻連蛋白,纖維蛋白原,BD Matrigel®
,基底膜基質,硫酸皮膚素蛋白聚醣,聚D-離胺酸,和/或其組合。
根據本揭示案,將非聚集細胞以限定的單細胞密度接種在基質上。適用於本揭示案的單細胞密度可以在標準6孔板中為約1.0-50×106
個細胞/孔(例如,約1.0-40×106
個細胞/孔,約1.0-30×106
個細胞/孔,約1.0-20×106
個細胞/孔,約1.0-10×106
個細胞/孔,1.0-8×106
個細胞/孔,約1.0-5×106
個細胞/孔,約1.0-4.5×106
個細胞/孔,約1.0-4×106
個細胞/孔,約1.0-3.6×106
個細胞/孔,約1.0-3×106
個細胞/孔,約1.0-2.5×106
個細胞/孔,約1.0-2.0×106
個細胞/孔,約1.0-1.5×106
個細胞/孔,約1.5-10×106
個細胞/孔,約1.5-8×106
個細胞/孔,約1.5-4×106
個細胞/孔,約1.5-3.5×106
個細胞/孔,約1.5-3.0×106
個細胞/孔,約1.5-2.5×106
個細胞/孔,約1.5-2.0×106
個細胞/孔)。
在一些實施例中,細胞以限定的單細胞密度(例如,約1.8×106
個細胞/孔,約3.6×106
個細胞/孔,約7.2×106
個細胞/孔)進行傳代。
在一些實施例中,細胞以約1.5x105
至約8x105
個細胞/cm2
(例如,1.89x105
個細胞/cm2
,約3.2x105
個細胞/cm2
,約3.4x105
個細胞/cm2
,約3.6x105
個細胞,約3.79×105
個細胞/cm2
,約7.2×105
個細胞/cm2
或約7.58×105
個細胞/cm2
)進行傳代。
在一些實施例中,接種時限定的單細胞密度表示為匯合百分比。根據本揭示案,以限定的細胞密度接種,使得表面匯合的範圍為1%至100%(例如,約1%,約5%,約10%,約15%,約20%,約25%,約30%,約35%,約40%,約45%,約50%,約55%,約60%,約65%,約70%,約75%,約80%,約85%,約90%,約95%,約97%,約99%)。在一些實施例中,細胞以高匯合百分比(例如,約70-100%,約80%)傳代。在一些實施例中,細胞以中等匯合百分比(例如,約30-70%,約40%)進行傳代。在一些實施例中,細胞以低匯合百分比(例如,約1-30%,約20%)進行傳代。
在一些實施例中,將細胞接種在生長培養基中。在其他實施例中,將細胞接種在誘導培養基中。在一些實施例中,將細胞接種於誘導培養基中,根據本揭示案生長至期望的匯合並重新鋪放在誘導培養基中。 細胞培養條件
根據本揭示案,ES或iPS細胞可適於在懸浮培養物中作為單細胞生長。在一些實施例中,ES或iPS細胞保持在懸浮中。懸浮在營養培養基中的ES或iPS細胞可以用循環裝置維持,其確保分離的細胞保持懸浮在營養培養基中。 培養基
根據本揭示案可以使用各種細胞培養基和條件。例如,細胞可以在含血清或無血清的細胞培養基中生產。在一些實施例中,培養基是無血清培養基。在一些實施例中,培養基是無動物培養基,亦即缺乏動物衍生組分的培養基。在一些實施例中,培養基是化學上確定的培養基。如本文所用,術語「化學上確定的營養培養基」是指基本上所有化學組分都是已知的培養基。在一些實施例中,化學成分確定的營養培養基不含動物來源的成分,例如血清、血清來源的蛋白質(例如白蛋白或胎球蛋白)和其他成分。在一些情況下,化學成分確定的培養基包含一種或多種蛋白質(例如蛋白質生長因子或細胞介素)。在一些情況下,化學成分確定的營養培養基包含一種或多種蛋白質水解產物。在其它情況下,化學成分確定的營養培養基是不含蛋白質的培養基,亦即不含蛋白質、水解產物或組成未知的成分的無血清培養基。
在一些實施例中,化學成分確定的培養基可以用一種或多種動物來源的成分補充。此等動物來源的成分包括但不限於胎牛血清,馬血清,山羊血清,驢血清,人血清和血清衍生的蛋白質例如白蛋白(例如牛血清白蛋白或人血清白蛋白)。
在某些實施例中,可以選擇在特定條件下的某些較佳屬性或生長用於培養細胞。熟習此項技術者將理解,可以基於已建立的細胞系(亦即特徵化的商業上可獲得的細胞系)的已知特徵和/或性狀或藉由經驗評估來確定這些屬性。在一些實施例中,可以針對細胞系在飼養細胞層上生長的能力來選擇細胞系。在一些實施例中,可以針對細胞系作為貼壁單層細胞生長的能力來選擇細胞系。在一些實施例中,該等方法涉及包括在包含培養基的細胞培養物中培養幹細胞和/或先驅細胞。
根據本揭示案,產生人胚胎間充質先驅(hEMP)細胞包含生長期和分化期。在一些實施例中,生長期期間的培養基與分化期期間的培養基顯著不同。在某些實施例中,將mTESR1培養基用於生長期,並將X-VIVOTM
15培養基用於分化期。
可以使用各種培養基。示例性但非限制性的培養基包括但不限於MEM(最小必需培養基),DMEM(杜爾貝科改良伊格爾培養基),BME(伊格爾基礎培養基),RPMI 1640,DMEM / F-12(杜爾貝科改良伊格爾培養基:營養混合物F-12),DMEM / F-10(杜爾貝科改良伊格爾培養基:營養混合物F-10),a-MEM(a-最小必需培養基),G-MEM(格拉斯哥最小必需培養基),FMDM(Isocove改良杜爾貝科培養基),必需8(E8)培養基,KnockOut DMEM,AIM V,mTeSRTM
1,X-VIVOTM
15,StemSpan,CellGro樹突狀細胞培養基。
在一些實施例中,使用用於人胚胎幹細胞(ES細胞)和誘導多能幹細胞(iPS細胞)的無飼養細胞培養基。在一些實施例中,使用本揭示案產生非聚集ES或iPS細胞。在一些實施例中,適用於本揭示案的無血清培養基缺乏動物來源組分。在一些實施例中,適用於本揭示案的無血清培養基是化學成分確定的培養基。例如,mTeSRTM
1培養基可用於細胞生長。MTeSR™1是一種高度專門化、無血清且完整的細胞培養基。
在某些實施例中,培養基補充有Rho相關蛋白激酶(ROCK)途徑的抑制劑(例如Y27632)。ROCK抑制劑可用於幫助重新程式化、保持、自我更新和/或分化。 誘導時的期望匯合
根據本揭示案,將非聚集細胞重新懸浮或轉移到誘導培養基中並以限定的單細胞密度鋪放在基質上。適用於本揭示案的單細胞密度的範圍可以在標準6孔板中為約1.0-50×106
個細胞/孔(例如,約1.0-40×106
個細胞/孔,約1.0-30×106
個細胞/孔,約1.0-20×106
個細胞/孔,約1.0-10×106
個細胞/孔,1.0-8×106
個細胞/孔,約1.0-5×106
個細胞/孔,約1.0-4.5×106
個細胞/孔,約1.0-4×106
個細胞/孔,約1.0-3.6×106
個細胞/孔,約1.0-3×106
個細胞/孔,約1.0-2.5×106
個細胞/孔,約1.0-2.0×106
個細胞/孔,約1.0-1.5×106
個細胞/孔,約1.5-10×106
個細胞/孔,約1.5-8×106
個細胞/孔,約1.5-4×106
個細胞/孔,約1.5-3.5×106
個細胞/孔,約1.5-3.0×106
個細胞/孔,約1.5-2.5×106
個細胞/孔,約1.5-2.0×106
個細胞/孔)。
在一些實施例中,將非聚集細胞重新懸浮於或轉移至誘導培養基中並以限定的單細胞密度(例如1.8×106
個細胞/孔,約3.6×106
個細胞/孔,約7.2×106
個細胞/孔)鋪放在基質上。
在一些實施例中,將非聚集細胞重新懸浮或轉移到誘導培養基中,並以約1.5×105
至約8×105
個細胞/cm2
(例如,1.89×105
個細胞/cm2
,約3.2×105
個細胞/cm2
,約3.4×105
個細胞/cm2
,約3.6×105
個細胞/cm2
,約3.79×105
個細胞/cm2
,約7.2×105
個細胞/cm2
或約7.58×105
個細胞/cm2
)的限定單細胞密度鋪放在基質上。
在一些實施例中,誘導時限定的單細胞密度表示為匯合百分比。根據本揭示案,將非聚集細胞重新懸浮或轉移到誘導培養基中,並以限定的細胞密度鋪放在基質上,使得表面匯合的範圍為1%-100%(例如約1%,約5%,約10%,約15%,約20%,約25%,約30%,約35%,約40%,約45%,約50%,約55%,約60%,約65%,約70%,約75%,約80%,約85%,約90%,約95%,約97%,約99%)。在一些實施例中,以高匯合百分比(例如,約70-100%,約80%)誘導細胞。在一些實施例中,以中等匯合百分比(例如,約30-70%,約40%)誘導細胞。在一些實施例中,以低匯合百分比(例如,約1-30%,約20%)誘導細胞。 生長和分化期
在一些實施例中,細胞在約30-37℃(例如,約31-37℃,約32-37℃,約33-37℃,約34-37℃,約35-37℃,約36-37℃)範圍內之溫度下培養。在一些實施例中,細胞在大約30℃、31℃、32℃、33℃、34℃、35℃、36℃或37℃的溫度下培養。本文所述的任何溫度都可以用於生長和/或分化期。在一些實施例中,細胞在生長期和分化期期間在不同溫度下培養。在一些實施例中,細胞在生長期和分化期期間在基本上相同的溫度下培養。本文所述的任何培養基pH可以用於生長和/或分化期。在一些實施例中,生長期和分化期的培養基pH不同。在一些實施例中,生長期和分化期的培養基pH基本相同。
在一些實施例中,ES或iPS細胞在生長期中生長並保持。在一些實施例中,將ES或iPS細胞接種並在分化期之前生長至期望的匯合度(例如,約20%,約30%,約40%,約50%,約60%,約70%,約80%或約90%匯合)。在其他實施例中,ES或iPS細胞在分化期之前未接種。在某些實施例中,將ES或iPS細胞重新懸浮於分化培養基中並以期望的匯合度(例如,約20%,約30%,約40%,約50%,約60%,約70%,約80%或約90%的匯合)來鋪放。在一些實施例中,ES或iPS細胞在生長期期間在Matrigel®
或玻連蛋白上培養。在一些實施例中,ES或iPS細胞在生長期期間在小鼠胚胎纖維母細胞(MEF)上培養。
在一些實施例中,生長期的溫育時間為約1-6天(例如約1-5天,約1-4天,約1-3天,約1-2天,約1天,約2天,約2.5天,約3天,約3.5天,約4天)。在一些實施例中,生長期的溫育時間分兩步發生,其中將培養物接種。在一些實施例中,生長期的每個步驟為約1-6天(例如約1-5天,約1-4天,約1-3天,約1-2天,約1天,約2天,約2.5天,約3天,約3.5天,約4天)。在一些實施例中,分化期持續約2、3、4、5、6或7天。
在一些實施例中,分化期的溫育時間為約1-6天(例如約1-5天,約1-4天,約1-3天,約1-2天,約1天,約2天,約2.5天,約3天,約3.5天,約4天)。在一些實施例中,分化期的孵育時間分兩步進行,其中培養物被重新鋪放。在一些實施例中,分化期的每個步驟為約1-6天(例如約1-5天,約1-4天,約1-3天,約1-2天,約1天,約2天,約2.5天,約3天,約3.5天,約4天)。在一些實施例中,分化期持續約2、3、4、5、6或7天。 幹細胞分化
使用根據本揭示案的單細胞非聚集方法產生的hEMP細胞可以進一步分化成各種細胞類型。 中胚層誘導
在激活素A、BMP4、VEGF和FGF2存在下由hESC或iPSC產生的最早的CD326-CD56+ hEMP細胞代表多能中胚層定型先驅細胞群。CD326-CD56+先驅細胞在產生包括造血細胞、內皮細胞、間充質細胞(骨、軟骨、脂肪、纖維母細胞)、平滑肌和心肌細胞的所有中胚層譜系的能力方面是獨特的,同時缺乏hESC或iPSC的多能性。CD326-CD56+ hEMP細胞是更多譜系限制性中胚層先驅細胞的前體。
CD326-CD56+ hEMP細胞可以用BMP4、VEGF和bFGF的組合以及瞬時暴露於激活素A的方式產生。 選擇hEMP細胞
過渡至hEMP的ESC或iPSC的特徵在於CD326 EPCAM的喪失和CD56 NCAM(CD326-CD56+)的獲得。上皮標誌物CD326在來自人胚胎幹細胞系(例如H9、H1和HES3)或iPSC的未分化細胞中以高水準均勻表達,而CD56在未分化的hESC或iPSC中不表達。在中內胚層誘導條件下分化後,明顯可檢測到以損失CD326表達和獲得CD56(CD326-CD56+)為特徵的群體。
另外,在hEMP分化後,E-鈣黏蛋白、CD326 / TACSTD1、密連蛋白3、密連蛋白6、密連蛋白7、多配體蛋白1、多配體蛋白2、β-連環蛋白、緊連蛋白、Nanog、Sox 2和/或OCT4可以下調。在hEMP分化之後,Snail-1、Snail2 / Slug、Twist 1、LEF1、ZEB1、MMP9、纖連蛋白、波形蛋白和/或ZEB2可以上調。
hEMP細胞標誌物的調節可藉由此項技術中已知技術來確定,包括蛋白質檢測方法(例如流動式細胞測量術,FACS,蛋白質印跡,ELISA,HPLC,LC/MS,蛋白質免疫沉澱,免疫電泳,蛋白質免疫染色等)和核酸檢測方法(例如mRNA轉錄物分析,Northern印跡,cDNA,DNA微陣列分析,聚合酶鏈式反應,基因表達譜分析等)。 T細胞的分化和選擇
hEMP細胞具有分化成血管內皮細胞(例如血液、內皮),心血管(例如內皮、心肌細胞、平滑肌)和間充質細胞(例如平滑肌、纖維母細胞、骨、軟骨、脂肪)的潛力。淋巴樣細胞包括T細胞,B細胞和天然殺傷細胞。T細胞來源於骨髓中的造血幹細胞。來自造血幹細胞的造血先驅細胞(例如hEMP細胞)填充胸腺並藉由細胞分裂來擴增以產生大量未成熟胸腺細胞。最早的胸腺細胞既不表達CD4也不表達CD8,然而,隨著它們發育,它們變成雙陽性(DP)胸腺細胞(CD4+ CD8+),並最終成熟為單陽性(SP)(CD4+ CD8-或CD4-CD8+)胸腺細胞,然後從胸腺釋放到外周組織。
根據本揭示案的hEMP細胞的增加的效率和產量導致快速且穩健的T譜系定型。在一些實施例中,T細胞可以在ATO系統中從hEMP細胞中分化。在一些實施例中,可使用慢病毒轉導方法使T細胞從hEMP細胞中分化。在一些實施例中,T細胞可以使用基質單層從hEMP細胞中分化。
CD4+ CD3-未成熟單陽性(ISP)細胞和CD4+ CD8+(DP)細胞的出現表明hEMP細胞向T細胞的分化。更成熟的CD3+TCRαβ+細胞出現並隨時間增加。也可產生較小比例的CD3+TCRγδ+ T細胞以逐漸成熟為CD8SP,以及在較小程度上CD4SP T細胞,此情形與ATO中的陽性選擇一致。
胸腺和ATO衍生的T細胞先驅細胞的流動式細胞測量術分析可用於評估以下表面表型:早期胸腺先驅細胞(ETP;CD34+ CD7-CD1a-),CD1a-pro-T(CD34+ CD7+ CD1a-)和CD1a + pro-T(CD34+ CD7+ CD1a+);或CD5-pro-T(pro-T1;CD34+ CD7+ CD5-)和CD5+ pro-T(pro-T2;CD34+ CD7+ CD5+)。將胸腺和ATO衍生的T細胞和前體與以下表型組合來定義為CD14-CD56-:總T系細胞(CD7+ CD5+),雙陰性(DN;CD4-CD8-),CD4未成熟單陽性(CD4 ISP;CD5+CD4+CD3-),雙陽性(DP;CD4+ CD8+),CD8SP(CD3+TCRαβ+ CD8+ CD4-),CD4SP(CD3+TCRαβ+ CD8-CD4+),未成熟初始(CD45RA-CD45RO+,其為CD8SP或CD4SP),成熟初始(CD45RA+ CD45RO-,其為CD8SP或CD4SP)。藉由對CD1a、CD27、CD28和CCR7進行共染色來證實未成熟和成熟的初始表型。 人造胸腺類器官(ATO)
活體內遺傳修飾的鼠模型,人源化小鼠和活體外系統例如OP9-DLL1或最近描述的人造胸腺類器官(ATO)已經顯示出多種途徑,藉由該等途徑可以修飾或培養幹細胞以產生期望的成熟T細胞,包括具有針對抗癌抗原的抗原受體。
根據本揭示案的多能幹細胞和/或hEMP可以在OP9-DLL1或人造胸腺類器官(ATO)細胞培養系統中進一步分化。ATO是一種無血清的三維細胞培養技術,其重現T細胞分化。ATO技術有可能產生現成的工程T細胞來治療癌症和其他疾病。
合適的人造胸腺類器官(ATO)系統支援來自臍帶血、骨髓和外周血HSPC的天然和TCR工程化人T細胞的高效活體外分化和陽性選擇。ATO衍生的T細胞表現出初始表型、不同的TCR庫和TCR依賴性激活和增殖。ATO衍生的工程化T細胞也成熟為初始表型,並進一步在活體外和活體內顯示抗原特異性腫瘤殺傷作用。因此ATO提供了一種有效的方法來產生用於過繼性細胞治療的成熟初始和潛在非同種異體反應的工程化T細胞。用ATO培養系統生產工程化T細胞的示例性方法描述於例如Seet CS, He C, Bethune MT等人Generation of mature T cells from human hematopoietic stem/progenitor cells in artificial thymic organoids. Nature methods. 2017;14(5):521-530. doi:10.1038/nmeth.4237,其內容以引用之方式併入本文中。
高純度的T細胞群可以藉由機械分離從ATO中容易地收集,並且可以藉由標準方法進一步純化以去除<0.5%的污染性基質細胞。每個幹細胞或先驅細胞的ATO細胞產量與接種的細胞(例如hEMP細胞)的數量以及輸入細胞與基質細胞的比率成反比。
ATO系統能夠支援來自先驅細胞(例如hEMP細胞)的人T細胞的分化和陽性選擇,同時保留關鍵的轉化特性,例如標準化組分、再現性和適合於產生用於治療應用的T細胞的可擴展性。本揭示案提供了與人胸腺相比ATO中T細胞分化顯著保真度的手段,最終形成類似於胸腺和血液中發現的T細胞的真正初始T細胞。
根據本揭示案提供有先驅細胞的ATO支援人T細胞的穩健的活體外分化、陽性選擇和成熟。ATO衍生的成熟T細胞表現出抗原初始表型、不同的TCR庫,以及響應於抗原刺激的活化/增殖。ATO還支援從對於腫瘤相關抗原具有特異性的先驅細胞來高效分化TCR工程抗原特異性T細胞。 細胞
本揭示案的細胞可以藉由此項技術已知的任何來源獲得。例如,T細胞可以在活體外從造血幹細胞群體或多能幹細胞分化,或T細胞可以從受試者獲得。T細胞可獲自例如周邊血單核球(PBMC)、骨髓、淋巴結組織、臍帶血、胸腺組織、來自感染部位之組織、腹水、胸膜滲出液、脾組織、及腫瘤。另外,T細胞可以來源於此項技術中可用的一種或多種T細胞系。還可以使用熟習此項技術者已知的許多技術,例如FICOLLTM
分離和/或血球分離,從由受試者採集的血液單位獲得T細胞。在某些實施例中,藉由分離術所收集之細胞可經洗滌以移除血漿級分,且置於適當緩衝液或培養基中以進行後續加工。在一些實施例中,細胞用PBS洗滌。如應當理解,可諸如藉由使用半自動流過離心機(semiautomated flowthrough centrifuge) (例如CobeTM
2991細胞處理機、Baxter CytoMateTM
、或類似者)來使用洗滌步驟。在一些實施例中,將洗滌過的細胞重新懸浮於一種或多種生物相容性緩衝液或含有或不含緩衝液的其他鹽水溶液中。在某些實施例中,可移除分離術樣品之非所要組分。美國專利公開案第2013/0287748號中揭示了分離T細胞用於T細胞療法的另外的方法,其以全文引用之方式併入本文中。
在某些實施例中,T細胞係藉由溶解紅血球且清除單核球(例如經由PERCOLLTM
梯度使用離心)來從PBMC中分離。在一些實施例中,藉由此項技術已知的陰性或陽性選擇技術進一步分離T細胞的特定亞群,例如CD4+、CD8+、CD28+、CD45RA+和CD45RO+ T細胞。例如,藉由陰性選擇來富集T細胞群體可以藉由針對經陰性選擇之細胞所特有的表面標誌物的抗體之組合來完成。可使用經由陰性磁性免疫黏附或流動式細胞測量術進行的細胞分選及/或選擇,其使用針對存在於經陰性選擇之細胞上的細胞表面標誌物的單株抗體之混合物(cocktail)。例如,為了藉由陰性選擇來富集CD4+細胞,單株抗體混合物通常包括針對CD8、CD11b、CD14、CD16、CD20和HLA-DR的抗體。在某些實施例中,使用流動式細胞測量術和細胞分選來分離用於本揭示案的感興趣的細胞群。
在一些實施例中,CD8+細胞藉由鑒別細胞表面抗原來進一步分選成初始細胞、幹細胞記憶細胞、中央記憶細胞、效應記憶細胞及效應細胞,該等細胞表面抗原與此等類型的CD8+細胞中之各者相關。在一些實施例中,中央記憶T細胞之表型標誌物之表現包括CCR7、CD3、CD28、CD45RO、CD62L及CD127,且對顆粒酶B係陰性的。在一些實施例中,中央記憶T細胞係CD8+、CD45RO+及CD62L+ T細胞。在一些實施例中,效應T細胞對CCR7、CD28、CD62L及CD127係陰性的,且對顆粒酶B及穿孔蛋白係陽性的。在某些實施例中,CD4+ T細胞進一步分選成亞群體。例如,CD4+ T輔助細胞可藉由鑒別具有細胞表面抗原之細胞群體來分選成初始細胞、中央記憶細胞、及效應細胞。
在一些實施例中,免疫細胞(諸如T細胞)可在分離後使用已知方法來遺傳修飾,或免疫細胞可在遺傳修飾之前體外活化且擴增(或在先驅細胞之情況下經分化)。在另一個實施例中,多能幹細胞在被誘導成hEMP之前被修飾。在另一個實施例中,藉由ATO來處理經轉導的hEMP。在另一個實施例中,用嵌合抗原受體或TCR(例如,用包含編碼CAR或TCR的一個或多個核苷酸序列的病毒載體轉導)對免疫細胞(例如T細胞)進行遺傳修飾,然後在活體外活化和/或擴增。用於活化和擴增T細胞的方法是此項技術已知的並且描述於例如美國專利案第6,905,874、6,867,041和6,797,514號以及PCT公開案第WO 2012/079000號中,其內容以全文引用之方式併入本文中。通常,此類方法包括在具有適當細胞介素(諸如IL-2)之培養基中將PBMC或經分離之T細胞與通常連接至珠粒或其他表面的刺激藥劑及共刺激藥劑(諸如抗CD3及抗CD28抗體)接觸。連接至相同珠粒的抗CD3及抗CD28抗體用作「替代」抗原呈現細胞(APC)。一個實例係Dynabeads®系統,即針對人類T細胞之生理活化的CD3/CD28活化劑/刺激劑系統。在其他實施例中,使用例如美國專利案第6,040,177、5,827,642號和PCT公開案第WO 2012/129514號中所述的方法,用飼養細胞和合適的抗體和細胞介素將T細胞活化並刺激以便增殖,該等文獻之內容以全文引用之方式併入本文中。
在某些實施例中,T細胞從供體受試者獲得。在一些實施例中,供體受試者是罹患癌症或腫瘤的人類患者。在其他實施例中,供體受試者是不患有癌症或腫瘤的人類患者。
本揭示案的其他態樣涉及包含本文描述的多核苷酸、本文描述的載體、本文描述的多肽或本文描述的活體外細胞的組成物。在一些實施例中,該組合物包含醫藥學上可接受之載劑、稀釋劑、增溶劑、乳化劑、防腐劑或佐劑。在一些實施例中,組成物包含賦形劑。
在其他實施例中,組成物可經選擇以供腸胃外傳遞、吸入、或透過消化道傳遞,諸如經口傳遞。此等醫藥學上可接受的組成物的製備在熟習此項技術者的能力範圍內。在某些實施例中,使用緩衝劑將組成物維持在生理pH或稍低的pH下,通常在約5至約8的pH範圍內。在某些實施例中,當考慮腸胃外投與時,組成物可呈無熱原、腸胃外可接受之水溶液之形式,其包含在醫藥學上可接受之媒劑中的本文所述組成物(其具有或不具有另外的治療劑)。在某些實施例中,用於腸胃外注射之媒劑係無菌蒸餾水,在該無菌蒸餾水中將本文所述組成物(其具有或不具有至少一種另外的治療劑)調配為適當保存的無菌等滲溶液。在某些實施例中,製備可涉及調配所要分子與可提供然後可經由儲槽注射傳遞之產品之控制或持續釋放的聚合化合物(諸如聚乳酸或聚乙醇酸)、珠粒、或脂質體。在某些實施例中,可使用可植入藥物傳遞裝置來引入所要分子或細胞。 癌症治療
本揭示案的方法可用於治療受試者中的癌症,減小腫瘤的大小,殺死腫瘤細胞,防止腫瘤細胞增殖,阻止腫瘤生長,消除患者的腫瘤,防止腫瘤復發,預防腫瘤轉移,誘導患者緩解或其任何組合。在某些實施例中,該等方法誘導完全響應。在其他實施例中,該等方法誘導部分響應。
可能治療的癌症包括沒有血管化、尚未實質血管化或血管化的腫瘤。癌症也可能包括實體瘤或非實體瘤。在一些實施例中,癌症是血液學癌症。在一些實施例中,癌症是白血球。在其他實施例中,癌症是漿細胞。在一些實施例中,癌症是白血病、淋巴瘤或骨髓瘤。在某些實施例中,癌症是急性淋巴母細胞性白血病(ALL)(包括非T細胞ALL),急性淋巴細胞白血病(ALL)和噬血細胞淋巴組織細胞增多症(HLH)),B細胞幼淋巴細胞白血病,B細胞急性淋巴樣白血病(「BALL」),漿細胞樣樹突細胞腫瘤,伯基特淋巴瘤,慢性淋巴細胞白血病(CLL),慢性骨髓性白血病(CML),慢性粒細胞白血病(CML),慢性或急性肉芽腫疾病,慢性或急性白血病,彌漫性大B細胞淋巴瘤,彌漫性大B細胞淋巴瘤(DLBCL),濾泡性淋巴瘤,濾泡性淋巴瘤(FL),毛細胞白血病,噬血細胞症候群(巨噬細胞活化症候群(MAS),霍奇金病,大細胞肉芽腫,白血球黏附缺陷,惡性淋巴增生症,MALT淋巴瘤,套細胞淋巴瘤,邊緣區淋巴瘤,意義未明的單株丙種球蛋白病(MGUS),多發性骨髓瘤,骨髓增生異常和骨髓增生異常症候群(MDS),骨髓疾病包括但不限於急性骨髓性白血病(AML),非霍奇金氏淋巴瘤(NHL),漿細胞增殖性病症(例如,無症狀性骨髓瘤(陰燃性多發性骨髓瘤或無痛性骨髓瘤),漿細胞淋巴瘤,漿細胞樣樹突狀細胞瘤,漿細胞瘤(例如漿細胞惡病質;孤立性骨髓瘤;孤立性漿細胞瘤;髓外漿細胞瘤;和多發性漿細胞瘤),POEMS症候群(Crow-Fukase症候群;Takatsuki病;PEP症候群),原發性縱隔大B細胞淋巴瘤(PMBC),小細胞或大細胞濾泡性淋巴瘤,脾邊緣區淋巴瘤(SMZL),全身性澱粉狀蛋白輕鏈澱粉樣變性病,T細胞急性淋巴性白血病(「TALL」),T細胞淋巴瘤,轉化的濾泡性淋巴瘤,瓦爾登斯特倫巨球蛋白血症或其組合。
在一個實施例中,癌症是骨髓瘤。在一個具體的實施例中,該癌症為多發性骨髓瘤。在另一個實施例中,癌症是白血病。在某些實施例中,癌症為急性骨髓性白血病。
在一些實施例中,該等方法進一步包括投與化學治療劑。在某些實施例中,所選擇的化學治療劑係淋巴球清除(預調節)化學治療劑。有益的預調節治療方案連同相關的有益的生物標誌物描述於美國臨時專利申請案62/262,143及62/167,750中,該等專利特此以全文引用之方式併入本文中。此等專利描述例如用於調節需要T細胞療法之患者的方法,其包含向患者投與指定有益劑量的環磷醯胺(介於200 mg/m2/天與2000 mg/m2/天之間)及指定劑量的氟達拉濱(介於20 mg/m2/天與900 mg/m2/天之間)。一種此類劑量方案涉及治療患者,其包含每日向患者投與約500 mg/m2/天的環磷醯胺及約60 mg/m2/天的氟達拉濱持續三天,之後向患者投與治療有效量的經工程改造之T細胞。
在其他實施例中,抗原結合分子、經轉導之(或以其他方式經工程改造之)細胞(諸如CAR或TCR)、及化學治療劑各自以有效治療受試者之疾病或病狀的量投與。
在某些實施例中,包含本文所揭示之表現CAR及/或TCR的免疫效應細胞之組成物可結合任何數目的化學治療劑投與。化學治療劑之實例包括:烷化劑,諸如噻替派(thiotepa)及環磷醯胺(CYTOXANTM
);烷基磺酸酯,諸如白消安(busulfan)、英丙舒凡(improsulfan)、及哌泊舒凡(piposulfan);氮丙啶類,諸如苯并多巴(benzodopa)、卡巴醌(carboquone)、麥曲多巴(meturedopa)、及左多巴(uredopa);乙烯亞胺類及甲基三聚氰胺類,包括六甲嘧胺(altretamine)、三伸乙基三聚氰胺(triethylenemelamine)、三伸乙基磷醯胺(trietylenephosphoramide)、三伸乙基硫代磷醯胺(triethylenethiophosphaoramide)、及三羥甲基三聚氰胺(trimethylolomelamine resume);氮芥類,諸如氮芥苯丁酸(chlorambucil)、萘氮芥(chlornaphazine)、環磷醯胺(cholophosphamide)、雌氮芥(estramustine)、異環磷醯胺(ifosfamide)、甲氮芥(mechlorethamine)、氧化甲氮芥鹽酸鹽(mechlorethamine oxide hydrochloride)、美法侖(melphalan)、新氮芥(novembichin)、苯芥膽甾醇(phenesterine)、潑尼莫司汀(prednimustine)、氯乙環磷醯胺(trofosfamide)、尿嘧啶氮芥(uracil mustard));亞硝基脲類(諸如亞硝基脲氮芥(carmustine)、氯脲菌素(chlorozotocin)、福莫司汀(fotemustine)、洛莫司汀(lomustine)、尼莫司汀(nimustine)、雷莫司汀(ranimustine);抗生素,諸如阿克拉黴素(aclacinomysins)、放線菌素(actinomycin)、安麯黴素(authramycin)、重氮絲胺酸(azaserine)、博來黴素(bleomycins)、放線菌素C (cactinomycin)、卡奇黴素(calicheamicin)、卡柔比星(carabicin)、洋紅黴素(carminomycin)、嗜癌菌素(carzinophilin)、色黴素(chromomycin)、放線菌素D (dactinomycin)、柔紅黴素(daunorubicin)、地托比星(detorubicin)、6-重氮基-5-側氧基-L-正白胺酸、多柔比星(doxorubicin)、表柔比星(epirubicin)、依索比星(esorubicin)、伊達比星(idarubicin)、麻西羅黴素(marcellomycin)、絲裂黴素(mitomycin)、黴酚酸(mycophenolic acid)、諾加黴素(nogalamycin)、橄欖黴素(olivomycin)、培洛黴素(peplomycin)、泊非黴素(potfiromycin)、嘌呤黴素(puromycin)、三鐵阿黴素(quelamycin)、羅多比星(rodorubicin)、鏈黑菌素(streptonigrin)、鏈脲黴素(streptozocin)、殺結核菌素(tubercidin)、烏苯美司(ubenimex)、淨司他丁(zinostatin)、佐柔比星(zorubicin);抗代謝物,諸如甲胺蝶呤及5-氟尿嘧啶(5-FU);葉酸類似物,諸如二甲葉酸(denopterin)、甲胺蝶呤、蝶羅呤(pteropterin)、三甲曲沙(trimetrexate);嘌呤類似物,諸如氟達拉濱(fludarabine)、6-巰嘌呤、硫咪嘌呤(thiamiprine)、硫鳥嘌呤(thioguanine);嘧啶類似物,諸如環胞苷(ancitabine)、阿紮胞苷(azacitidine)、6-氮尿苷、卡莫氟(carmofur)、阿糖胞苷(cytarabine)、雙去氧尿苷、去氧氟尿苷(doxifluridine)、依諾他濱(enocitabine)、氟尿苷(floxuridine)、5-FU;雄激素,諸如卡魯睾酮(calusterone)、屈他雄酮丙酸酯(dromostanolone propionate)、硫雄甾醇(epitiostanol)、美雄烷(mepitiostane)、睾內酯(testolactone);抗腎上腺劑,諸如胺魯米特(aminoglutethimide)、米托坦(mitotane)、曲洛司坦(trilostane);葉酸補充劑,諸如亞葉酸(frolinic acid);醋葡醛內酯(aceglatone);醛磷醯胺醣苷(aldophosphamide glycoside);胺基酮戊酸(aminolevulinic acid);安吖啶(amsacrine);阿莫司汀(bestrabucil);比生群(bisantrene);依達曲沙(edatraxate);地氟法胺(defofamine);地美可辛(demecolcine);地吖醌(diaziquone);埃氟米辛(elformithine);依利醋銨(elliptinium acetate);依託格魯(etoglucid);硝酸鎵;羥基脲;香菇多糖(lentinan);氯尼達明(lonidamine);米托胍腙(mitoguazone);米托蒽醌(mitoxantrone);莫哌達醇(mopidamol);二胺硝吖啶(nitracrine);噴司他丁(pentostatin);蛋胺氮芥(phenamet);吡柔比星(pirarubicin);鬼臼酸(podophyllinic acid);2-乙基醯肼;丙卡巴肼(procarbazine);PSK®;雷佐生(razoxane);西佐喃(sizofiran);鍺螺胺(spirogermanium);細交鏈孢菌酮酸(tenuazonic acid);三亞胺醌(triaziquone);2, 2',2''-三氯三乙基胺;烏拉坦(urethan);長春地辛(vindesine);達卡巴嗪(dacarbazine);甘露醇氮芥(mannomustine);二溴甘露醇(mitobronitol);二溴衛矛醇(mitobronitol);哌泊溴烷(pipobroman);胞嘧啶(gacytosine);阿拉伯糖苷(arabinoside,「Ara-C」);環磷醯胺;噻替派;紫杉烷類,例如太平洋紫杉醇(paclitaxel) (TAXOLTM
, Bristol-Myers Squibb)及歐洲紫衫醇(doxetaxel) (TAXOTERE®, Rhone-Poulenc Rorer);氮芥苯丁酸;吉西他濱;6-硫鳥嘌呤;巰基嘌呤;甲胺蝶呤;鉑類似物,諸如順鉑及卡鉑;長春花鹼;鉑;依託泊苷(VP-16);異環磷醯胺;絲裂黴素C;米托蒽醌;長春新鹼;長春瑞濱;諾維本;諾安托;替尼泊苷;道諾黴素;胺基蝶呤;希羅達;伊班膦酸鹽;CPT-11;拓撲異構酶抑制劑RFS2000;二氟甲基鳥胺酸(DMFO);視黃酸衍生物,諸如TargretinTM
(蓓薩羅丁)、PanretinTM
、(阿利維A酸);ONTAKTM
(地尼白介素);卡培他濱;及以上任一者之醫藥學上可接受之鹽、酸、或衍生物。在一些實施例中,包含本文所揭示之表現CAR及/或TCR的免疫效應細胞之組成物可結合用於調控或抑制激素對腫瘤之作用之抗激素藥劑來投與,諸如抗雌激素,包括例如他莫昔芬、雷洛昔芬、芳香酶抑制性4(5)-咪唑、4-羥基他莫昔芬、曲沃昔芬、克昔芬、LY117018、奧那司酮、及托瑞米芬(法樂通);及抗雄激素,諸如氟他胺、尼魯米特、比卡魯胺、亮丙瑞林、及戈舍瑞林;及以上任一者之醫藥學上可接受之鹽、酸、或衍生物。適當時,亦投與化學治療劑之組合,其包括但不限於CHOP,(即,環磷醯胺(Cytoxan®))、多柔比星(羥基多柔比星)、長春新鹼(Oncovin®)、及強的松。
在一些實施例中,化學治療劑係在投與經工程改造之細胞或核酸同時或之後一週內投與。在其他實施例中,化學治療劑係在投與經工程改造之細胞或核酸之後1至4週、1週至1個月、1週至2個月、1週至3個月、1週至6個月、1週至9個月、或1週至12個月投與。在其他實施例中,化學治療劑係在投與細胞或核酸之前至少1個月投與。在一些實施例中,該等方法進一步包含投與二或更多種化學治療劑。
多種另外的治療劑可結合本文所述之組成物使用。例如,潛在有用的另外治療劑包括PD-1抑制劑,諸如納武單抗(nivolumab) (OPDIVO®
)、派姆單抗(pembrolizumab)(KEYTRUDA®
)、派姆單抗、pidilizumab (Cure Tech)、及阿特朱單抗(atezolizumab)(Roche)。
適合與本揭示案組合使用的另外的治療劑包括但不限於依魯替尼(IMBRUVICA®
),奧法木單抗(ARZERRA®
),利妥昔單抗(RITUXAN®
),貝伐單抗(AVASTIN®
),曲妥珠單抗(HERCEPTIN®
),曲妥珠單抗埃他替尼(KADCYLA®
),伊馬替尼(GLEEVEC®
),西妥昔單抗(ERBITUX®
),帕尼單抗(VECTIBIX®
),卡妥索單抗,替伊莫單抗,奧法木單抗,托西莫單抗,本妥昔單抗,阿侖單抗,吉姆單抗,埃羅替尼,吉非替尼,凡德他尼,阿法替尼,拉帕替尼,奈拉替尼,阿西替尼,馬西替尼,帕唑帕尼,舒尼替尼,索拉非尼,塞來尼布,舒尼替尼,塞馬替尼,索拉非尼,托西尼布,來他替尼,阿西替尼,西地尼布,樂伐替尼,尼達尼布,帕唑帕尼,瑞格非尼,司馬沙尼,索拉非尼,舒尼替尼,tivozanib,托西尼布,凡德他尼,恩曲替尼,卡博替尼,伊馬替尼,達沙替尼,尼羅替尼,普那替尼,拉多替尼,波舒替尼,來他替尼,魯索替尼,pacritinib,考比替尼,司美替尼,曲美替尼,binimetinib,艾樂替尼,色瑞替尼,克唑替尼,阿柏西普,adipotide,denileukin diftitox,mTOR抑制劑如依維莫司和西羅莫司,hedgehog抑制劑如索尼德吉和維莫德吉,CDK抑制劑如CDK抑制劑(帕博西尼)。
在另外的實施例中,包含含有CAR及/或TCR之免疫之組成物可與抗炎劑一起投與。抗炎劑或藥物可包括但不限於類固醇及糖皮質素(包括倍他米松(betamethasone)、布地奈德(budesonide)、地塞米松(dexamethasone)、乙酸氫化可的松(hydrocortisone acetate)、氫化可的松(hydrocortisone)、氫化可的松、甲基強的松龍(methylprednisolone)、強的松龍(prednisolone)、強的松(prednisone)、曲安西龍(triamcinolone));非類固醇抗炎藥(NSAIDS),包括阿司匹林、布洛芬(ibuprofen)、萘普生(naproxen)、甲胺蝶呤、柳氮磺胺吡啶(sulfasalazine)、來氟米特(leflunomide)、抗TNF藥物、環磷醯胺、及黴酚酸酯。示範性NSAID包括布洛芬、萘普生、萘普生鈉、Cox-2抑制劑、及唾液酸酯(sialylate)。示範性止痛劑包括乙醯酚胺(acetaminophen)、羥考酮(oxycodone)、曲馬多(tramadol)、或鹽酸普帕西芬(proporxyphene hydrochloride)。示範性糖皮質素包括可的松、地塞米松、氫化可的松、甲基強的松龍、強的松龍、或強的松。示範性生物反應修飾劑包括針對細胞表面標誌物(例如,CD4、CD5等等)之分子、細胞介素抑制劑諸如TNF拮抗劑(例如,依那西普(etanercept) (ENBREL®
)、阿達木單抗(HUMIRA®
)及英夫利昔單抗(REMICADE®
)、趨化介素抑制劑、及黏附分子抑制劑。生物反應修飾劑包括單株抗體以及重組形式的分子。示範性DMARD包括硫唑嘌呤、環磷醯胺、環孢素、甲胺蝶呤、青黴胺、來氟米特、柳氮磺胺吡啶、羥氯喹(hydroxychloroquine)、Gold (口服(金諾芬(auranofin))及肌內)、及米諾環素(minocycline)。
在某些實施例中,本文所述之組成物係結合細胞介素投與。如本文所使用之「細胞介素」係指一個細胞群體所釋放之作為細胞間介體作用於另一個細胞的蛋白質。細胞介素之實例係淋巴因子、單核因子、及傳統多肽激素。細胞介素中包括:生長激素,諸如人類生長激素、N-甲硫胺醯人類生長激素、及牛生長激素;副甲狀腺激素;甲狀腺素;胰島素;胰島素原;鬆弛素;鬆弛素原;醣蛋白激素,諸如濾泡刺激素(FSH)、甲狀腺刺激素(TSH)、及黃體成長激素(LH);肝生長因子(HGF);纖維母細胞生長因子(FGF);催乳素;胎盤生乳素;慕氏抑制物質(mullerian-inhibiting substance);小鼠促性腺素相關肽;抑制素;活化素;血管內皮生長因子;整合蛋白;血小板生成素(TPO);神經生長因子(NGF),諸如NGF-β;血小板生長因子;轉化生長因子(TGF),諸如TGF-α及TGF-β;胰島素樣生長因子-I及胰島素樣生長因子-II;紅血球生成素(EPO);骨誘導因子( osteoinductive factor);干擾素,諸如干擾素-α、干擾素-β、及干擾素-γ;群落刺激因子(CSF),諸如巨噬細胞-CSF(M-CSF);顆粒球-巨噬細胞-CSF (GM-CSF);及顆粒球-CSF (G-CSF);白介素(IL),諸如IL-1、IL-1α、IL-2、IL-3、IL-4、IL-5、IL-6、IL-7、IL-8、IL-9、IL-10、IL-11、IL-12、IL-15;腫瘤壞死因子,諸如TNF-α或TNF-β;及其他多肽因子,包括LIF及kit配位體(KL)。如本文所使用,術語細胞介素包括來自天然來源或重組細胞培養物之蛋白質、及生物活性當量的原態序列細胞介素。
本揭示案的另一個態樣涉及誘導針對腫瘤的免疫力的方法,其包括向受試者投與有效量的本文揭示的修飾的T細胞。本揭示案的另一態樣涉及在受試者中誘導免疫應答的方法,其包括投與有效量的本申請案的工程化免疫細胞。在一些實施例中,免疫反應是T細胞介導之免疫反應。在一些實施例中,T細胞介導之免疫反應係針對一或多種靶細胞。在一些實施例中,工程化免疫細胞包含CAR或TCR,其中CAR或TCR包含本揭示案中描述的THD。在一些實施例中,靶細胞係腫瘤細胞。
本揭示案的另一個態樣涉及治療或預防惡性腫瘤的方法,該方法包括向有需要的受試者投與有效量的至少一種免疫細胞,其中該免疫細胞包含至少一種CAR或TCR。
本揭示案的另一個態樣涉及治療有需要的受試者中的癌症的方法,其包括向受試者投與多核苷酸、載體、CAR或TCR、細胞或本文揭示的組成物。在一個實施例中,該方法包括投與編碼CAR或TCR的多核苷酸。在另一個實施例中,該方法包括投與包含編碼CAR或TCR的多核苷酸的載體。在另一個實施例中,該方法包括投與由本文揭示的多核苷酸編碼的CAR或TCR。在另一個實施例中,該方法包括投與包含編碼CAR或TCR的多核苷酸的細胞或包含該多核苷酸的載體。
在一些實施例中,用於T細胞療法的供體T細胞從患者獲得(例如,用於自體T細胞療法)。在其他實施例中,待分化成用於T細胞療法的T細胞的供體幹細胞從不是患者的受試者獲得。
T細胞可以以治療有效量投與。例如,治療有效量的T細胞可以是至少約104
個細胞,至少約105
個細胞,至少約106
個細胞,至少約107
個細胞,至少約108
個細胞,至少約109
或在至少約1010
。在另一個實施例中,T細胞的治療有效量是約104
個細胞,約105
個細胞,約106
個細胞,約107
個細胞或約108
個細胞。在一個具體的實施例中,CAR T細胞或TCR T細胞的治療有效量為約2×106
個細胞/kg,約3×106
個細胞/kg,約4×106
個細胞/kg,約5×106
個細胞/kg,約6×106
個細胞/kg,約7×106
個細胞/kg,約8×106
個細胞/kg,約9×106
個細胞/kg,約1×107
個細胞/kg,約2×107
個細胞/kg,約3×107
個細胞/kg,約4×107
個細胞/kg,約5×107
個細胞/kg,約6×107
個細胞/kg,約7×107
個細胞/kg,約8×107
個細胞/kg或9×107
個細胞/kg。 免疫耐受
本揭示案的方法可以用於治療受試者的免疫耐受性疾病。在某些實施例中,該等方法誘導完全響應。在其他實施例中,該等方法誘導部分響應。
中樞或外周耐受缺陷可導致自身免疫性疾病,導致症候群諸如全身性紅斑狼瘡,類風濕性關節炎,1型糖尿病,1型自身免疫性多內分泌症候群(APS-1)和免疫失調性多內分泌疾病腸病X連鎖症候群(IPEX),並可能導致哮喘、過敏和炎症性腸病。免疫耐受在移植排斥中也可能是有問題的,例如幹細胞移植、腎移植、肝移植等。
本說明書中提及之所有公開案、專利及專利申請案均以引用之方式併入本文,達到如同明確及個別地指示將各個個別公開案、專利或專利申請案以引用之方式併入的相同程度。然而,本文對參考文獻之引用不應解釋為承認此類參考文獻為本發明之先前技術。在以引用之方式併入的參考文獻中所提供之任何定義或術語與在本文中所提供之術語及討論不同的情況下,以本發明術語及定義為準。
本發明係由以下實例進一步說明,不應將該等以下實例視為作進一步限制。本申請案通篇引用的所有參考文獻的內容明確地以引用之方式併入本文中。實例 實例 1 :集群與單細胞之間的 hEMP 誘導的比較
這個實例說明了集群與單細胞之間hEMP誘導的比較。
將呈集群形式的ES細胞的匯合板手動傳代,並以相當於孔的20%、40%和80%來鋪放在經Matrigel®塗覆的6孔板中。此外,藉由酶消化將ES細胞的匯合板以化學方式破碎並計數以確定每表面積的細胞數。單細胞以1.8x106
(20%匯合)、3.6x106
(40%匯合)和7.2x106
(80%匯合)來接種。細胞在已知將ES細胞保持處於未分化狀態下作為對照的mTeSR1培養基中或在X-VIVOTM
-15 hEMP推動培養基中培養。在所有條件下,包括小分子Y27632 ROCK抑制劑以幫助ES細胞在傳代期間存活。在d1、d2、d3和d4的所有條件下收穫細胞。表1、表2和表3顯示了實驗的圖。
過渡至hEMP的ES細胞的特徵在於CD326 EPCAM的喪失和CD56 NCAM的獲得。基於表面表達的CD326和CD56的變化的表型分析表明單細胞方法比基於集群的方法在產生具有在6孔板中1.8-7.2x106
個細胞/孔或2.53-7.58×105
個細胞/cm2
的最佳密度的hEMP方面更有效。示例性流動式細胞測量術資料和說明表面表達CD326和CD56的變化的匯總圖分別顯示在圖1和圖2中。圖3中顯示了用於產生hEMP細胞的示例性過程。實例 2 : Matrigel ® 和玻連蛋白在中胚層推動中的比較以及細胞擴增的評估
該實例提供了Matrigel®
或玻連蛋白存在下hEMP誘導的比較。為了研究從hEMP誘導過程中除去由小鼠肉瘤細胞產生的不確定產物Matrigel®
的效果,進行中胚層推動實驗。
將單細胞以5%或40%匯合接種在用Matrigel®
(組織培養物處理的板)或重組人玻連蛋白(非組織培養物處理的板)包被的6孔板中。細胞生長3天,並將一部分細胞傳代並以5%或40%密度重新鋪放在新鮮塗布的板上,並再生長3天。收穫細胞並評估CD326和CD56表達。實驗設計之概述示出於表4中。
如圖4所示,在所有測試的實驗條件下均觀察到Matrigel®
和玻連蛋白塗布表面之間的等效hEMP表型。重組人玻連蛋白至少等同於Matrigel®
作為將hEMP從ES細胞中分化的基質。有趣的是,如表5和表6所總結的,40%的初始接種密度在d3分裂為5%密度允許從輸入ES細胞的數量擴增hEMP約10倍(13.31)。圖5中示出了包括接種步驟的用於產生hEMP細胞的示例性方法。 實例 3 :將 hEMP 細胞分化成 T 細胞
根據本揭示案的非聚集細胞方法產生的hEMP細胞可用於增加活體外系統(例如ATO系統)中T細胞分化的效率。如所述誘導hEMP細胞,並在FACSAria Fusion(BD)上分選。對於非hEMP和hEMP,分選後純度測定為> 95%(圖6)。使用由在PBS,1%青黴素/鏈黴素(Gemini Bio-Products,West Sacramento,CA),1%Glutamax(ThermoFisher Scientific,Grand Island,NY),5 ng/ml rhFLT3L,5 ng/ml rhIL-7和50ng/ml SCF(Peprotech,Rocky Hill,NJ)中重構的RPMI 1640(Corning,Manassas,VA),2%XenoFree B27(ThermoFisher Scientific,Grand Island,NY),30 μM L-抗壞血酸2-磷酸鹽倍半鎂鹽水合物(Sigma-Aldrich,St.Louis,MO)組成的無血清ATO培養基(「RB27」)來誘導T細胞分化。2%XenoFree B27代替B27。
每個ATO將0.5x106
個MS5-hDL4細胞與1x104
純化的hEMP細胞在50ml錐形小瓶中合併,並以500 g在擺動桶式離心機中離心5 min。小心移除上清液,並藉由短暫渦旋使細胞沉澱重新懸浮。對於每個ATO,將0.4 μm Millicell transwell插入物(EMD Millipore,Billerica,MA;Cat.PICM0RG50)置於每孔含有1 ml RB27的6孔板中。為了塗覆ATO,將插入物取出並放在板的邊緣以排出多餘的培養基。將細胞漿液調整至每ATO 5 μl,用20 μl移液管末端吸入,並藉由在移液管末端形成滴液進行接種,滴液輕輕地沉積在細胞插入物上。將細胞插入物放回含有1 mL RB27的孔中。每3-4天,藉由從細胞插入物周圍抽吸,隨後用1 ml新鮮RB27/細胞介素替換,從而徹底更換培養基。ATO以這種方式培養長達8週。藉由向每個孔中加入FACS緩衝液(PBS / 0.5%牛血清蛋白/ 2mM EDTA),並藉由移液來短暫解聚ATO,然後穿過70 μm尼龍過濾器,從而收穫ATO細胞。
收集的細胞在4C在黑暗中用以下抗原的抗體:CD45、CD56、CD3、CD4、CD8、TCRab(Biolegend)來染色30分鐘。細胞用PBS洗滌並在Fortessa X20(BD)上分析以分析T細胞發育。圖7顯示了第4週的細胞實例。
從以下結合附圖的詳細描述中將更清楚地理解以上和其他特徵。然而,圖式僅為了說明目的,並非具有限制性。
圖1顯示了說明表面表達CD326和CD56的變化的示例性流動式細胞測量術資料。
圖2顯示了示例性流動式細胞測量術資料的匯總圖,其說明了表面表達的CD326和CD56中的變化。
圖3顯示了由ES或iPS細胞產生hEMP細胞的示例性流程圖。
圖4顯示了示例性流動式細胞測量術資料,其說明Matrigel®
和玻連蛋白基質上表面表達的CD326和CD56的變化。
圖5顯示了由ES或iPS細胞產生hEMP細胞的示例性流程圖。
圖6顯示流動式細胞測量術資料,說明細胞是誘導和分選的hEMP細胞的純度。對於非hEMP和hEMP細胞,分選後純度均測定為> 95%。
圖7顯示流動式細胞測量術資料,其說明在第4週T細胞發育的分析。收穫的細胞用以下抗原的抗體染色:CD45、CD56、CD3、CD4、CD8、TCRab。
Claims (47)
- 一種產生人胚胎間充質先驅(hEMP)細胞的方法,該方法包括以下步驟: (a) 使非聚集幹細胞在限定的單細胞密度下與基質接觸; (b) 在促進細胞生長的培養條件下培養該等幹細胞至所需匯合度;和 (c) 改變該等培養條件以誘導該等幹細胞分化成hEMP細胞達所需的溫育時間; 從而產生hEMP細胞。
- 如請求項1之方法,其中該等幹細胞是人胚胎幹(ES)細胞或誘導多能幹(iPS)細胞。
- 如請求項2之方法,其中該等ES或iPS細胞來源於人。
- 如請求項3之方法,其中該等ES或iPS細胞是H1細胞、H9細胞、HES3細胞、HSF1細胞、HSF6細胞、ESI-017細胞、CS02iCTR-NTn1細胞、CS03iCTR-NTn1細胞、CS80iCTR-Tn3細胞、CS179iCTR- NTn1細胞、CS201iCTR-NTn4細胞、CS202iCTR-NTn2細胞或CS206iCTR-Tn5細胞。
- 如前述請求項中任一項之方法,其中該限定的單細胞密度在約1.5×105 與約8×105 個細胞/cm2 之間。
- 如請求項5之方法,其中該限定的單細胞密度為約1.89×105 個細胞/cm2 、約3.2×105 個細胞/cm2 、約3.4×105 個細胞/cm2 、約3.6×105 個細胞/cm2 、約3.79×105 個細胞/cm2 、約7.2×105 個細胞/cm2 或約7.58×105 個細胞/cm2 。
- 如前述請求項中任一項之方法,其中該基質用Matrigel® 或重組人玻連蛋白而不用小鼠胚胎纖維母細胞(MEF)來包被。
- 如前述請求項中任一項之方法,其中該基質是孔板、細胞培養皿、膜、袋、培養瓶、反蛋白石、聚合物晶格、靜態細胞懸浮液、攪動的細胞懸浮液或血漿處理的聚合物。
- 如請求項8之方法,其中該基質包含膜。
- 如前述請求項中任一項之方法,其中促進細胞生長的該等培養條件包括在mTeSR1培養基中培養該等幹細胞。
- 如請求項10之方法,其中該mTeSR1培養基包含該ROCK抑制劑Y27632。
- 如前述請求項中任一項之方法,其中該期望的匯合度在約20%與約80%之間。
- 如請求項12之方法,其中該匯合度為約20%、約30%、約40%、約50%、約60%、約70%或約80%。
- 如前述請求項中任一項之方法,其中改變該等培養條件的步驟包括添加X-VIVOTM 15。
- 如前述請求項中任一項之方法,其中該溫育時間在約2天與約4天之間。
- 如請求項15之方法,其中該溫育時間為約2.0、約2.5、約3.0、約3.5或約4.0天。
- 如請求項16之方法,其中該溫育時間為約3.5天。
- 如前述請求項中任一項之方法,其進一步包括使該等hEMP細胞分化成T細胞的步驟。
- 如前述請求項中任一項之方法,其中該方法進一步包括破壞幹細胞集群以產生該等非聚集幹細胞的步驟。
- 如請求項19之方法,其中該等幹細胞集群藉由機械或化學破壞來破壞。
- 如請求項20之方法,其中該化學破壞包括與胰蛋白酶樣酶一起溫育。
- 如請求項21之方法,其中該胰蛋白酶樣酶是胰蛋白酶、TrypLE Express、TrypLE Select、膠原酶、分散酶、胰蛋白酶-EDTA。
- 一種人胚胎間充質先驅(hEMP)細胞,其根據前述請求項中任一項之方法來產生。
- 一種組成物,其包含根據請求項1至22中任一項之方法產生的人胚胎間充質先驅(hEMP)細胞群。
- 一種產生T細胞之方法,該方法包含以下步驟: (a) 使非聚集幹細胞在限定的單細胞密度下與基質接觸,其中該等幹細胞不包含小鼠胚胎纖維母細胞(MEF); (b) 在促進細胞生長的培養條件下培養該等幹細胞至期望的匯合度;和 (c) 改變該等培養條件以誘導該等幹細胞分化成T細胞達所需的溫育時間; 由此從幹細胞產生T細胞。
- 如請求項25之方法,其中該等幹細胞是人胚胎幹(ES)細胞或誘導多能幹(iPS)細胞。
- 如請求項26之方法,其中該等ES或iPS細胞來源於人。
- 如請求項26或27之方法,其中該等ES或iPS細胞是H1細胞、H9細胞、HES3細胞、HSF1細胞、HSF6細胞、ESI-017細胞、CS02iCTR-NTn1細胞、CS03iCTR-NTn1細胞、CS80iCTR-Tn3細胞、CS179iCTR-NTn1細胞、CS201iCTR-NTn4細胞、CS202iCTR-NTn2細胞或CS206iCTR-Tn5細胞。
- 如請求項25至28中任一項之方法,其中該限定的單細胞密度在約1.5×105 與約8×105 個細胞/cm2 之間。
- 如請求項25至29中任一項之方法,其中該限定的單細胞密度為約1.89×105 個細胞/cm2 、約3.2×105 個細胞/cm2 、約3.4×105 個細胞/cm2 、約3.6×105 個細胞/cm2 、約3.79×105 細胞/cm2 、約7.2×105 個細胞/cm2 或約7.58×105 個細胞/cm2 。
- 如請求項25至30中任一項之方法,其中該基質用Matrigel® 或重組人玻連蛋白而不用小鼠胚胎纖維母細胞(MEF)來包被。
- 如請求項25至31中任一項之方法,其中該基質是孔板、細胞培養皿、膜、袋、培養瓶、反蛋白石、聚合物晶格、靜態細胞懸浮液、攪動的細胞懸浮液或血漿處理的聚合物。
- 如請求項32之方法,其中該基質包含膜。
- 如請求項25至33中任一項之方法,其中促進細胞生長的該等培養條件包括在mTeSR1培養基中培養該等幹細胞。
- 如請求項34之方法,其中該mTeSR1培養基包含該ROCK抑制劑Y27632。
- 如請求項25至35中任一項之方法,其中所需的匯合度在約20%與約80%之間。
- 如請求項36之方法,其中該匯合度為約20%、約30%、約40%、約50%、約60%、約70%或約80%。
- 如請求項25至37中任一項之方法,其中改變該等培養條件的步驟包括添加X-VIVOTM 15。
- 如請求項25至38中任一項之方法,其中該溫育時間在約2天與約4天之間。
- 如請求項39之方法,其中該溫育時間為約2.0、約2.5、約3.0、約3.5或約4.0天。
- 如請求項40之方法,其中該溫育時間為約3.5週。
- 如請求項25至41中任一項之方法,其中該方法進一步包括破壞幹細胞的集群以產生該等非聚集幹細胞的步驟。
- 如請求項42之方法,其中該等幹細胞集群藉由機械或化學破壞來破壞。
- 如請求項43之方法,其中該化學破壞包括與胰蛋白酶樣酶一起溫育。
- 如請求項44之方法,其中該胰蛋白酶樣酶是胰蛋白酶、TrypLE Express、TrypLE Select、膠原酶、分散酶、胰蛋白酶-EDTA。
- 一種T細胞,其根據請求項25至45中任一項之方法產生。
- 一種組成物,其包含根據請求項25至45中任一項之方法產生的T細胞群。
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US11058669B2 (en) * | 2015-01-19 | 2021-07-13 | Keio University | Therapeutic agents for inner ear hearing impairment |
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JP2020521467A (ja) | 2020-07-27 |
MX2019014088A (es) | 2020-02-07 |
JP2022058672A (ja) | 2022-04-12 |
CN110662831A (zh) | 2020-01-07 |
AU2022200647A1 (en) | 2022-02-24 |
CA3064018A1 (en) | 2018-11-29 |
KR20210118479A (ko) | 2021-09-30 |
WO2018218105A1 (en) | 2018-11-29 |
KR20200010424A (ko) | 2020-01-30 |
KR20230143631A (ko) | 2023-10-12 |
AU2018272017A1 (en) | 2019-12-05 |
KR20220039859A (ko) | 2022-03-29 |
MA49351A (fr) | 2020-04-08 |
BR112019024613A2 (pt) | 2020-06-16 |
IL270770A (en) | 2020-01-30 |
EP3630950A1 (en) | 2020-04-08 |
CO2019013175A2 (es) | 2020-01-17 |
NZ759234A (en) | 2022-12-23 |
AU2018272017B2 (en) | 2021-11-04 |
JP7014820B2 (ja) | 2022-02-01 |
JP2024045306A (ja) | 2024-04-02 |
IL270770B2 (en) | 2024-03-01 |
US20180369284A1 (en) | 2018-12-27 |
IL270770B1 (en) | 2023-11-01 |
KR102426447B1 (ko) | 2022-07-29 |
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