TW202045533A - 用於治療癌症之經修飾il-12 t細胞療法 - Google Patents
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Abstract
本文提供包括腫瘤靶向及膜錨定之IL-12之嵌合抗原受體(CAR)樣構築體。本文亦提供表現該CAR樣IL-12構築體之T細胞。另外,本文提供治療癌症之方法,其包括投與表現CAR樣IL-12之T細胞。
Description
本發明概言之係關於免疫學及醫學之領域。更特定而言,其係關於經修飾IL-12 T細胞療法及其用於治療癌症之用途。
自體腫瘤浸潤性淋巴球(TIL)輸注已成為治療難治性黑色素瘤患者之重大突破且其反應率高於BRAF靶向療法或CTLA-4阻斷療法。大部分患者應經歷對TIL轉移之反應,此乃因可自其腫瘤分離TIL。然而,在實踐中,反應率僅為約50% (包含10%-15%完全反應率) (Besser等人,2010;Radvanyi等人,2012;Dudley等人,2005)。
TIL療法中之主要難題在於TIL在再輸注後之腫瘤歸向能力降低以及腫瘤微環境之變化。在最新臨床試驗中,輸注1.5-2×1011
個TIL以確保足夠腫瘤靶向TIL及成功腫瘤緩解(Radvanyi等人,2012;Dudley等人,2005)。然而,將如此多之TIL轉移至癌症患者中可引起脫靶不良效應。需要使得能夠將TIL更有效地遞送至腫瘤位點且由此需要極少數量之輸注T細胞之方式。
TIL不能到達腫瘤位點之一個原因在於在離體培養期間損失腫瘤歸向特性;因此,新療法使用已經識別腫瘤抗原(例如CD19)之受體改造之T細胞且稱為嵌合抗原受體(CAR)-T細胞療法。CAR-T細胞療法更特異性地靶向腫瘤細胞且在治療血液學惡性腫瘤方面取得重大成功(其中CAR-T細胞靶向血液及骨髓中之腫瘤細胞)。然而,CAR-T細胞療法在實體腫瘤中之效能有限。實體腫瘤細胞因其異質性而缺乏常見抗原。另外,宿主條件化通常可避免T細胞進入腫瘤間質中。
在使用T細胞療法(包含CAR-T、TIL及TCR-T (CTL)細胞)治療實體腫瘤中存在多個難題,包含逃避抗原或靶特異性T細胞攻擊之腫瘤異質性、T細胞滲透至實體腫瘤中、浸潤T細胞由免疫抑制環境不活化及效應T細胞耗竭。因此,未滿足性地需要能夠深度滲透至實體腫瘤中之T細胞療法。
在第一實施例中,本發明提供編碼腫瘤靶向及膜錨定介白素12 (IL-12)之構築體。IL-12可包括IL-12 α亞單元p35及IL-12 β亞單元p40。
在一些態樣中,p35亞單元融合至跨膜域(TM) (例如EGFR跨膜域)。在某些態樣中,p35/TM亞單元進一步融合至信號傳導域(SD)。舉例而言,信號傳導域係CD3ζ、CD28及/或4-1BB信號傳導域。在特定態樣中,信號傳導域包括CD3ζ及4-1BB信號傳導域。在一些態樣中,信號傳導域係4-1BB。
在某些態樣中,p40亞單元融合至腫瘤靶向部分。舉例而言,腫瘤靶向部分係肽、抗體或其片段。在一些態樣中,抗體或其片段係選自由以下組成之群:F(ab’)2、Fab’、Fab、Fv及scFv。在特定態樣中,抗體或其片段係scFv。在一些態樣中,腫瘤靶向部分係肽。在具體態樣中,腫瘤靶向部分特異性結合細胞表面波形蛋白(CSV),例如CSV肽。在其他態樣中,p40亞單元融合至跨膜域及/或信號傳導域且p35亞單元融合至腫瘤靶向部分。包括p35融合亞單元(p35/TM/SD)及p40融合體(p40-腫瘤靶向部分)之異源二聚體在本文中稱為嵌合抗原受體(CAR)樣IL12 (CARL-IL12)。
在一些態樣中,構築體係病毒載體。舉例而言,病毒載體係逆轉錄病毒載體或慢病毒載體。
在另一實施例中,提供經改造以表現實施例之構築體之宿主細胞(例如表現腫瘤靶向及膜錨定IL-12或CARL-IL12之構築體)。在一些態樣中,宿主細胞係免疫細胞。舉例而言,免疫細胞係腫瘤歸向細胞。在某些態樣中,免疫細胞係T細胞。在一些態樣中,T細胞係周邊血T細胞。在一些態樣中,T細胞係CD4+
T細胞或CD8+
T細胞。在某些態樣中,T細胞係自體或同種異體的。在其他態樣中,免疫細胞係NK細胞。
本文進一步提供包括實施例之IL-12免疫細胞(例如經改造以表現腫瘤靶向及膜錨定IL-12或CARL-IL12之免疫細胞)及醫藥載劑之醫藥組合物。另一實施例提供包括有效量之實施例之IL-12免疫細胞(例如經改造以表現表現膜錨定IL-12之構築體之免疫細胞)之組合物,其用於治療個體之癌症。
在又一實施例中,提供治療個體之癌症之方法,其包括向個體投與有效量之實施例之IL-12免疫細胞(例如經改造以表現腫瘤靶向及膜錨定IL-12或CARL-IL12基因之免疫細胞)。在特定態樣中,CARL-IL12錨定至該等免疫細胞之膜。
在一些態樣中,癌症係神經膠母細胞瘤、子宮頸癌、胰臟癌、卵巢癌、子宮癌、食道癌、黑色素瘤癌、頭頸癌、結腸直腸癌、膀胱癌、肺癌、前列腺癌、肉瘤癌、乳癌、肝癌、腎癌或急性骨髓性白血病。
在其他態樣中,該方法進一步包括向個體至少投與第二抗癌療法。在一些態樣中,第二抗癌療法係手術療法、化學療法、輻射療法、冷療法、激素療法、免疫療法或細胞介素療法。在特定態樣中,第二抗癌療法係化學療法。在一些態樣中,化學療法係環磷醯胺(cyclophosphamide)、胺甲喋呤(methotrexate)、氟尿嘧啶(fluorouracil)、多柔比星(doxorubicin)、長春新鹼(vincristine)、異環磷醯胺(ifosfamide)、順鉑(cisplatin)、吉西他濱(gemcytabine)、白消安(busulfan)或ara-C。在具體態樣中,化學療法係多柔比星。在一些態樣中,在IL-12 (例如CARL-IL12)免疫細胞之前投與化學療法。在特定態樣中,在IL-12 (例如CARL-IL12)免疫細胞之前24-48小時投與化學療法。在某些態樣中,在IL-12 (例如CARL-IL12)免疫細胞之前15-25小時投與化學療法。在一些態樣中,投與IL-12 (例如CARL-IL12)免疫細胞並不誘導內源性IL-12分泌及/或IFNγ釋放。在某些態樣中,經靜脈內、經腹膜腔內、經氣管內、經腫瘤內、經肌內、經內視鏡、經病灶內、經皮、經皮下、經區域或藉由直接注射或灌注來投與T細胞及/或至少一種其他治療劑。在具體態樣中,與投與含有野生型IL-12之T細胞相比,投與IL-12 (例如CARL-IL12) T細胞並不誘導IFNγ或誘導較低含量之IFNγ。在一些態樣中,在血清試樣中量測IFNγ。在特定態樣中,投與T細胞及/或第二抗癌療法一次以上。在一些態樣中,T細胞滲透至個體內腫瘤之中心或其附近。
自下列詳細說明可易知本發明之其他目標、特徵及優點。然而,應理解,在指示本發明之較佳實施例時,詳細說明及具體實例僅以闡釋方式給出,此乃因熟習此項技術者由該詳細說明可明瞭本發明之精神及範圍內之各種變化及修改。
本申請案主張2019年2月提出申請之美國臨時專利申請案第62/800,136號之權益,該美國臨時專利申請案之全部內容以引用方式併入本文中。
在某些實施例中,本發明提供具有膜錨定及/或腫瘤靶向IL-12之CAR樣構築體。該構築體可包括腫瘤靶向部分(例如肽、抗體或其片段)。實例性腫瘤靶向部分係細胞表面波形蛋白(CSV)肽或scFv。構築體可為逆轉錄病毒載體或慢病毒載體。本文進一步提供經改造以表現CARL-IL12載體之細胞,例如免疫細胞、尤其T細胞。可使用CARL IL-12 T細胞來治療疾病或病症(例如實體腫瘤或血癌)。
具體而言,本發明構築體可為表現具有細胞內細胞活化/存活域之腫瘤靶向及膜錨定介白素12 (IL-12)之CARL-IL-12構築體(圖6、7)。IL-12可包括與細胞膜靶定域融合之IL-12 α亞單元p35 (含有或不含細胞存活/活化域)及與腫瘤靶向肽融合之IL-12 β亞單元p40。在本發明研究中,不含細胞存活/活化域之單獨腫瘤靶向部分(ATT-IL-12)展示增加之抗腫瘤效能(圖9)。CARL-IL12及ATT-IL-構築體二者皆會增加宿主T細胞增殖。
具體而言,IL-12可包括p35亞單元及p40亞單元二者。p40亞單元可融合至腫瘤靶向部分(例如CSV肽)。p35亞單元可融合至跨膜域(例如EGFR)。p35亞單元可進一步融合至細胞信號傳導域(例如4-1BB及CD3ζ)。兩種亞單元一起可形成CARL-IL12構築體。構築體可使用p40亞單元中之腫瘤靶向肽或scFV直接靶向腫瘤且經由膜錨定p35-TM-4-1BB或p35-TM (亦即不含4-1BB)亞單元誘導T細胞增殖。端視細胞類型,4-1BB可經其他細胞活化/存活信號傳導域代替。因此,CARL-IL12可用於治療大腫瘤(例如抗藥物肉瘤)。CARL-IL12可進一步藉由使T細胞快速靶向腫瘤來減少來自 CAR T細胞療法及IL-12療法之毒性問題。CARL-IL12療法可與化學療法(例如多柔比星)組合投與,且其可加強腫瘤特異性TCR-T細胞誘導。CARL-IL12 T細胞療法亦可減少細胞介素釋放症候群。實際上,本發明研究展示,與野生型IL-12 T細胞療法及膜錨定IL-12 T細胞療法相比,本發明CARL-IL12療法具有優良抗腫瘤效能。
亦提供自個體血液分離T細胞、使用CARL-IL12修飾、擴增且投與個體之方法。另外,可使用多柔比星或其他T細胞募集誘導劑來預治療個體。
I. 定義
如本文中所使用,關於指定組分之「基本上不含」在本文中用於意指,並無指定組分有意調配至組合物中及/或僅作為污染物或以痕量存在。源自組合物之任何非預期污染之指定組分之總量由此遠低於0.05%、較佳地低於0.01%。最佳地,在組合物中使用標準分析方法檢測不到指定組分之量。
如本文之說明書中所使用,「一個(a或an)」可意指一或多個。如本文在申請專利範圍中所使用,在聯合詞語「包括」使用時,詞語「一個(a或an)」可意指一個或一個以上。
除非明確指示僅係指替代物或該等替代物相互排斥,否則說明書中所用之術語「或」用於意指「及/或」,但本發明支持僅係指替代物及「及/或」之定義。如本文中所使用,「另一」可意指至少第二者或更多者。術語「約」、「實質上」及「大約」通常意指所陳述值加上或減去5%。
「治療(treating或treatment)」疾病或病狀係指執行一定方案,其可包含向患者投與一或多種藥物以試圖緩解該疾病之體徵或症狀。期望治療效應包含降低疾病進展速率、改善或減輕疾病狀態及緩解或改良預後。緩解可發生於疾病或病狀之體徵或症狀出現之前以及其出現之後。因此,「治療(treating或treatment)」可包含「預防(preventing或prevention)」疾病或不期望病狀。另外,「治療(treating或treatment)」未必完全緩解體徵或症狀,未必治癒,且特定而言包含僅對患者具有較小效應之方案。
本申請案通篇所用之術語「治療益處」或「治療有效」係指就此病狀之醫學治療而言促進或增強個體幸福感之任何事物。此包含(但不限於)減小疾病之體徵或症狀之頻率或嚴重程度。舉例而言,癌症治療可涉及(例如)減小腫瘤大小、減小腫瘤侵襲性、減小癌症生長速率或預防轉移。癌症治療亦可係指延長癌症個體之存活。
「個體」及「患者」係指人類或非人類,例如靈長類動物、哺乳動物及脊椎動物。在特定實施例中,個體係人類。
片語「醫藥或藥理學可接受」係指分子實體及組合物在適宜地投與動物(例如人類)時不產生不良、過敏或其他不利反應。熟習此項技術者根據本發明將已知包括抗體或其他活性成分之醫藥組合物之製備。此外,對於動物(例如人類)投與而言,應理解,製劑應符合FDA Office of Biological Standards所要求之無菌性、熱原性、一般安全性及純度標準。
如本文中所使用,「醫藥上可接受之載劑」包含如熟習此項技術者之已知任何及所有水性溶劑(例如水、醇/水溶液、鹽水溶液、非經腸媒劑(例如氯化鈉)、林格氏右旋糖(Ringer's dextrose)等)、非水性溶劑(例如丙二醇、聚乙二醇、植物油及可注射有機酯(例如油酸乙酯))、分散介質、塗層、表面活性劑、抗氧化劑、防腐劑(例如抗細菌或抗真菌劑、抗氧化劑、螯合劑及惰性氣體)、等滲劑、吸收延遲劑、鹽、藥物、藥物穩定劑、凝膠、黏合劑、賦形劑、崩解劑、潤滑劑、甜味劑、矯味劑、染料、液體及營養補充劑、類似材料及其組合。根據熟知參數來調節醫藥組合物中之各種組分之pH及確切濃度。
術語「膜錨定IL-12」係指包括跨膜域之IL-12蛋白(圖6)。術語「膜錨定腫瘤靶向IL-12 (attIL-12)」係指包括跨膜域及腫瘤靶向域二者之IL-12蛋白(例如圖6)。
多核苷酸或多核苷酸區(或多肽或多肽區)具有某一百分比(例如80%、85%、90%或95%)之「類似性百分比」或「序列類似性」,其係指一個胺基酸可在不損失功能下取代另一胺基酸之程度。可經由使用諸如PAM250或BLOSUM62基質等基質來測定此類似性百分比。
多核苷酸或多核苷酸區(或多肽或多肽區)與另一序列具有某一百分比(例如80%、85%、90%或95%)之「序列一致性」或「同源性」意指,在所比較兩個序列經比對時,該百分比之鹼基(或胺基酸)係相同的。可使用業內已知之軟體程式(例如闡述於CURRENT PROTOCOLS IN MOLECULAR BIOLOGY (F. M. Ausubel等人編輯,1987),增刊30,第7.7.18部分,表7.7.1中者)來測定此比對及同源性或序列一致性百分比。較佳地,使用預設參數進行比對。較佳比對程式係使用預設參數之BLAST。特定而言,較佳程式係BLASTN及BLASTP,且使用下列預設參數:基因代碼=標準;篩選=無;鏈=兩條;截止值= 60;預期= 10;矩陣= BLOSUM62;說明=50個序列;分類依據=高評分;資料庫=非冗餘,基因庫+ EMBL + DDBJ + PDB +基因庫CDS轉譯+ SwissProtein + SPupdate + PIR。
II. CAR樣IL-12 (CARL-IL12) T細胞療法
本發明之某些實施例係關於具有膜錨定IL-12之CAR樣構築體。在一些態樣中,構築體或表現載體係逆轉錄病毒表現載體、腺病毒表現載體、DNA質體表現載體或AAV表現載體。構築體可為病毒載體,例如逆轉錄病毒載體或慢病毒載體。具體而言,IL-12可包括p35亞單元及p40亞單元二者。p40亞單元可融合至腫瘤靶向部分。p35亞單元可融合至跨膜域。p35亞單元可進一步融合至細胞信號傳導域。信號傳導域可為CD3ζ、CD28及/或4-1BB信號傳導域。兩種融合亞單元一起可形成CARL-IL12構築體。
構築體可包括腫瘤靶向部分(例如肽、抗體或其片段)。腫瘤靶向部分可為抗體分子之一或多個抗原結合部分,例如衍生自單株抗體(mAb)之可變重(VH)鏈及可變輕(VL)鏈之單鏈抗體片段(scFv)。
實例性腫瘤靶向部分係細胞表面波形蛋白(CSV)肽或scFv。除經由此CARL-IL12 T細胞療法加上先期化學療法(例如多柔比星)在腫瘤中誘導之NKG2D配體靶外,第二通用腫瘤特異性靶係細胞表面波形蛋白(CSV)。CSV檢測於任何類型之高度惡性腫瘤中且主要發現於諸如轉移性腫瘤及復發性腫瘤等高度惡性腫瘤上。舉例而言,研究已展示,CSV存在於結腸腫瘤中100%之轉移性腫瘤細胞表面及97-98%之藥物或CAR-T細胞抗性或復發性ALL上。
CARL-IL12構築體可包括跨膜域以(例如)使抗體錨定至細胞。業內已知之任一跨膜域可用於CARL-IL12至宿主細胞(例如T細胞)之膜錨定表現。實例性跨膜域係EGFR跨膜域。在其他實施例中,跨膜域可包括業內已知之其他跨膜序列,例如揭示於Kozma等人,Nucleic Acids Research
41資料庫期號,D524-D529, 2013中者。在其他實施例中,IL-12 p35包括跨膜域。具有一或多個跨膜多肽域之跨膜蛋白之熟知實例包含整聯蛋白家族、CD44、血型醣蛋白、MHC I及II類醣蛋白、EGF受體、G蛋白偶合受體(GPCR)家族、受體酪胺酸激酶(例如胰島素樣生長因子1受體(IGFR)及血小板源生長因子受體(PDGFR))、孔蛋白家族及其他跨膜蛋白之成員。本發明之某些實施例涵蓋使用跨膜多肽域之一部分,例如具有如可根據標準及熟知方法測得之膜插入特性之截短多肽。
可用於各個實施例中之膜錨定IL-12蛋白序列包含野生型IL-12之胺基酸序列以及其類似物及衍生物。類似物及衍生物可包含(但不限於)由核苷酸序列編碼之胺基酸序列內之胺基酸殘基之添加或取代,但其可引起沉默變化,由此產生在功能上等效之基因產物。胺基酸取代可基於所涉及殘基在以下方面中之類似性來進行:極性、電荷、溶解性、疏水性、親水性及/或兩親性性質。舉例而言,非極性(疏水性)胺基酸包含丙胺酸、白胺酸、異白胺酸、纈胺酸、脯胺酸、苯丙胺酸、色胺酸及甲硫胺酸;極性中性胺基酸包含甘胺酸、絲胺酸、蘇胺酸、半胱胺酸、酪胺酸、天門冬醯胺酸及麩醯胺酸;帶正電荷(鹼性)胺基酸包含精胺酸、離胺酸及組胺酸;且帶負電荷(酸性)胺基酸包含天門冬胺酸及麩胺酸。
胺基酸取代可替代地基於胺基酸之親疏水指數來進行。每一胺基酸已基於其疏水性及電荷特性來指定親疏水指數。其係:異白胺酸(+4.5);纈胺酸(+4.2);白胺酸(+3.8);苯丙胺酸(+2.8);半胱胺酸/胱胺酸(+2.5);甲硫胺酸(+1.9);丙胺酸(+1.8);甘胺酸(-0.4);蘇胺酸(-0.7);絲胺酸(-0.8);色胺酸(-0.9);酪胺酸(-1.3);脯胺酸(-1.6);組胺酸(-3.2);麩胺酸鹽(-3.5);麩醯胺酸(-3.5);天門冬胺酸鹽(-3.5);天門冬醯胺酸(-3.5);離胺酸(-3.9);及精胺酸(-4.5)。業內已理解親疏水胺基酸指數在賦予蛋白質交互生物功能中之用途(Kyte及Doolittle,J. Mol. Biol.
157:105-132, 1982)。眾所周知,在某些情況下,某些胺基酸可取代為具有類似親疏水指數或評分且仍保留類似生物活性之其他胺基酸。在基於親疏水指數作出改變時,在某些實施例中,包含親疏水指數在± 2內之胺基酸取代,而在其他實施例中,包含± 1內之胺基酸取代,且在其他實施例中,包含± 0.5內之胺基酸取代。
胺基酸取代可替代地基於親水性來進行,尤其在由此產生之生物功能蛋白質或肽意欲用於免疫學實施例中時。在某些實施例中,蛋白質之最大局部平均親水性(如由其毗鄰胺基酸之親水性所決定)與其免疫原性及抗原性相關,亦即與蛋白質之生物性質相關。向該等胺基酸殘基指定下列親水值:精胺酸(+3.0);離胺酸(+3.0);天門冬胺酸鹽(+3.0 ± 1);麩胺酸鹽(+3.0 ± 1);絲胺酸(+0.3);天門冬醯胺酸(+0.2);麩醯胺酸(+0.2);甘胺酸(0);蘇胺酸(-0.4);脯胺酸(-0.5 ± 1);丙胺酸(-0.5);組胺酸(-0.5);半胱胺酸(-1.0);甲硫胺酸(-1.3);纈胺酸(-1.5);白胺酸(-1.8);異白胺酸(-1.8);酪胺酸(-2.3);苯丙胺酸(-2.5)及色胺酸(-3.4)。在基於類似親水值作出改變時,在某些實施例中,包含親水值在±2內之胺基酸取代,在某些實施例中,包含±1內者,且在某些實施例中,包含± 0.5內者。亦可基於親水性來鑑別來自一級胺基酸序列之表位。
取代變體通常在蛋白質內之一或多個位點處含有一個胺基酸至另一胺基酸之交換,且可經設計以調節多肽之一或多種性質,且損失或不損失其他功能或性質。取代可為保守的,亦即,一個胺基酸經具有類似形狀及電荷者代替。保守取代在業內已眾所周知且包含(例如)以下變化:丙胺酸至絲胺酸;精胺酸至離胺酸;天門冬醯胺酸至麩醯胺酸或組胺酸;天門冬胺酸鹽至麩胺酸鹽;半胱胺酸至絲胺酸;麩醯胺酸至天門冬醯胺酸;麩胺酸鹽至天門冬胺酸鹽;甘胺酸至脯胺酸;組胺酸至天門冬醯胺酸或麩醯胺酸;異白胺酸至白胺酸或纈胺酸;白胺酸至纈胺酸或異白胺酸;離胺酸至精胺酸;甲硫胺酸至白胺酸或異白胺酸;苯丙胺酸至酪胺酸、白胺酸或甲硫胺酸;絲胺酸至蘇胺酸;蘇胺酸至絲胺酸;色胺酸至酪胺酸;酪胺酸至色胺酸或苯丙胺酸;及纈胺酸至異白胺酸或白胺酸。或者,取代可為非保守的,從而影響多肽之功能或活性。非保守變化通常涉及使用化學相異性殘基取代一個殘基,例如使用極性或帶電胺基酸取代非極性或不帶電胺基酸,且反之亦然。
A. T細胞製備
本文進一步提供經改造以表現CARL-IL12載體之細胞,例如免疫細胞、尤其T細胞。可使用CARL-IL12 T細胞來治療疾病或病症(例如實體腫瘤或血癌)。
本發明之某些實施例係關於獲得T細胞之起始群體,修飾T細胞,且將經修飾T細胞作為免疫療法投與個體以靶向癌細胞。特定而言,T細胞表現CARL-IL12。最近二十年,已闡述用於衍生、活化及擴增功能性抗腫瘤效應T細胞之若干基本方式。該等方式包含:自體細胞,例如腫瘤浸潤性淋巴球(TIL);使用自體DC、淋巴球、人工抗原呈遞細胞(APC)或經T細胞配體及活化抗體塗覆之珠粒或藉助捕獲靶細胞膜而分離之細胞離體活化之T細胞;天然表現抗宿主腫瘤T細胞受體(TCR)之同種異體細胞;及經基因再程式化或「重置」以表現顯示抗體樣腫瘤識別能力之腫瘤反應性TCR或嵌合TCR分子(稱為「T小體」)之非腫瘤特異性自體或同種異體細胞。該等方式已產生可用於本文所闡述方法中之T細胞製備及免疫化之諸多方案。
在一些實施例中,T細胞之起始群體係衍生自血液、骨髓、淋巴或淋巴樣器官。在一些態樣中,細胞係人類細胞。細胞通常係一級細胞,例如自個體直接分離者及/或自個體分離且冷凍者。在一些實施例中,細胞包含T細胞或其他細胞類型(例如全T細胞群體、CD4+
細胞、CD8+
細胞及其亞群體)之一或多個子組,例如根據以下各項所定義者:功能、活化狀態、成熟度、分化、擴增、再循環、局部化及/或持久能力之潛力、抗原特異性、抗原受體類型、特定器官或腔室中之存在、標記物或細胞介素分泌特徵及/或分化程度。對於擬治療個體而言,細胞可為同種異體及/或自體的。在一些態樣中,例如對於現有技術而言,細胞係多潛能及/或多能性的,例如幹細胞,例如經誘導多潛能幹細胞(iPSC)。在一些實施例中,該等方法包含自個體分離細胞、製備、處理、培養及/或改造(如本文所闡述),且在冷凍保存之前或之後將其再引入相同患者中。
T細胞(例如CD4+
及/或CD8+
T細胞)之亞型及亞群體係幼稚T (TN
)細胞、效應T細胞(TEFF
)、記憶性T細胞及其亞型(例如幹細胞記憶性T細胞(TSCM
)、中央記憶性T細胞(TCM
)、效應記憶性T (TEM
)或終末分化效應記憶性T細胞)、腫瘤浸潤性淋巴球(TIL)、不成熟T細胞、成熟T細胞、輔助性T細胞、細胞毒性T細胞、黏膜相關恆定T (MAIT)細胞、天然及適應性調控性T (Treg)細胞、輔助性T細胞(例如TH1細胞、TH2細胞、TH3細胞、TH17細胞、TH9細胞、TH22細胞、濾泡性輔助性T細胞)、α/β T細胞及δ/γ T細胞。
在一些實施例中,一或多種T細胞群體富集或空乏特定標記物(例如表面標記物)之陽性細胞或特定標記物之陰性細胞。在一些情形下,該等標記物係不存在或以相對較低含量表現於某些T細胞群體(例如非記憶細胞)上但以相對較高含量存在或表現於某些其他T細胞群體(例如記憶細胞)上者。
在一些實施例中,自PBMC試樣藉由負向選擇表現於非T細胞(例如B細胞、單核球或其他白血球)上之標記物(例如CD14)來分離T細胞。在一些態樣中,使用CD4+
或CD8+
選擇步驟來分離CD4+
輔助性及CD8+
細胞毒性T細胞。可藉由正向或負向選擇表現或以相對較高程度表現於一或多種幼稚、記憶及/或效應T細胞亞群體上之標記物來將該等CD4+
及CD8+
群體進一步分選成亞群體。
在一些實施例中,舉例而言,藉由基於與各別亞群體有關之表面抗原進行正向或負向選擇來使CD8+
T細胞進一步富集或空乏幼稚、中央記憶性、效應記憶性及/或中央記憶性幹細胞。在一些實施例中,富集中央記憶性T (TCM
)細胞增加效能,例如改良投與後之長期存活、擴增及/或植入(其在一些態樣中於該等亞群體中尤其穩定)。參見Terakura等人(2012)Blood
. 1:72- 82;Wang等人(2012)J Immunother
. 35(9):689-701。
在一些實施例中,T細胞係自體T細胞。在此方法中,自患者獲得腫瘤試樣且獲得單細胞懸浮液。單細胞懸浮液可以任一適宜方式獲得,例如以機械方式(例如使用Miltenyi Biotec, Auburn, Calif.之gentleMACS™解離器解聚腫瘤)或以酶促方式(例如膠原酶或DNase)。在介白素-2 (IL-2)中培養腫瘤酶促消解之單細胞懸浮液。培養細胞直至鋪滿(例如約2×106
個淋巴球),例如持續約5天至約21天、較佳地約10天至約14天。舉例而言,細胞可培養5天、5.5天或5.8天至21天、21.5天或21.8天,例如10天、10.5天或10.8天至14天、14.5天或14.8天。
可彙集經培養T細胞且快速擴增。快速擴增可在約10天至約14天之時段內將抗原特異性T細胞之數量增加至少約50倍(例如50-、60-、70-、80-、90-或100倍或更多)。更佳地,快速擴增可在約10天至約14天之時段內增加至少約200倍(例如200-、300-、400-、500-、600-、700-、800-、900倍或更多)。
可藉由業內已知之諸多方法中任一者來達成擴增。舉例而言,可使用非特異性T細胞受體刺激在飼養淋巴球及介白素-2 (IL-2)或介白素-15 (IL-15)存在下來快速擴增T細胞。非特異性T細胞受體刺激物可包含約30 ng/ml OKT3,其係小鼠單株抗CD3抗體(可自Ortho-McNeil®, Raritan, N.J.獲得)。或者,可藉由在活體外使用一或多種癌症抗原(包含其抗原性部分(例如表位)或細胞),可視情況自載體表現,例如人類白血球抗原A2 (HLA-A2)結合肽,在T細胞生長因子(例如300 IU/ml IL-2)存在下刺激周邊血單核細胞(PBMC)來快速擴增T細胞。藉由使用脈衝於表現HLA-A2之抗原呈遞細胞上之相同癌症抗原再刺激來快速擴增活體外誘導之T細胞。或者,舉例而言,可使用經輻照之自體淋巴球或使用經輻照之HLA-A2+
同種異體淋巴球及IL-2再刺激T細胞。
可修飾自體T細胞以表現促進自體T細胞之生長及活化之T細胞生長因子。適宜T細胞生長因子包含例如介白素(IL)-2、IL-7、IL-15及IL-12。業內已知適宜修飾方法。參見例如Sambrook等人,Molecular Cloning: A Laboratory Manual ,
第3版,Cold Spring Harbor Press, Cold Spring Harbor, N.Y. 2001;及Ausubel等人,Current Protocols in Molecular Biology
, Greene Publishing Associates and John Wiley & Sons, NY, 1994。在特定態樣中,經修飾之自體T細胞表現高量T細胞生長因子。業內可輕易獲得T細胞生長因子編碼序列(例如IL-12之編碼序列)以及啟動子,啟動子可操作地鍵聯至T細胞生長因子編碼序列促進高量表現。
B. T細胞活化
在一些實施例中,本發明提供活化T細胞以增加NKG2D受體在T細胞(例如CD8+
T細胞)上表現之方法。可使用抗CD3 (例如抗CD3珠粒)預處理起始T細胞群體。預處理可約12小時至3天,例如約24小時。然後可將經擴增T細胞與CD80蛋白(例如CD80-Fc重組蛋白)一起培養以誘導CD28活化且由此NKG2D表現。與CD80之培養可約1-6天,例如約1、2、3、4、5或6天、尤其約4天。在一些態樣中,可用抗CD3及CD80同時處理T細胞。
C. 經基因改造之T細胞
本發明之T細胞可經基因經改造以表現本發明CARL IL-12構築體。該構築體可包括在一些態樣中經由連接體及/或跨膜域連接至一或多種細胞內信號傳導組分之細胞外抗原(或配體)結合域。該等分子通常模擬或近似表示經由天然抗原受體之信號、經由此一受體與共刺激受體之組合之信號及/或僅經由共刺激受體之信號。
在一些態樣中,抗原特異性結合或識別組分融合至在生理上於細胞外附接至p35融合亞單元以形成異源二聚體之p40亞單元,從而變成具有負責細胞內信號傳導之p35融合體及負責抗原特異性結合之p40融合亞單元之CARL結構。
在一些實施例中,跨膜域係衍生自天然或合成來源。在來源為天然時,該域在一些態樣中係衍生自任一膜結合蛋白或跨膜蛋白。跨膜區域包含衍生自(亦即至少包括跨膜區) T-細胞受體、CD28、CD3ε、CD45、CD4、CD5、CDS、CD9、CD 16、CD22、CD33、CD37、CD64、CD80、CD86、CD 134、CD137、CD 154之α、β或ζ鏈者。或者,跨膜域在一些實施例中係合成的。在一些態樣中,合成跨膜域主要包括疏水性殘基(例如白胺酸及纈胺酸)。在一些態樣中,發現苯丙胺酸、色胺酸及纈胺酸之三聯體位於合成跨膜域之每一端處。
CARL-IL12通常包含至少一種細胞內信號傳導組分。在一些實施例中,CARL-IL12包含TCR複合物之細胞內組分(例如調介T細胞活化及細胞毒性之TCR CD3+
鏈,例如CD3 ζ鏈)。因此,在一些態樣中,抗原結合分子連接至一或多個細胞信號傳導模組。在一些實施例中,細胞信號傳導模組包含CD3跨膜域、CD3細胞內信號傳導域及/或其他CD跨膜域。在一些實施例中,CAR進一步包含一或多種其他分子(例如Fc受體γ、CD8、CD4、CD25或CD16)之一部分。舉例而言,在一些態樣中,CARL-IL12包含CD3-ζ (CD3-Q或Fc受體γ與CD8、CD4、CD25或CD16之間之嵌合分子。
D. 遞送方法
熟習此項技術者熟知經由用於表現本發明之抗原受體之標準重組技術(例如參見Sambrook等人,2001及Ausubel等人,1996,二者皆以引用方式併入本文中)來構築載體。載體包含(但不限於)質體、黏粒、病毒(噬菌體、動物病毒及植物病毒)及人工染色體(例如YAC),例如逆轉錄病毒載體(例如衍生自莫洛尼鼠類白血病病毒載體(Moloney murine leukemia virus vector,MoMLV)、MSCV、SFFV、MPSV、SNV等)、慢病毒載體(例如衍生自HIV-1、HIV-2、SIV、BIV、FIV等)、腺病毒(Ad)載體(包含其複製勝任、複製缺陷及無病毒基因形式)、腺相關病毒(AAV)載體、猿病毒40 (SV-40)載體、牛乳頭瘤病毒載體、艾司坦-巴爾病毒載體(Epstein-Barr virus vector)、皰疹病毒載體、牛痘病毒載體、哈威鼠類肉瘤病毒載體(Harvey murine sarcoma virus vector)、鼠類乳房腫瘤病毒載體、勞斯肉瘤病毒載體(Rous sarcoma virus vector)、細小病毒載體、脊髓灰白質炎病毒載體、水疱性口炎病毒載體、馬拉巴病毒載體(maraba virus vector)及B組腺病毒艾納德諾載體(group B adenovirus enadenotucirev vector)。
a. 病毒載體
在本發明之某些態樣中,可提供編碼CARL之病毒載體。在生成重組病毒載體時,非必需基因通常經異源性(或非天然)蛋白質之基因或編碼序列代替。病毒載體係一類利用病毒序列將核酸及可能之蛋白質引入細胞中之表現構築體。某些病毒能夠經由受體介導之胞吞作用感染細胞或進入細胞中且整合至宿主細胞基因體中並穩定且有效地表現病毒基因,此使得其成為用於將外來核酸轉移至細胞(例如哺乳動物細胞)中之有吸引力候選者。可用於遞送本發明某些態樣之核酸之病毒載體之非限制性實例闡述於下文中。
慢病毒係複雜逆轉錄病毒,其除常見逆轉錄病毒基因gag
、pol
及env
外亦含有具有調控或結構功能之其他基因。慢病毒載體在業內已眾所周知(例如參見美國專利6,013,516及5,994,136)。
重組慢病毒載體能夠感染非分裂細胞且可用於活體內及離體基因轉移及核酸序列表現。舉例而言,能夠感染非分裂細胞(其中適宜宿主細胞經兩種或更多種攜載包裝功能之載體(亦即gag、pol及env以及rev及tat)轉染)之重組慢病毒闡述於美國專利5,994,136中,該專利以引用方式併入本文中。
b. 調控元件
可用於本發明之載體中所包含之表現盒尤其含有(在5'至3'方向上)可操作地連接至蛋白質編碼序列之真核轉錄啟動子、包含插入序列之剪接信號及轉錄終止/多腺苷酸化序列。控制真核細胞中之蛋白質編碼基因之轉錄之啟動子及增強子係由多種基因元件構成。細胞機構能夠收集並整合由每一元件傳送之調控資訊,從而容許不同基因進化出獨特、通常複雜之轉錄調控模式。本發明背景中所用之啟動子包含組成型啟動子、可誘導啟動子及組織特異性啟動子。
(i) 啟動子/增強子
本文所提供之表現構築體包括啟動子以驅動抗原受體之表現。啟動子通常包括用於定位RNA合成之起始位點之序列。此序列之最佳已知實例係TATA盒,但在一些缺乏TATA盒之啟動子(例如哺乳動物末端去氧核苷酸轉移酶基因之啟動子及SV40晚期基因之啟動子)中,覆蓋起始位點本身之離散元件可幫助固定起始位置。其他啟動子元件調控轉錄起始之頻率。通常,該等元件位於起始位點上游之30110 bp區域中,但多種啟動子已展示亦含有位於起始位點下游之功能元件。為使編碼序列「處於啟動子之控制下」,需將轉錄閱讀框之轉錄起始位點之5'端定位於所選啟動子之「下游」 (亦即3'端)。「上游」啟動子刺激DNA之轉錄且促進所編碼RNA之表現。
啟動子元件之間之間隔通常較靈活,以使得在相對於彼此插入或移動元件時保留啟動子功能。在tk啟動子中,啟動子元件之間之間隔可在活性開始下降之前增加至50 bp。端視啟動子,似乎個別元件可協同或獨立地發揮活化轉錄之功能。啟動子可或可不與「增強子」聯合使用,增強子係指涉及核酸序列之轉錄活化之順式作用性調控序列。
啟動子可為與核酸序列天然締合者,如可藉由分離位於編碼區段及/或外顯子上游之5'非編碼序列所獲得。此一啟動子可稱為「內源性」。類似地,增強子可為與核酸序列天然締合者,其位於該序列之下游或上游。或者,藉由使編碼核酸區段處於重組或異源性啟動子之控制下來獲得某些優點,該重組或異源性啟動子係指在其天然環境中通常並不與核酸序列締合之啟動子。重組或異源性增強子亦係指在其天然環境中通常不與核酸序列締合之增強子。該等啟動子或增強子可包含其他基因之啟動子或增強子及自任一其他病毒或原核或真核細胞分離之啟動子或增強子以及非「天然」 (亦即含有不同轉錄調控區之不同元件及/或改變表現之突變)之啟動子或增強子。舉例而言,最常用於重組DNA構築中之啟動子包含β內醯胺酶(青黴素酶)、乳糖及色胺酸(trp-)啟動子系統。除以合成方式產生啟動子及增強子之核酸序列外,可使用重組選殖及/或核酸擴增技術(包含PCR™)聯合本文所揭示之組合物來產生序列。另外,預計亦可採用引導非核細胞器(例如線粒體、葉綠體及諸如此類)內之序列之轉錄及/或表現之控制序列。
通常,重要的是採用有效地引導DNA區段表現於選擇用於表現之細胞器、細胞類型、組織、器官或生物體中之啟動子及/或增強子。熟習分子生物學技術者通常知曉用於蛋白質表現之啟動子、增強子及細胞類型組合之應用(例如參見Sambrook等人,1989,其以引用方式併入本文中)。所採用啟動子可為組成型、組織特異性、可誘導型及/或可在適當條件下用於引導所引入DNA區段之高程度表現,此可(例如)有利於重組蛋白及/或肽之大規模生產。啟動子可為異源性或內源性。
另外,亦可使用任一啟動子/增強子組合(例如根據真核啟動子數據庫(Eukaryotic Promoter Data Base,EPDB)經由epd.isb-sib.ch/處之全球資訊網)來驅動表現。T3、T7或SP6細胞質表現系統之應用係另一可能實施例。若提供適當細菌聚合酶(作為遞送複合物之一部分或作為額外基因表現構築體),則真核細胞可支持來自某些細菌啟動子之細胞質轉錄。
啟動子之非限制性實例包含早期或晚期病毒啟動子,例如SV40早期或晚期啟動子、巨細胞病毒(CMV)立即早期啟動子、勞斯肉瘤病毒(RSV)早期啟動子;真核細胞啟動子,例如β肌動蛋白啟動子、GADPH啟動子、金屬硫蛋白啟動子;及序連反應元件啟動子,例如環狀AMP反應元件啟動子(cre)、血清反應元件啟動子(sre)、佛波醇酯啟動子(TPA)及靠近最小TATA盒之反應元件啟動子(tre)。亦可使用人類生長激素啟動子序列(例如闡述於基因庫登錄號X05244處之人類生長激素最小啟動子,核苷酸283-341)或小鼠乳房腫瘤啟動子(可自ATCC目錄號ATCC 45007獲得)。在某些實施例中,啟動子係CMV IE、戴克丁(dectin)-1、戴克丁-2、人類CD11c、F4/80、SM22、RSV、SV40、Ad MLP、β-肌動蛋白、MHC I類或MHC II類啟動子,然而,任一可用於驅動治療基因之表現之其他啟動子適用於本發明實踐。
在某些態樣中,本發明方法亦係關於增強子序列,亦即,增加啟動子活性且可以順式且不論其定向如何甚至在相對較長距離(遠離靶啟動子高達幾千個鹼基)中發揮作用之核酸序列。然而,增強子功能未必限於如此長之距離,此乃因其亦可在既定啟動子附近發揮作用。
(ii) 起始信號及連接表現
特定起始信號亦可用於本發明中所提供之表現構築體中以有效轉譯編碼序列。該等信號包含ATG起始密碼子或毗鄰序列。可能需要提供外源性轉譯控制信號(包含ATG起始密碼子)。熟習此項技術者易於確定這一點且提供所需信號。眾所周知,起始密碼子必須與期望編碼序列之閱讀框「同框」以確保轉譯整個插入體。外源性轉譯控制信號及起始密碼子可為天然或合成的。可藉由納入適當轉錄增強子元件來增強表現效率。
另外,可使用某些2A序列元件來產生連接或共表現本發明中所提供構築體中之基因。舉例而言,可使用裂解序列藉由連接開放閱讀框以形成單一順反子來共表現基因。實例性裂解序列係F2A (口蹄疫病毒2A)或「2A樣」序列(例如明脈扁刺蛾病毒(Thosea asigna
virus) 2A;T2A)。
(iii) 複製起點
為在宿主細胞中繁殖載體,其可含有一或多個複製起點位點(通稱為「ori」),例如對應於如上文所闡述EBV之oriP或具有類似或升高之程式化功能之經基因改造之oriP的核酸序列,其係引發複製之特異性核酸序列。或者,可採用如上文所闡述之其他染色體外複製病毒之複製起點或自主複製序列(ARS)。
c. 選擇及可篩選標記物
在一些實施例中,可在活體外或在活體內藉由在表現載體中包含標記物來鑑別含有本發明構築體之細胞。該等標記物將賦予細胞可鑑別變化,從而允許容易地鑑別含有表現載體之細胞。通常,選擇標記物係賦予容許選擇之性質者。正向選擇標記物係其中標記物之存在容許其選擇者,而負向選擇標記物係其中其存在防止其選擇者。正向選擇標記物之一實例係抗藥物標記物。
通常,納入藥物選擇標記物有助於轉變體之選殖及鑑別,舉例而言,賦予新黴素(neomycin)、嘌呤黴素(puromycin)、潮黴素(hygromycin)、DHFR、GPT、吉歐黴素(zeocin)及組胺醇抗性之基因係有用之選擇標記物。除賦予容許基於實施條件來區分轉變體之表型之標記物外,亦涵蓋其他類型之標記物(包含可篩選標記物,例如基於比色分析之GFP)。或者,可利用作為負向選擇標記物之可篩選酶,例如單純皰疹病毒胸苷激酶(tk
)或氯黴素(chloramphenicol)乙醯基轉移酶(CAT)。熟習此項技術者亦知曉如何採用免疫學標記物且可能與FACS分析聯合。所用標記物並不視為係重要的,只要其能夠與編碼基因產物之核酸同時表現即可。選擇及可篩選標記物之其他實例為熟習此項技術者所熟知。
d. 其他核酸遞送方法
除編碼抗原受體之核酸之病毒遞送外,下文係將重組基因遞送至既定宿主細胞中之其他方法且由此在本發明中加以考慮。
可使用如本文所闡述或如熟習此項技術者已知用於遞送核酸以轉變細胞之任一適宜方法來將核酸(例如DNA或RNA)引入本發明之免疫細胞中。該等方法包含(但不限於)例如使用以下方式直接遞送DNA:藉由離體轉染、藉由注射(包含微注射)、藉由電穿孔、藉由磷酸鈣沈澱、藉由使用DEAE-葡聚糖且隨後使用聚乙二醇;藉由直接音波加載;藉由脂質體調介之轉染及受體調介之轉染;藉由微彈轟擊;藉由使用碳化矽纖維攪動;藉由土壤桿菌(Agrobacterium
)調介之轉變;藉由乾燥/抑制調介之DNA攝取及該等方法之任一組合。經由用於(例如)該等技術,可穩定或瞬時轉變細胞器、細胞、組織或生物體。
III. 治療方法
本文進一步提供治療個體之癌症或延遲其進展之方法,其包括向個體投與有效量之CARL IL-12 T細胞療法。預計用於治療之癌症之實例包含肺癌、頭頸癌、乳癌、胰臟癌、前列腺癌、腎癌、骨癌、睪丸癌、子宮頸癌、胃腸道癌、淋巴瘤、肺中之贅瘤形成前病灶、結腸癌、黑色素瘤及膀胱癌。
在一些實施例中,個體患有抵抗(已顯示抵抗)一或多種抗癌療法之癌症。在一些實施例中,抗癌療法抗性包含癌症或難治性癌症之復發。復發可係指在治療之後於原始位點或新位點再發生癌症。在一些實施例中,抗癌療法抗性包含癌症在使用抗癌療法治療期間之進展。在一些實施例中,癌症處於早期或處於晚期。
在一些實施例中,向個體投與化學治療與T細胞療法之組合。舉例而言,化學治療可為多柔比星(Dox)或環磷醯胺。可使用化學治療(例如多柔比星或其他T細胞募集誘導劑)預治療個體。預處理可在T細胞療法之前16-24小時。
在一些實施例中,T細胞係自體的。然而,若敲除內源性TCR,細胞可為同種異體的。在一些實施例中,T細胞係分離自患者本身,,從而細胞係自體的。若T細胞係同種異體的,則需要去除內源性TCR。將細胞以足以控制、減少或消除所治療疾病之症狀及體徵之量投與所關注個體。
可藉由熟習此項技術者已知之許多方法來量測治療有效性。在一實施例中,使用白血球計數(WBC)來測定個體免疫系統之反應性。WBC量測個體中之白血球之數量。使用業內熟知方法,使個體血樣中之白血球與其他血球分離並計數。白血球之正常值為約4,500至約10,000個白血球/μl。較低數量之白血球可指示個體中之免疫抑制狀態。
在另一實施例中,可使用T淋巴球計數來測定個體中之免疫抑制。使用業內熟知方法,使個體血樣中之白血球與其他血球分離。使用業內標準方法(例如免疫螢光或FACS)來區分T淋巴球與其他白血球。T細胞或特定T細胞群體之數量減小可用作免疫抑制之量度。T細胞或特定T細胞群體之數量小於治療前之T細胞數量(或特定群體中之細胞數量)可用於指示,已誘導免疫抑制。
在其他實施例中,實施測試以量測T細胞活化、增殖或細胞介素反應(包含對特定抗原之反應)。在一些實例中,可在來自個體之試樣中量測Treg或Breg細胞之數量。在其他實例中,在來自個體之試樣中量測細胞介素(例如IL-10)。
在其他實例中,為評價發炎,可量測發炎位點處之嗜中性球浸潤。為評價嗜中性球浸潤,可量測髓過氧化物酶活性。髓過氧化物酶係存在於多形核白血球及單核球之嗜苯胺藍顆粒中之血紅素蛋白。其催化鹵離子氧化成用於藉由吞噬細胞來殺死微生物之其各別次鹵酸。因此,組織中之髓過氧化物酶活性降低反映了嗜中性球浸潤之降低,且可用作發炎抑制之量度。
在另一實例中,可藉由量測個體中之細胞介素含量來分析個體之有效治療。藉由習用方法測定體液或細胞試樣中之細胞介素含量。舉例而言,可使用免疫斑點分析,例如酶聯免疫斑點或「ELISPOT」分析。免疫斑點分析係用於檢測單細胞層面下之細胞介素分泌之高度敏感及定量性分析。免疫斑點方法及應用在業內已眾所周知且闡述於(例如) Czerkinsky等人,1988;Olsson等人,1990;及EP 957359中。標準免疫斑點分析之變化形式在業內已眾所周知且可用於檢測本發明方法中細胞介素產生之改變(例如參見美國專利第5,939,281號及美國專利第6,218,132號)。
在一些實施例中,可在T細胞療法之前向個體投與非骨髓破壞式淋巴細胞清除性化學療法。非骨髓破壞式淋巴細胞清除性化學療法可為任一適宜此類療法,其可藉由任一適宜途徑投與。非骨髓破壞式淋巴細胞清除性化學療法可包括(例如)投與環磷醯胺及氟達拉濱(fludarabine),尤其在癌症係可轉移之黑色素瘤時。投與環磷醯胺及氟達拉濱之一實例性途徑係經靜脈內。同樣,可投與任一適宜劑量之環磷醯胺及氟達拉濱。在特定態樣中,投與約60 mg/kg環磷醯胺兩天,然後投與約25 mg/m2
氟達拉濱5天。
在某些實施例中,與自體T細胞同時或在自體T細胞之後向個體投與促進自體T細胞之生長及活化之T細胞生長因子。T細胞生長因子可為任一促進自體T細胞之生長及活化之適宜生長因子。適宜T細胞生長因子之實例包含介白素(IL)-2、IL-7、IL-15及IL-12,其可單獨或以各種組合(例如IL-2及IL-7、IL-2及IL-15、IL-7及IL-15、IL-2、IL-7及IL-15、IL-12及IL-7、IL-12及IL-15或IL-12及IL2)來使用。IL-12係較佳T細胞生長因子。
局部、區域或全身性投與可較為適當。對於>4 cm之腫瘤而言,擬投與體積為約4-10 ml (尤其10 ml),而對於<4 cm之腫瘤而言,使用約1-3 ml之體積(尤其3 ml)。以單一劑量遞送之多個注射包括約0.1 ml至約0.5 ml之體積。
B. 醫藥組合物
本文亦提供包括T細胞療法及醫藥上可接受之載劑之醫藥組合物及調配物。
可藉由混合具有期望純度之活性成分(例如抗體或多肽)與一或多種可選醫藥上可接受之載劑(Remington's Pharmaceutical Sciences,第22版,2012)以凍乾調配物或水溶液之形式來製備如本文所闡述之醫藥組合物及調配物。醫藥上可接受之載劑在所用劑量及濃度下通常對接受者無毒,且包含(但不限於):緩衝劑,例如磷酸鹽、檸檬酸鹽及其他有機酸;抗氧化劑,包含抗壞血酸及甲硫胺酸;防腐劑(例如十八烷基二甲基苄基氯化銨;氯化六甲雙銨;苯紮氯銨、苄索氯銨;苯酚、丁醇或苯甲醇;對羥基苯甲酸烷基酯,例如對羥基苯甲酸甲酯或對羥基苯甲酸丙酯;兒茶酚;間苯二酚;環己醇;3-戊醇;及間-甲酚);低分子量(小於約10個殘基)多肽;蛋白質,例如血清白蛋白、明膠或免疫球蛋白;親水聚合物,例如聚乙烯基吡咯啶酮;胺基酸,例如甘胺酸、麩胺醯胺、天門冬醯胺酸、組胺酸、精胺酸或離胺酸;單糖、二糖及其他碳水化合物,包含葡萄糖、甘露糖或糊精;螯合劑,例如EDTA;糖,例如蔗糖、甘露醇、海藻糖或山梨醇;成鹽相對離子,例如鈉;金屬錯合物(例如Zn-蛋白質錯合物);及/或非離子表面活性劑,例如聚乙二醇(PEG)。本文之實例性醫藥上可接受之載劑進一步包含間質性藥物分散劑,例如可溶性中性活性透明質酸酶醣蛋白(sHASEGP),例如人類可溶性PH-20透明質酸酶醣蛋白,例如rHuPH20 (HYLENEX®
, Baxter International, Inc.)。某些實例性sHASEGP及使用方法(包含rHuPH20)闡述於美國專利公開案第2005/0260186號及第2006/0104968號中。在一態樣中,將sHASEGP與一或多種額外醣胺多醣酶(例如軟骨素酶)組合。
C. 其他療法
在某些實施例中,本發明實施例之組合物及方法涉及CARL-IL12 T細胞群體與至少一種其他療法之組合。其他療法可為輻射療法、手術(例如病灶切除術及乳房切除術)、化學療法、基因療法、DNA療法、病毒療法、RNA療法、免疫療法、骨髓移植、奈米療法、單株抗體療法或前述療法之組合。其他療法可呈輔助或新輔助療法形式。
T細胞療法可在其他療法(例如多柔比星)之前、期間、之後或以各種組合來投與。投與可以介於同時至幾分鐘至幾天至幾週之間之間隔進行。在T細胞療法與另一治療劑分開提供至患者之實施例中,通常應確保在每一遞送時間之間不會經歷較長時間段,從而兩種化合物仍能夠對患者施加有利之組合效應。在該等情況下,預計可彼此在約12 h至24 h或72 h內及更特定而言彼此在約6-12 h內向患者提供T細胞療法及抗癌療法。在一些情況下,可期望顯著延長治療時間段,其中各別投與間隔數天(2、3、4、5、6或7天)至數週(1、2、3、4、5、6、7或8週)。
T細胞療法及其他治療劑可藉由相同投與途徑或藉由不同投與途徑來投與。在一些實施例中,經靜脈內、經肌內、經皮下、經局部、經口、經皮、經腹膜腔內、經眶內、藉由植入、藉由吸入、經鞘內、經心室內或經鼻內來投與T細胞療法及/或抗血小板劑。可投與有效量之T細胞療法及其他治療劑以預防或治療疾病。基於以下因素來確定T細胞療法及其他治療劑之適當劑量:擬治療疾病之類型、疾病之嚴重程度及病程、個體之臨床狀況、個體之臨床史及治療反應以及主治醫師之判斷。
在一些實施例中,其他療法係投與小分子酶促抑制劑或抗轉移劑。在一些實施例中,其他療法係投與副效應限制劑(例如意欲減弱治療副效應之發生及/或嚴重程度之藥劑,例如抗噁心劑等)。在一些實施例中,其他療法係輻射療法。在一些實施例中,其他療法係手術。在一些實施例中,其他療法係輻射療法及手術之組合。在一些實施例中,其他療法係γ輻照。在一些實施例中,其他療法係靶向PBK/AKT/mTOR路徑之療法、HSP90抑制劑、微管蛋白抑制劑、細胞凋亡抑制劑及/或化學預防劑。其他療法可為業內已知之化學治療劑中之一或多者。
可採用各種組合。在下文實例中,T細胞療法係「A」且另一治療劑係「B」:
A/B/A B/A/B B/B/A A/A/B A/B/B B/A/A A/B/B/B B/A/B/B
B/B/B/A B/B/A/B A/A/B/B A/B/A/B A/B/B/A B/B/A/A
B/A/B/A B/A/A/B A/A/A/B B/A/A/A A/B/A/A A/A/B/A
將本發明實施例之任一化合物或療法投與患者應慮及藥劑之毒性(若存在)遵循投與該等化合物之一般方案。因此,在一些實施例中,存在監測可歸因於組合療法之毒性之步驟。
1. 化學療法
眾多種化學治療劑可用於本發明實施例中。術語「化學療法」係指使用藥物來治療癌症。「化學治療劑」係用於涵蓋經投與以治療癌症之化合物或組合物。該等藥劑或藥物係藉由其在細胞內之活性模式(例如是否及在何階段其影響細胞週期)來分類。或者,可基於直接交聯DNA、插入DNA中或藉由影響核酸合成來誘導染色體及有絲分裂異常之能力來表徵藥劑。
化學治療劑之實例包含烷基化劑,例如噻替哌(thiotepa)及環磷醯胺;磺酸烷基酯,例如白消安(busulfan)、英丙舒凡(improsulfan)及哌泊舒凡(piposulfan);氮丙啶,例如苯并多巴(benzodopa)、卡波醌(carboquone)、米得哌(meturedopa)及烏得哌(uredopa);伸乙基亞胺及甲基密胺,包含六甲密胺(altretamine)、三伸乙基密胺、三伸乙基磷醯胺、三伸乙基硫化磷醯胺及三羥甲基密胺;番荔枝內酯(acetogenin) (尤其布拉他辛(bullatacin)及布拉他辛酮(bullatacinone));喜樹鹼(camptothecin) (包含合成類似物托泊替康(topotecan));苔蘚抑制素(bryostatin);卡利抑制素(callystatin);CC-1065 (包含其合成類似物阿多來新(adozelesin)、卡折來新(carzelesin)及比折來新(bizelesin));克利特非辛(cryptophycin) (尤其克利特非辛1及克利特非辛8);多拉司他汀(dolastatin);多卡米星(duocarmycin) (包含合成類似物KW-2189及CBI-TMI);艾榴塞洛素(eleutherobin);水鬼蕉鹼(pancratistatin);匍枝珊瑚醇(sarcodictyin);海綿素(spongistatin);氮芥(nitrogen mustard),例如苯丁酸氮芥(chlorambucil)、萘氮芥(chlornaphazine)、氯磷醯胺(cholophosphamide)、雌氮芥(estramustine)、異環磷醯胺(ifosfamide)、雙氯乙基甲胺(mechlorethamine)、雙氯乙基甲胺氧化物鹽酸鹽、美法倉(melphalan)、新氮芥(novembichin)、苯乙酸氮芥膽甾醇酯(phenesterine)、潑尼莫司汀(prednimustine)、曲磷胺(trofosfmaide)及尿嘧啶氮芥;亞硝基脲,例如卡莫司汀(carmustine)、氯脲菌素(chlorozotocin)、福莫司汀(fotemustine)、洛莫司汀(lomustine)、尼莫司汀(nimustine)及雷莫司汀(ranimnustine);抗生素,例如烯二炔抗生素(例如卡奇黴素(calicheamicin),尤其卡奇黴素γ1I及卡奇黴素ΩI1;達內黴素(dynemicin),包含達內黴素A;雙膦酸鹽類,例如氯膦酸鹽(clodronate);埃斯培拉黴素(esperamicin);以及新製癌菌素髮色團(neocarzinostatin chromophore)及相關色蛋白烯二炔抗生素發色團)、阿克拉黴素(aclacinomysin)、放線菌素(actinomycin)、安麯黴素(authramycin)、氮雜絲胺酸、博來黴素(bleomycin)、放線菌素C (cactinomycin)、卡拉黴素(carabicin)、洋紅黴素(carminomycin)、嗜癌黴素(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) (包含嗎啉基-多柔比星、氰嗎啉基-多柔比星、2-吡咯啉基-多柔比星及去氧多柔比星)、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) (例如絲裂黴素C)、黴酚酸(mycophenolic acid)、諾拉黴素(nogalarnycin)、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)、鏈脲菌素(streptozocin)、殺結核菌素(tubercidin)、烏苯美司(ubenimex)、淨司他丁(zinostatin)及佐柔比星(zorubicin);抗代謝物,例如胺甲蝶呤(methotrexate)及5-氟尿嘧啶(5-fluorouracil,5-FU);葉酸類似物,例如二甲葉酸(denopterin)、蝶羅呤(pteropterin)及曲美沙特(trimetrexate);嘌呤類似物,例如氟達拉濱(fludarabine)、6-巰基嘌呤及硫咪嘌呤(thiamiprine)、硫鳥嘌呤;嘧啶類似物,例如安西他濱(ancitabine)、阿紮胞苷(azacitidine)、6-阿紮尿苷(6-azauridine)、卡莫氟(carmofur)、阿糖胞苷(cytarabine)、二去氧尿苷、去氧氟尿苷(doxifluridine)、依諾他濱(enocitabine)及氟尿苷(floxuridine);雄激素,例如卡普睪酮(calusterone)、丙酸屈他雄酮(dromostanolone propionate)、環硫雄醇(epitiostanol)、美雄烷(mepitiostane)及睪內酯(testolactone);抗腎上腺素,例如米托坦(mitotane)及曲洛司坦(trilostane);葉酸補充劑,例如亞葉酸;乙醯葡醛酸內酯(aceglatone);醛磷醯胺糖苷(aldophosph glycoside);胺基乙醯丙酸(aminolevulinic acid);恩尿嘧啶(eniluracil);安吖啶(amsacrine);百思布希(bestrabucil);比生群(bisantrene);依達曲沙(edatraxate);地磷醯胺(defofamine);秋水仙胺(demecolcine);地吖醌(diaziquone);依氟鳥胺酸(eflornithine);依利乙銨(elliptinium acetate);埃博黴素(epothilone);依託格魯(etoglucid);硝酸鎵;羥基脲;香菇多糖(lentinan);氯尼達明(lonidainine);類美坦辛(maytansinoid),例如美坦辛(maytansine)及柄型菌素(ansamitocin);米托胍腙(mitoguazone);米托蒽醌(mitoxantrone);莫哌達醇(mopidamol);尼群克林(nitraerine);噴托他汀(pentostatin);蛋胺氮芥(phenamet);吡柔比星(pirarubicin);洛索蒽醌(losoxantrone);鬼臼酸(podophyllinic acid);2-乙基醯肼;丙卡巴肼(procarbazine);PSK多醣複合物;雷佐生(razoxane);根黴素(rhizoxin);西佐喃(sizofiran);鍺螺胺(spirogermanium);細格孢氮雜酸(tenuazonic acid);三亞胺醌(triaziquone);2,2',2''-三氯三乙胺;單端孢黴烯(trichothecene) (尤其T-2毒素、疣皰菌素A (verrucarin A)、桿孢菌素(roridin A)及蛇形菌素(anguidine));烏拉坦(urethan);長春地辛(vindesine);達卡巴嗪(dacarbazine);甘露莫司汀(mannomustine);二溴甘露醇(mitobronitol);二溴衛矛醇(mitolactol);哌泊溴烷(pipobroman);噶薩托辛(gacytosine);阿拉伯糖苷(arabinoside) (「Ara-C」);環磷醯胺;紫杉烷(taxoid),例如太平洋紫杉醇(paclitaxel)及多西紫杉醇(doxetaxel)-吉西他濱(gemcitabine);6-硫鳥嘌呤;巰基嘌呤;鉑配位錯合物,例如順鉑(cisplatin)、奧沙利鉑(oxaliplatin)及卡鉑(carboplatin);長春花鹼(vinblastine);鉑;依託泊苷(etoposide) (VP-16);異環磷醯胺;米托蒽醌;長春新鹼(vincristine);長春瑞濱(vinorelbine);諾安托(novantrone);替尼泊苷(teniposide);依達曲沙(edatrexate);道諾黴素(daunomycin);胺基蝶呤(aminopterin);希羅達(xeloda);伊班膦酸鹽(ibandronate);伊立替康(irinotecan) (例如CPT-11);拓撲異構酶抑制劑RFS 2000;二氟甲基鳥胺酸(DMFO);類視色素,例如視黃酸;卡培他濱(capecitabine);卡鉑、丙卡巴肼、普卡黴素(plicomycin)、吉西他濱、溫諾平(navelbine)、法呢基蛋白轉移酶抑制劑、反鉑(transplatinum);及上述藥劑中任一者之醫藥上可接受之鹽、酸或衍生物。
2. 放射療法
引起DNA損害且已廣泛使用之其他因素包含熟知之γ射線、X射線及/或將放射性同位素定向遞送至腫瘤細胞。亦涵蓋其他形式之DNA損害因素,例如微波、質子束輻照(美國專利5,760,395及4,870,287)及UV輻照。最可能的是,所有該等因素皆影響對DNA、DNA前體、DNA複製及修復以及染色體組裝及維持之多種損害。X射線之劑量範圍介於在延長時間段(3 wk至4 wk)內50倫琴至200倫琴日劑量至2000倫琴至6000倫琴之單一劑量之間。放射性同位素之劑量範圍廣泛變化,且取決於同位素半衰期、所發射輻射之強度及類型以及贅瘤性細胞之攝取。
3. 免疫療法
熟習此項技術者應理解,其他免疫療法可與實施例方法組合或聯合使用。在癌症治療中,免疫治療通常依賴於使用免疫效應細胞及分子來靶向且破壞癌細胞。利妥昔單抗(rituximab) (RITUXAN®)係此一實例。免疫效應物可為例如對腫瘤細胞表面上之一些標記物具有特異性之抗體。抗體單獨可用作療法效應物或其可募集其他細胞以實際上影響細胞殺死。抗體亦可偶聯至藥物或毒素(化學治療劑、放射性核素、蓖麻毒蛋白A鏈、霍亂毒素、百日咳毒素等)且用作靶向劑。或者,效應物可為攜載直接或間接與腫瘤細胞靶相互作用之表面分子之淋巴球。各種效應細胞包含細胞毒性T細胞及NK細胞
抗體-藥物偶聯物已呈現為研發癌症治療劑之突破方式。癌症係全世界之主要死亡原因之一。抗體-藥物偶聯物(ADCs)包括共價連接至細胞殺死藥物之單株抗體(MAbs)。此方式組合MAbs對其抗原靶之高特異性與高效細胞毒性藥物,產生「武裝」 MAbs,將酬載(藥物)遞送至具有富集量抗原之腫瘤細胞(Carter等人,2008;Teicher等人,2014;Leal等人,2014)。藥物之靶向遞送亦使其暴露於正常組織最少,從而降低毒性且改良治療指數。FDA批准之兩種ADC藥物,ADCETRIS® (貝倫妥單抗-維多汀(brentuximab vedotin),2011年)及KADCYLA® (曲妥珠單抗-美坦新(trastuzumab emtansine)或T-DM1,2013年),驗證該方式。當前,在癌症治療之各個臨床試驗階段有30種以上之ADC藥物候選者(Leal等人,2014)。因抗體改造及連接體-酬載最佳化變得愈加成熟,故新ADCs之發現及發展逐漸依賴於適用於此方式之新靶之鑑別及驗證(Teicher等人,2009)及靶向MAbs的生成。ADC靶之兩個準則係在腫瘤細胞中表現之上調/高量及穩定內化。
在免疫療法之一態樣中,腫瘤細胞必須具有一些適於靶向,亦即不存在於大部分其他細胞上之標記物。存在許多腫瘤標記物,且該等標記物中任一者可適用於本發明實施例中之靶向。常見腫瘤標記物包含CD20、癌胚抗原、酪胺酸酶(p97)、gp68、TAG-72、HMFG、唾液醯基路易斯抗原(Sialyl Lewis Antigen)、MucA、MucB、PLAP、層黏蛋白(laminin)受體、erb B及p155。免疫療法之一替代態樣係組合抗癌效應與免疫刺激效應。亦存在免疫刺激分子,包含:細胞介素(例如IL-2、IL-4、IL-12、GM-CSF、γ-IFN)、趨化介素(例如MIP-1、MCP-1、IL-8)及生長因子(例如FLT3配體)。
當前正在探究或正在使用之免疫療法之實例係免疫佐劑,例如牛分枝桿菌(Mycobacterium bovis)、惡性瘧原蟲(Plasmodium falciparum)、二硝基氯苯及芳香族化合物(美國專利5,801,005及5,739,169;Hui及Hashimoto, 1998;Christodoulides等人,1998);細胞介素療法,例如干擾素α、β及γ、IL-1、GM-CSF及TNF (Bukowski等人,1998;Davidson等人,1998;Hellstrand等人,1998);基因療法,例如TNF、IL-1、IL-2及p53 (Qin等人,1998;Austin-Ward及Villaseca, 1998;美國專利5,830,880及5,846,945);及單株抗體,例如抗CD20、抗神經節苷酯GM2及抗p185 (Hollander, 2012;Hanibuchi等人,1998;美國專利5,824,311)。一或多種抗癌療法預計可與本文所闡述之抗體療法一起採用。
在一些實施例中,免疫療法可為免疫檢查點抑制劑。免疫檢查點係免疫系統中增加信號(例如共刺激分子)或減小信號之調控劑。可藉由免疫檢查點阻斷靶向之抑制檢查點包含腺苷A2A受體(A2AR)、B7-H3 (亦稱為CD276)、B及T淋巴球弱化因子(BTLA)、細胞毒性T淋巴球相關蛋白4 (CTLA-4,亦稱為CD152)、吲哚胺2,3-二氧酶(IDO)、殺手細胞免疫球蛋白(KIR)、淋巴球活化基因-3 (LAG3)、程式化死亡1 (PD-1)、T細胞免疫球蛋白域及黏蛋白域3 (TIM-3)及T細胞活化之V-域Ig抑制因子(VISTA)。特定而言,免疫檢查點抑制劑靶向PD-1軸及/或CTLA-4。
免疫檢查點抑制劑可為藥物(例如小分子)、重組形式之配體或受體,或尤其係抗體(例如人類抗體) (例如國際專利公開案WO2015016718;Pardoll,Nat Rev Cancer,
12(4): 252-64, 2012;二者以引用方式併入本文中)。可使用免疫檢查點蛋白或其類似物之已知抑制劑,尤其可使用抗體之嵌合、人類化或人類形式。如熟習此項技術者所知曉,本發明中所提及之某些抗體可使用替代及/或等效名稱。該等替代及/或等效名稱在本發明上下文中可互換使用。舉例而言,眾所周知,蘭布魯珠單抗(lambrolizumab)亦已知具有替代及等效名稱MK-3475及派姆單抗(pembrolizumab)。
在一些實施例中,PD-1結合拮抗劑係抑制PD-1與其配體結合配偶體結合之分子。在一具體態樣中,PD-1配體結合配偶體係PDL1及/或PDL2。在另一實施例中,PDL1結合拮抗劑係抑制PDL1與其結合配偶體結合之分子。在一具體態樣中,PDL1結合配偶體係PD-1及/或B7-1。在另一實施例中,PDL2結合拮抗劑係抑制PDL2與其結合配偶體結合之分子。在一具體態樣中,PDL2結合配偶體係PD-1。拮抗劑可為抗體、其抗原結合片段、免疫黏附素、融合蛋白或寡肽。實例性抗體闡述於美國專利第US8735553號、第US8354509號及第US8008449號中,該等專利皆以引用方式併入本文中。業內已知用於本文所提供方法中之其他PD-1軸拮抗劑,如美國專利申請案第US20140294898號、第US2014022021號及第US20110008369號中所闡述,該等專利申請案皆以引用方式併入本文中。
在一些實施例中,PD-1結合拮抗劑係抗PD-1抗體(例如人類抗體、人類化抗體或嵌合抗體)。在一些實施例中,抗PD-1抗體係選自由以下組成之群:尼沃魯單抗(nivolumab)、派姆單抗及CT-011。在一些實施例中,PD-1結合拮抗劑係免疫黏附素(例如包括融合至恆定區(例如免疫球蛋白序列之Fc區)之PDL1或PDL2之細胞外或PD-1結合部分之免疫黏附素)。在一些實施例中,PD-1結合拮抗劑係AMP- 224。尼沃魯單抗(亦稱為MDX-1106-04、MDX-1106、ONO-4538、BMS-936558及OPDIVO®
)係WO2006/121168中所闡述之抗PD-1抗體。派姆單抗(亦稱為MK-3475、Merck 3475、蘭布魯珠單抗、KEYTRUDA®
及SCH-900475)係WO2009/114335中所闡述之抗PD-1抗體。CT-011 (亦稱為hBAT或hBAT-1)係WO2009/101611中所闡述之抗PD-1抗體。AMP-224 (亦稱為B7-DCIg)係WO2010/027827及WO2011/066342中所闡述之PDL2-Fc融合可溶性受體。
可在本文所提供方法中靶向之另一免疫檢查點係細胞毒性T淋巴球相關蛋白4 (CTLA-4),亦稱為CD152。人類CTLA-4之完整cDNA序列具有基因庫登錄號L15006。CTLA-4發現於T細胞表面上且在結合至抗原呈遞細胞表面上之CD80或CD86時用作「關斷」開關。CTLA4係免疫球蛋白超家族之成員,其表現於輔助性T細胞之表面上且將抑制信號傳輸至T細胞。CTLA4類似於T細胞共刺激蛋白CD28,且兩種分子皆結合至抗原呈遞細胞上之CD80及CD86 (亦分別稱為B7-1及B7-2)。CTLA4將抑制信號傳輸至T細胞,而CD28傳輸刺激信號。細胞內CTLA4亦發現於調控性T細胞上且可對於其功能較為重要。經由T細胞受體及CD28之T細胞活化可增加CTLA-4 (B7分子之抑制受體)之表現。
在一些實施例中,免疫檢查點抑制劑係抗CTLA-4抗體(例如人類抗體、人類化抗體或嵌合抗體)、其抗原結合片段、免疫黏附素、融合蛋白或寡肽。
可使用業內已熟知方法來生成適用於本發明方法之抗人類CTLA-4抗體(或自其衍生之VH及/或VL域)。或者,可使用業內公認之抗CTLA-4抗體。舉例而言,可在本文所揭示方法中使用揭示於以下文獻中之抗CTLA-4抗體:US 8,119,129、WO 01/14424、WO 98/42752;WO 00/37504 (CP675,206,亦稱為曲美目單抗(tremelimumab);先前之替西木單抗(ticilimumab))、美國專利第6,207,156號;Hurwitz等人(1998) Proc Natl Acad Sci USA 95(17): 10067-10071;Camacho等人(2004) J Clin Oncology 22(145):文摘號2505 (抗體CP-675206);及Mokyr等人(1998) Cancer Res 58:5301-5304。上文所提及公開案中之每一者之教示內容以引用方式併入本文中。亦可使用與該等業內公認抗體中之任一者競爭結合至CTLA-4之抗體。舉例而言,人類化CTLA-4抗體闡述於國際專利申請案第WO2001014424號、第WO2000037504號及美國專利第US8017114號中;其皆以引用方式併入本文中。
一實例性抗CTLA-4抗體係伊匹單抗(ipilimumab) (亦稱為10D1、MDX- 010、MDX- 101及Yervoy®)或其抗原結合片段及變體(例如參見WOO 1/14424)。在其他實施例中,抗體包括伊匹單抗之重鏈及輕鏈CDR或VR。因此,在一實施例中,抗體包括伊匹單抗之VH區之CDR1、CDR2及CDR3域及伊匹單抗之VL區之CDR1、CDR2及CDR3域。在另一實施例中,抗體與上文所提及抗體競爭結合及/或結合至CTLA-4上之相同表位。在另一實施例中,抗體與上文所提及抗體具有至少約90%之可變區胺基酸序列一致性(例如與伊匹單抗具有至少約90%、95%或99%之可變區一致性)。
用於調節CTLA-4之其他分子包含CTLA-4配體及受體,如美國專利第US5844905號、第US5885796號及國際專利申請案第WO1995001994號及第WO1998042752號(其皆以引用方式併入本文中)中所闡述;及免疫黏附素,如美國專利第US8329867號(其以引用方式併入本文中)中所闡述。
4. 手術
大約60%之癌症患者將進行一定類型之手術,包含預防性、診斷性或分期性、治癒性及姑息性手術。治癒性手術包含切除術(其中將所有或一部分癌性組織以物理方式去除、切除及/或破壞)且可與其他療法(例如本發明實施例治療、化學療法、放射療法、激素療法、基因療法、免疫療法及/或替代療法)聯合使用。腫瘤切除術係指物理性去除至少一部分腫瘤。除腫瘤切除術外,手術治療包含雷射手術、冷凍手術、電手術及顯微控制手術(莫氏手術(Mohs' surgery))。
在切除一部分或所有癌性細胞、組織或腫瘤後,可在身體中形成空腔。可藉由灌注、直接注射或局部施加其他抗癌療法來達成治療。可(例如)每1、2、3、4、5、6或7天或每1、2、3、4及5週或每1、2、3、4、5、6、7、8、9、10、11或12個月重複該治療。該等治療亦可使用不同劑量。
5. 其他藥劑
其他藥劑預計可與本發明實施例之某些態樣組合使用以改良治療之治療效能。該等其他藥劑包含影響細胞表面受體及間隙連接上調之藥劑、細胞生長抑制及分化劑、細胞黏附抑制劑、增加過度增殖性細胞對細胞凋亡誘導劑之敏感性之藥劑或其他生物藥劑。藉由升高間隙連接數來增加細胞內信號傳導將增加對相鄰過度增殖性細胞群體之抗過度增殖性效應。在其他實施例中,細胞生長抑制或分化劑可與本發明實施例之某些態樣組合使用以改良治療之抗過度增殖性效能。細胞黏附抑制劑預計可改良本發明實施例之效能。細胞黏附抑制劑之實例係成簇黏附激酶(FAKs)抑制劑及洛伐他汀(Lovastatin)。另外預計,增加過度增殖性細胞對細胞凋亡之敏感性之其他藥劑(例如抗體c225)可與本發明實施例之某些態樣組合使用以改良治療效能。
IV. 製品或套組
本文亦提供一種製品或套組,其包括表現CARL IL-12之T細胞。製品或套組可進一步包括包裝插頁,該包裝插頁包括視情況聯合使用接受性T細胞與另一治療劑(例如多柔比星)來治療個體之癌症或延遲其進展或增強患有癌症之個體之免疫功能的說明書。本文所闡述之任一接受性T細胞及/或其他治療劑可包含於製品或套組中。在一些實施例中,接受性T細胞及其他治療劑位於同一容器或單獨容器中。適宜容器包括(例如)瓶、小瓶、袋及注射器。容器可自各種材料形成,該等材料係(例如)玻璃、塑膠(例如聚氯乙烯或聚烯烴)或金屬合金(例如不銹鋼或赫史特合金(hastelloy))。在一些實施例中,容器容納調配物且位於容器上或伴隨容器提供之標記可指示使用說明。製品或套組可進一步包含自商業及使用者角度所期望之其他材料,包含其他緩衝液、稀釋劑、過濾器、針、注射器及具有使用說明之包裝插頁。在一些實施例中,製品進一步包含一或多種另一藥劑(例如化學治療劑及抗腫瘤劑)。用於一或多種藥劑之適宜容器包含(例如)瓶、小瓶、袋及注射器。
V. 實例
本發明包含下列實例以證實本發明之較佳實施例。熟習此項技術者應瞭解,下列實例中揭示之技術代表本發明者發現在實踐本發明中運行良好之技術,且因此可認為構成其實踐之較佳方式。然而,熟習此項技術者借助於本揭示內容應瞭解,可對所揭示特定實施例作出多種改變且仍獲得相同或類似結果,此並不背離本發明之精神及範圍。實例 1 - CAR 樣構築體中之 IL-12 表現
使用融合至腫瘤靶向肽CSV之膜結合IL-12來研發嵌合抗原受體樣構築體。簡言之,將IL12之兩個亞單元選殖至單一載體中。使p35亞單元與EGFR跨膜域及同一閱讀框中之4-lBB編碼序列融合且使p40亞單元與CSV結合肽編碼序列融合。將CARL-IL12融合基因包裝至慢病毒載體中。
使用具有間質腫瘤之小鼠來測試CARL-IL12療法。將含有CARL-IL12融合基因之病毒轉染至自周邊血擴增之T細胞中且在投與多柔比星(DOX)之後一天經由尾部靜脈投與具腫瘤小鼠中。多柔比星治療劑量為l mg/kg,且在不同治療之前一或兩天。其他對照組包含無治療(Notx)、單獨多柔比星(Dox)、對照單獨T細胞(ctrl-T)及Dox+對照T細胞(Ctrl-T)。CARL-IL12 T細胞療法標記為attIL12BBT,其中在治療前一天投與Dox且每一小鼠實施總共兩個治療。分別在第56及68天將2.5百萬個T細胞投與治療小鼠中;分別在第54及67天投與多柔比星(圖1)。然後重複研究,其中分別在第25及41天投與多柔比星,而在第27及43天投與T細胞(圖2)。經CARL-IL12 T細胞治療之小鼠之腫瘤體積顯著小於對照(圖2)。
然後對CAR IL-12 T細胞與具有膜錨定IL-12之T細胞進行比較(圖4)。使用T細胞在第78、93及105天以2.5×106
/小鼠之劑量來治療小鼠。在第77及91天以1 mg/kg之劑量投與多柔比星。據觀察,在CAR IL-12 T細胞及多柔比星存在下治療之小鼠之腫瘤體積低於經IL-12 T細胞治療之小鼠(圖4-5)。
圖6展示各種IL-12構築體,包含CARL-IL12構築體以及並無細胞細胞內信號傳導之ATT-IL-12構築體。兩種構築體皆增強T細胞增殖(圖8)。另外,ATT-IL-12構築體可降低一些腫瘤模型中之腫瘤體積(圖9)。因此,兩種構築體皆可用作治療劑。
* * *
根據本發明無需過多實驗即可獲得並執行本文所揭示及主張之所有方法。儘管本發明之組合物及方法已根據較佳實施例闡述,但熟習此項技術者應明瞭,可對該等方法及本文所闡述方法之步驟或步驟順序作出改變,此並不背離本發明之概念、精神及範圍。更特定而言,應明瞭,某些在化學及生理上皆相關之試劑可代替本文所闡述試劑且同時可達成相同或類似結果。對熟習此項技術者顯而易見之所有該等類似替代物及修改皆視為在由隨附申請專利範圍所界定之本發明的精神、範圍及概念內。參考文獻
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下列圖式形成本說明書之一部分且包含其以進一步闡釋本發明之某些態樣。可藉由參照該等圖式中之一或多者結合本文所示特定實施例之詳細說明來更好地理解本發明。
圖 1 :
使用單獨CARL-IL12 T細胞療法(標記為attIL12BBT)或其與多柔比星之組合治療之小鼠之腫瘤體積。
圖 2 :
使用CARL-IL12 T細胞治療之具有上皮腫瘤之小鼠之腫瘤體積。
圖 3 :
在預多柔比星治療存在下人類骨肉瘤模型中經CARL-IL12 (ATTIL12BB)修飾之T細胞療法與未修飾T細胞療法之間之並排對比。向約1000 mm3大小之骨肉瘤隨機指派不同治療,如下文所詳述。投與多柔比星(Dox)。在T細胞療法之前2天以1mg/kg之劑量經腹膜腔內投與。經由靜脈內途徑以2.5 × 10E6/每一投與之劑量來投與T細胞。針對每一具腫瘤小鼠實施兩個獨立投與。Notx:無治療;多柔比星:僅多柔比星治療;CtrlT:僅投與未修飾T細胞;CtrlT+Dox:使用未修飾T細胞+多柔比星;ATTIL12T+Dox:使用經腫瘤靶向及膜錨定IL12修飾之T細胞+多柔比星;ATTIL12BBT+Dox:經CARL-IL12修飾之T細胞+多柔比星治療;ttIL12T+Dox:經腫瘤靶向IL12修飾之T細胞+多柔比星治療;wtIL12T+Dox:經野生型IL12修飾之T細胞+多柔比星治療;anIL12T+Dox:經膜錨定野生型IL12修飾之T細胞+多柔比星治療。
圖 4
:人類骨肉瘤模型中CARL-12 T (ATTIL12BBT)細胞療法及其他可能之經IL12修飾之T細胞療法之間之並排對比(參見圖3之注釋)。
圖 5
:具有毛細血管擴張性骨癌(OS)腫瘤之患者源異種移植物之小鼠之腫瘤體積。使用多柔比星、對照T細胞或T細胞及多柔比星之組合治療小鼠。T細胞係CAR IL-12 T細胞(上圖)或含有膜錨定IL-12之T細胞(下圖)。
圖 6
:繪示各種IL-12構築體(包含CARL-IL12構築體)之示意圖。
圖 7
:繪示細胞膜處之CARL-IL12之示意圖。
圖 8
:在第19天不含細胞介素或抗體之基本培養基中之T細胞存活率。
圖 9
:使用具有腫瘤靶向部分且無細胞內信號傳導組分之ATT-IL-12治療之小鼠之腫瘤體積。
Claims (46)
- 一種構築體,其編碼腫瘤靶向及膜錨定之IL-12。
- 如請求項1之構築體,其中該腫瘤靶向及膜錨定之IL-12包括IL-12 p35亞單元及IL-12 p40亞單元。
- 如請求項1或2之構築體,其中IL-12 p35編碼DNA融合至相同閱讀框中之跨膜域編碼DNA。
- 如請求項3之構築體,其中該跨膜域係EGFR跨膜域。
- 如請求項1至4中任一項之構築體,其中該p35亞單元連接至信號傳導域編碼序列。
- 如請求項5之構築體,其中該信號傳導域係CD3ζ、CD28及/或4-1BB信號傳導域。
- 如請求項5之構築體,其中該信號傳導域包括CD3ζ及4-1BB信號傳導域。
- 如請求項5之構築體,其中該信號傳導域係4-1BB。
- 如請求項1至8中任一項之構築體,其中p40亞單元編碼DNA融合至相同閱讀框中之腫瘤靶向部分編碼DNA。
- 如請求項9之構築體,其中藉由腫瘤靶向部分來達成腫瘤靶向,該腫瘤靶向部分包括肽、抗體或其片段。
- 如請求項10之構築體,其中該抗體或其片段係選自由以下組成之群:F(ab’)2、Fab’、Fab、Fv及scFv。
- 如請求項10之構築體,其中該抗體或其片段係scFv。
- 如請求項10之構築體,其中該腫瘤靶向部分包括肽。
- 如請求項1至10中任一項之構築體,其中該腫瘤靶向IL-12特異性結合細胞表面波形蛋白(vimentin)(CSV)。
- 如請求項13之構築體,其中該腫瘤靶向部分係CSV肽。
- 如請求項1至15中任一項之構築體,其中該構築體係病毒載體。
- 如請求項16之構築體,其中該病毒載體係慢病毒載體。
- 一種宿主細胞,其經改造以表現如請求項1至17中任一項之構築體。
- 如請求項18之宿主細胞,其中該宿主細胞係免疫細胞。
- 如請求項19之宿主細胞,其中該免疫細胞係腫瘤歸向細胞(tumor-homing cell)。
- 如請求項19之宿主細胞,其中該免疫細胞係T細胞。
- 如請求項21之宿主細胞,其中該T細胞係周邊血T細胞。
- 如請求項21之宿主細胞,其中該T細胞係CD4+ T細胞或CD8+ T細胞。
- 如請求項21之宿主細胞,其中該T細胞係自體的。
- 如請求項21之宿主細胞,其中該T細胞係同種異體的。
- 如請求項19之宿主細胞,其中該免疫細胞係NK細胞。
- 一種醫藥組合物,其包括如請求項18至26中任一項之IL-12免疫細胞及醫藥載劑。
- 一種組合物,其包括有效量之如請求項18至26中任一項之腫瘤靶向IL-12免疫細胞,其用於治療個體之癌症。
- 一種治療個體之癌症之方法,其包括向該個體投與有效量之如請求項18至26中任一項之免疫細胞。
- 如請求項29之方法,其中腫瘤靶向IL-12錨定該等免疫細胞之膜。
- 如請求項29之方法,其中該癌症係神經膠母細胞瘤、子宮頸癌、胰臟癌、卵巢癌、子宮癌、食道癌、黑色素瘤癌、頭頸癌、結腸直腸癌、膀胱癌、肺癌、前列腺癌、肉瘤癌、乳癌、肝癌、腎癌或急性骨髓性白血病。
- 如請求項29至31中任一項之方法,其進一步包括向該個體投與至少第二抗癌療法。
- 如請求項32之方法,其中該第二抗癌療法係手術療法、化學療法、輻射療法、冷療法、激素療法、免疫療法或細胞介素療法。
- 如請求項32之方法,其中該第二抗癌療法係化學療法。
- 如請求項34之方法,其中該化學療法係環磷醯胺(cyclophos-phamide)、胺甲喋呤(methotrexate)、氟尿嘧啶(fluorouracil)、多柔比星(doxorubicin)、長春新鹼(vincristine)、異環磷醯胺(ifosfamide)、順鉑(cisplatin)、吉西他濱(gemcytabine)、白消安(busulfan)或ara-C。
- 如請求項34之方法,其中該化學療法係多柔比星。
- 如請求項34或36之方法,其中該化學療法係在該等IL-12免疫細胞之前投與。
- 如請求項37之方法,其中該化學療法係在該等IL-12免疫細胞之前24至48小時投與。
- 如請求項37之方法,其中該化學療法係在該等IL-12免疫細胞之前15至25小時投與。
- 如請求項29至38中任一項之方法,其中投與該等IL-12免疫細胞不誘導內源性IL-12分泌及/或IFNγ釋放。
- 如請求項29至38中任一項之方法,其中該方法誘導內源性腫瘤特異性T細胞擴增及腫瘤殺死。
- 如請求項58之方法,其中該等T細胞及/或至少一種其他治療劑係經靜脈內、經腹膜腔內、經氣管內、經腫瘤內、經肌內、經內視鏡、經病灶內、經皮、經皮下、經區域,或藉由直接注射或灌注投與。
- 如請求項48之方法,其中與投與具有野生型IL-12之T細胞相比,投與該等IL-12 T細胞不誘導IFNγ或誘導較低量之IFNγ。
- 如請求項43之方法,其中該IFNγ係在血清試樣中量測。
- 如請求項58之方法,其中投與該等T細胞及/或該第二抗癌療法一次以上。
- 如請求項58之方法,其中該等T細胞滲透至該個體內腫瘤之中心或其附近。
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EP3212215A4 (en) * | 2014-10-31 | 2018-07-11 | Neumedicines, Inc | Uses of il-12 as an hematopoietic immunotherapy (hit) |
WO2017062953A1 (en) * | 2015-10-10 | 2017-04-13 | Intrexon Corporation | Improved therapeutic control of proteolytically sensitive, destabilized forms of interleukin-12 |
EP3184548A1 (en) * | 2015-12-23 | 2017-06-28 | Miltenyi Biotec GmbH | Chimeric antigen receptor with cytokine receptor activating or blocking domain |
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