TW201734033A - 惡性病變的組合治療 - Google Patents
惡性病變的組合治療 Download PDFInfo
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- TW201734033A TW201734033A TW105136056A TW105136056A TW201734033A TW 201734033 A TW201734033 A TW 201734033A TW 105136056 A TW105136056 A TW 105136056A TW 105136056 A TW105136056 A TW 105136056A TW 201734033 A TW201734033 A TW 201734033A
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Abstract
本發明係關於一種用於治療惡性病變的新方法。本發明提供一種使用傳統抗癌治療與包含CTLA-4和PD-1的DNA或蛋白疫苗或包含CTLA-4和PD-L1的DNA或蛋白疫苗的組合治療惡性病變的新方法。
Description
本發明係關於用於治療惡性病變的新方法。
細胞毒性T淋巴細胞抗原-4(CTLA-4)在1987年被發現是免疫球蛋白超家族的新成員,其特徵在於與可變(V)或恆定(C)免疫球蛋白域共享關鍵結構特徵的域(Brunet等人,Nature 328, 267-270)。據說明,CTLA-4在免疫系統的調節中扮演關鍵的角色(Keilholz, U., J Immunother 31, 431-439)。據報告CTLA-4藉由與CD28競爭CD80/CD86的結合位點來降低T細胞活化(Rudd等人,Immunol Rev 229, 12-26)。雖然CTLA-4保護個體免受自身免疫疾病,但CTLA-4也會抑制抗癌免疫力。為了避免CTLA-4在癌症治療中引起不期望的免疫反應,正在探索操作T細胞共刺激途徑的幾種方法,以增強抗癌免疫反應。靶向CTLA-4的治療是最先進的策略之一,並且已在晚期臨床試驗中顯示出有希望的結果(Hodi等人,N Engl J Med 363, 711-723; Hodi, F. S., Asia Pac J Clin Oncol 6 Suppl 1, S16-23;Weber, J., Oncologist 13 Suppl 4, 16-25;及Ribas, A., Oncologist 13 Suppl 4, 10-15)。對抗CTLA-4的單株抗體之一ipilimumab已在2011年3月由FDA同意核准用於治療轉移性黑色素瘤。除了轉移性黑色素瘤之外,CTLA-4抗體目前正進行用於治療惡性腫瘤的許多臨床試驗,該惡性腫瘤包括胰腺癌、結腸直腸癌、肝細胞癌、淋巴瘤、激素難治的前列腺癌、卵巢癌及急性骨髓性白血病。
程式性死亡-1(PD-1)是CD28超家族的成員,其在結合其配體程式性死亡配體1和2(PD-L1和PD-L2)時觸發陰性訊號傳遞途徑(Riley, J. L., Immunol Rev 229, 114-125)。PD-1與其配體之間的相互作用導致增殖、細胞因子產生、及T細胞的溶細胞功能的抑制,從而耗盡T細胞並抑制其免疫反應。PD-1/PD-L途徑在耐受力和免疫力中起重要的作用。PD-1/PD-L途徑保護組織和器官免受免疫介導的損傷。然而,已證明此途徑被慢性感染和腫瘤的病原體用來抑制抗微生物和抗癌免疫力。已知PD-1/PD-L軸的免疫調節活性,已經開發出針對此途徑的治療劑用於治療範圍從感染、自身免疫到癌症的病變(Weber, J., Semin Oncol 37, 430-439)。
仍然需要增強免疫力同時避免抑制免疫反應的抗癌治療的新方法。
因此,本發明提供一種將傳統抗癌治療與DNA或蛋白疫苗組合用於惡性病變的組合治療,該組合治療在腫瘤生長的抑制中表現出意想不到的改善功效。
在一個態樣中,本發明提供用於治療個體的惡性病變,包含對該個體投予疫苗與抗癌治療的組合,其中該疫苗為醫藥組合物,該醫藥組合物包含DNA構築體或融合蛋白,該DNA構築體或融合蛋白包含細胞毒性T淋巴細胞抗原-4(CTLA-4)、及程式性死亡-1(PD-1)或程式性細胞死亡1配體1(PD-L1)、或上述之組合。
在另一個態樣中,本發明提供一種用於在接受惡性病變治療的個體體內增強免疫反應的醫藥組合物,該醫藥組合物包含含有CTLA-4和PD-1的DNA疫苗或含有CTLA-4和PD-L1的DNA疫苗。
在本發明的一個具體實施例中,該DNA疫苗為CTLA-4的DNA疫苗與PD-L1的疫苗或CTLA-4-PD-L1的疫苗之組合。
在本發明的另一個具體實施例中,該DNA疫苗為CTLA-4的DNA疫苗與PD-1的疫苗或CTLA-4-PD-1的疫苗之組合。
在本發明的進一步具體實施例中,該疫苗為針對PD-1片段(PD1 Frag)、CTLA-4-PD-L1(CTLA4-PDL1 Elec)、或CTLA-4-PD-L1融合蛋白的疫苗。
在進一步的態樣中,本發明提供一種用於治療個體的惡性病變的方法,包含對該個體投予抗癌治療與DNA疫苗的組合,其中該DNA疫苗為醫藥組合物,該醫藥組合物包含含有編碼細胞毒性T淋巴細胞抗原-4(CTLA-4)的多核苷酸序列的DNA構築體、及含有程式性死亡-1(PD-1)或程式性細胞死亡1配體1(PD-L1)、或上述之組合的DNA構築體,或其蛋白。
在本發明的一個或更多個實例中,該抗癌治療為放射或抗癌抗體治療。
除非另有定義,否則本文中使用的所有技術和科學用語都具有本發明所屬技術領域中具有通常知識之人士一般理解的含義。如本文所用,以下用語具有歸屬於它們的含義,除非另有說明。
本文中使用的冠詞「一(a)」和「一(an)」是指冠詞的一個或超過一個(即至少一個)文法上的受詞。舉例來說,「一元件」意指一個元件或超過一個元件。
「編碼」乙詞是指多核苷酸中核苷酸的特定序列(例如基因、cDNA或mRNA)的固有性質,以作為在具有限定的核苷酸序列(即rRNA、tRNA及mRNA)或限定的胺基酸序列和從而產生的生物學性質的生物過程中用於合成其它聚合物和大分子的模板。因此,假使基因產生的mRNA的轉錄和轉譯在細胞或其他生物系統中產生蛋白質,則基因編碼蛋白質。具有通常知識之人士應當理解的是,由於遺傳密碼的簡併性,許多不同的多核苷酸和核酸可以編碼相同的多肽。還應當理解的是,具有通常知識之人士可以使用例行技術來進行不影響由所述多核苷酸編碼的多肽序列的核苷酸取代,以反映其中將表現多肽的任何特定宿主生物體的密碼子使用。因此,除非另有說明,否則「編碼胺基酸序列的多核苷酸」包括是彼此的簡併形式並且編碼相同胺基酸序列的所有多核苷酸。編碼蛋白質和RNA的多核苷酸可以包括內含子。
「疫苗」乙詞是指含有活性成分的試劑或組合物,該活性成分在個體中針對某種病原體或疾病有效誘導治療程度的免疫力。傳統上,疫苗的活性成分是衍生自病原體的多肽,病原體是疫苗的攻擊目標。「DNA疫苗」乙詞是指其中活性成分為DNA的疫苗。「蛋白質疫苗」乙詞是指其中活性成分為多肽的疫苗。
「醫藥組合物」乙詞是指適用於個體體內的醫藥用途的組合物。醫藥組合物包含有效量的活性劑和醫藥上可接受載體。「有效量」乙詞是指有效產生預期結果(例如本發明中的免疫反應)的試劑量。「醫藥上可接受載體」乙詞是指任何的標準醫藥載體、緩衝液、及賦形劑,例如磷酸鹽緩衝鹽溶液、5%葡萄糖水溶液、及乳液(例如油/水或水/油乳液)、以及各種類型的潤濕劑及/或佐劑。較佳的醫藥載體取決於活性劑的預期投藥模式。典型的投藥模式包括腸內(例如口服)或胃腸外(例如皮下、肌肉內、靜脈內或腹膜內注射;或局部、經皮、或經黏膜投藥)。「佐劑」乙詞是指改變其它藥劑(例如藥物、疫苗)的效果同時當自身被單獨投藥時幾乎沒有直接作用的醫藥或免疫藥劑。佐劑時常被包括在疫苗中以增強受體對供應的抗原的免疫反應,同時將注射的外來物質保持在最少。
「個體」是人或非人哺乳動物。非人哺乳動物包括、但不限於靈長類動物、有蹄類哺乳動物、犬科動物及貓科動物。
「裸露DNA」是指不與脂質體耦接的DNA構築體(用於對個體投藥)。
本發明的醫藥組合物可以藉由傳統習知的方法以一種或更多種醫藥上可接受載體製造。本文所用的「醫藥上可接受載體」乙詞涵括任何的標準醫藥載體。此類載體可以包括、但不限於:鹽水、緩衝鹽水、葡萄糖、水、甘油、乙醇及上述之組合。
本發明提供一種用於治療個體的惡性病變的方法,包含對該個體投予DNA疫苗與抗癌治療的組合,其中該DNA疫苗為醫藥組合物,該醫藥組合物包含含有編碼細胞毒性T淋巴細胞抗原-4(CTLA-4)的多核苷酸序列的DNA構築體、及含有程式性死亡-1(PD-1)或程式性細胞死亡1配體1(PD-L1)、或上述之組合的DNA構築體。
在本發明的一個具體實施例中,該抗癌治療可以是放射治療或抗體治療。
本發明還提供一種用於在接受惡性病變治療的個體體內增強免疫反應的醫藥組合,該醫藥組合包含含有編碼CTLA-4的多核苷酸序列的DNA構築體與含有PD-1或PD-L1或上述之組合的DNA構築體之組合。
此外,本發明提供一種用於治療個體的惡性病變的方法,包含對該個體投予放射治療或抗體治療與含有編碼CTLA-4的多核苷酸序列的DNA構築體及含有PD-1或PD-L1或上述之蛋白的DNA構築體之組合。
依據本發明,該疫苗可以是CTLA-4的DNA疫苗與PD-L1的疫苗或CTLA-4-PD-L1的疫苗之組合。或者,該DNA疫苗可以是CTLA-4的DNA疫苗與PD-1的疫苗或CTLA-4-PD-1的疫苗之組合。此外,該疫苗可以是針對PD-1片段(PD1 Frag)、CTLA-4-PD-L1(CTLA4-PDL1 Elec)、或CTLA-4-PD-L1融合蛋白的疫苗。
在以下實例中證實了針對免疫檢查點蛋白的DNA基疫苗可以增強對腫瘤的免疫反應。與一些傳統化學療法類似的電離放射具有免疫調節性能。在本發明中,與可使腫瘤相關抗原暴露於T細胞的放射組合,這些免疫調節DNA疫苗可以逆轉腫瘤誘導的免疫逃避並進一步產生可持續的抗腫瘤免疫力。
在本發明的具體實施例中,用抗癌藥物治療個體,例如抗體治療,從而在個體體內引起免疫反應的刺激。
依據本發明,惡性病變可以選自由轉移性黑色素瘤、胰腺癌、結腸直腸癌、肝細胞癌、淋巴瘤、激素難治的前列腺癌、卵巢癌、急性骨髓性白血病、及肺癌所組成之群組。
藉由以下實施例進一步說明本發明,提供該等實例是為了說明的目的而不是限制的目的。
材料
使用分別從小鼠和人的白血球獲得的cDNA庫作為模板將編碼鼠CTLA-4、PD1、或PD-L1的DNA序列PCR擴增。將生成的PCR產物與胎盤鹼性磷酸酶(PLAP)的跨膜域序列融合到哺乳動物表現質體pVAC-1中,從而形成CTLA-4和PD1或PD-L1以獲得DNA疫苗。
使用4個具有黑色素瘤B16F10、鼠結腸直腸癌CT26、肺癌LLC、及肝癌BNL細胞的動物模型進行體內研究。
實施例
1
:放射加針對
CTLA-4
和
PD-1
的
DNA
疫苗用於黑色素瘤的組合治療
如圖1A所示,在電穿孔輔助下每週對c58B9BL/6小鼠(5隻小鼠/組)肌內注射DNA疫苗或對照質體1次,共3次。在最後一次疫苗接種後一週,對來自免疫小鼠的血清進行ELISA測定,以檢測針對各免疫檢查點蛋白的抗體滴定量。在c58B9BL/6小鼠上建立B16F10鼠黑色素瘤腫瘤。在建立腫瘤之後,使用的放射方案(當適用時)為2週次的5 Gy。將小鼠分組,每組用放射、放射加CTLA-4疫苗、放射加PD-1疫苗、放射加CTLA-4和PD-1疫苗、或無治療(對照組)治療。
發現與對照組相比,用CTLA-4或PD-1 DNA疫苗接種的小鼠表現出增加的、針對各蛋白的抗體滴定量(p < 0.005)。如圖1B所示,對荷瘤小鼠的治療沒有導致實驗小鼠之間體重有明顯差異,表示缺乏可辨別的毒性。與單獨放射相比,放射治療組合CTLA-4疫苗的治療導致在放射開始後1個月有更多的腫瘤消退(腫瘤體積減少53.2%;p = 0.125)。然而,用PD-1疫苗的免疫法並未明顯增強放射的腫瘤抑制(腫瘤體積減少14.7%;p = 0.55)。還觀察到在實驗結束時,與其它組相比,在用放射加CTLA-4和PD-1疫苗治療的荷瘤小鼠中腫瘤被明顯抑制。如圖1C所示,在用放射加上CTLA-4和PD-1疫苗治療的小鼠中觀察到B16F10腫瘤接近完全消退,相對於單獨放射組腫瘤體積減少了92.4%(p = 0.037)。
實施例
2
:放射加針對
CTLA-4
和
PD-1
的
DNA
疫苗用於結腸直腸癌的組合治療
使用Balb/c小鼠(每組5隻小鼠)來接種1×106
個結腸直腸CT26癌細胞。疫苗接種和放射治療的治療時間表類似於荷B16小鼠的第一個實驗的治療方案,不同之處僅在於每次用8 Gy照射小鼠(參見圖2A)。
如圖2B所示,在用各種方案治療的實驗小鼠之間體重沒有明顯差異。不同治療策略的抗癌作用結果也與實施例1的結果相似,顯示在治療組之間最明顯的腫瘤抑制效果是藉由放射治療組合CTLA-4和PD-1 DNA疫苗的治療(p <0.01)。具體而言,用放射組合CTLA-4和PD-1疫苗治療的小鼠表現出比用放療治療與CTLA-4疫苗(p = 0.003)或PD1 DNA疫苗(p = 0.001)治療的組更好的腫瘤抑制效果。還觀察到,在實驗結束時,與其它組相比,用放射加CTLA-4和PD-1疫苗治療的荷瘤小鼠中腫瘤被明顯抑制了。
實施例
3
:放射加針對
CTLA-4
和
PD-L1
的
DNA
疫苗用於結腸直腸癌的組合治療
我們檢視CTLA-4和PD-L1 DNA疫苗與放射治療組合在體內對CT26腫瘤生長的作用。此實驗的進行類似於實施例2,不同之處僅在於將PD-1 DNA疫苗替換為PD-L1 DNA疫苗,並且只用12 Gy的放射治療治療小鼠一次,如圖3A所示。
不同治療策略的抗癌效果也與實施例2的抗癌效果相似,顯示最明顯的腫瘤抑制效果是在用放射治療組合CTLA-4和PD-L1 DNA疫苗治療的小鼠中。如圖3B所示,與僅用放射治療的組相比,在僅用單一DNA疫苗(CTLA-4或PD-L1)組合放射治療治療的組中沒有觀察到明顯的抗癌作用;然而,與單獨用放射治療的組相比,在用放射組合CTLA-4和PD-L1 DNA疫苗治療的組和用放射加CTLA-4-PD-L1融合基因疫苗的組中腫瘤被明顯抑制了(p <0.05)。
實施例
4
:放射加針對
CTLA-4
和
PD-L1
的
DNA
疫苗用於結腸直腸癌的組合治療
分別製備耦接脂質體的CTLA-4+PD-1 DNA疫苗和CTLA-4-PD-L1融合DAN疫苗。將小鼠接種1×105
個細胞,並用兩次10 Gy的放射治療治療,各如圖4A所示,並用脂質體治療。
如圖4B所示,與單獨用放射治療的組相比,藉由耦接脂質體的CTLA-4-PD-L1 DNA疫苗與放射治療組合實現了最明顯的抗腫瘤效果(p < 0.05)。
實施例
5
:放射加針對
PD-1
片段(
PD1 Frag
)、
CTLA-4-PD-L1
(
CTLA4-PDL1 Elec
)、或
CTLA-4-PD-L1
融合蛋白疫苗的
DNA
疫苗用於結腸直腸癌的組合治療
研究了PD-1片段DNA疫苗(PD1 Frag)、CTLA-4-PD-L1 DNA疫苗(CTLA4-PDL1 Elec)及CTLA-4-PD-L1蛋白疫苗(CTLA-4-PDL1 Prot)與放射治療(RT)組合在體內對CT26腫瘤生長的抗癌效果。此實驗設計和治療時間表類似於實施例4,不同之處僅在於使用5x104
而不是1×105
個CT26細胞來接種每隻小鼠。
就皮下接種的CT26的大小變化而言,與放射治療相比,僅CTLA-4-PD-L1 DNA疫苗顯示統計顯著性(圖5B)。如圖5B所示,CTLA-4-PD-L1 Prot疫苗和PD1 Frag疫苗兩者與放射(RT)組合在抑制腫瘤生長上提供更好的效果,但與單獨RT相比則沒有統計顯著性。然而,如圖5C所示,當與RT組合時,CTLA4-PDL1 Prot疫苗和PD1 Frag疫苗皆顯示統計顯著性。
實施例
6
:
CTLA-4-PD-L1
疫苗對結腸直腸癌的遠位效應(
A
bscopal
effect
)
放射對未經照射腫瘤的抗癌作用是所謂的「遠位效應」。在本施實例中測試CTLA-4-PD-L1 DNA疫苗或蛋白疫苗的腫瘤抑制。不僅在實驗小鼠的右側腹部的經照射腫瘤,而且還在左側腹部的未經照射腫瘤。免疫檢查點疫苗可產生這種罕見但非常有益的放射「遠位效應」。實驗設計如圖6A所示。
如圖6B所示,與放射治療組合的疫苗沒有表現出進一步增強的放射抗癌作用,但CTLA-4-PD-L1 DNA疫苗抑制了接種在小鼠左側腹部的未經照射腫瘤的生長,表示CTLA-4-PD-L1 DNA疫苗能夠誘導放射的遠位效應。
實施例
7
:放射治療組合針對
CTLA-4
和
PD-1
的疫苗在結腸直腸癌的遠位效應
在用各種DNA疫苗與放射組合處理的CT26腫瘤模型中證明遠位效應。實驗設計如圖7A所示。將Balb/c小鼠在兩條腿上接種CT26結腸腫瘤,然後注射指定的抗CTLA-4(mCTLA)及/或抗PD-1(mPD1)DNA疫苗。RT:當指示時照射右腿上的腫瘤。
如圖7B所示,發現在治療組之間平均體重沒有明顯的差異。將每組經照射(指標)腫瘤的平均腫瘤生長圖示於圖7C,並將未經照射腫瘤的平均腫瘤生長圖示於圖7D。類似於在實施例6觀察到的結果,與單獨用放射治療的組相比,接受放射和兩種免疫檢查點DNA疫苗組合治療的Balb/c小鼠的經照射(指標)CT26腫瘤表現出改善的腫瘤消退。如在用放射加疫苗治療的組中觀察到的,腫瘤有明顯消退,表示遠位效應增強。
實施例
8
:抗
-PD-1
抗體加
CTLA-4-PD-L1 DNA
或蛋白疫苗對抑制的效果
為了測試CTLA-4-PD-L1 DNA或蛋白疫苗與抗PD-1抗體J43組合的協同作用,如圖8A所示設計治療時間表。
如圖8B所示,與對照組相比,J43和CTLA-4-PD-L1 DNA疫苗的組合顯示優異的抗癌效果(p < 0.01),而抗PD-1抗體J43未能在體內抑制B16腫瘤生長上顯示統計顯著性。
實施例
9
:抗
PD-1
抗體加
CTLA-4-PD-L1 DNA
或蛋白疫苗對肺癌抑制的效果
在Lewis肺癌(LLC)細胞中檢測兩種不同的DNA疫苗CTLA-4-PD-L1和PD-1片段及其組合在抗PD-1抗體J43存在或不存在的情況下的抗癌作用。實驗設計和治療時間表如圖9A所示。
類似於實施例8中使用B16黑色素瘤模型的結果,抗PD-1抗體J43無法表現出統計學上顯著的Lewis肺癌(LLC)生長抑制。另一方面,與單獨的對照DNA或抗-PD1抗體J43相比,CTLA-4-PD-L1 DNA疫苗無論單獨或與J43或PD-1 DNA片段疫苗組合都表現出明顯的LLC生長抑制(圖9B)。此外,PD-1片段DNA疫苗還顯示出比J43優異的LLC生長抗癌作用,表示免疫檢查點DNA疫苗可以如同那些核准的抗體在人類臨床環境中起作用。將統計結果列於表1。表 1 統計結果
實施例
10
:抗
PD-1
抗體加
CTLA-4-PD-L1 DNA
或蛋白疫苗對肝癌抑制的效果
為了測試CTLA-4-PD-L1 DNA疫苗在體內對肝細胞癌細胞(BNL)生長的影響,如圖10A所示對免疫的BALB/c小鼠皮下接種肝細胞株BNL/Luc(2×105
個細胞/小鼠)。對小鼠進行螢光素酶活性成像,螢光素酶活性成像表示腫瘤生長的程度。
在疫苗接種之後第10天,用BNL/Luc肝癌細胞(2*105
)刺激BALB/c小鼠。觀察接受pVAC-1(對照)和pVAC-1-mCTLA4-PDL1的小鼠的肝細胞癌。如圖10B所示,在治療組與對照組之間平均腫瘤生長沒有差異;然而,與對照組相比,在pVAC-1-mCTLA4-PDL1免疫小鼠中表現出抑制的腫瘤生長(p < 0.005)。
基於以下在上述實施例中的發現得出的結論是,針對CTLA-4、PD-1或PD-L1的DNA疫苗的組合對於增強放射或抗PD-1抗體的組合在體內抑制腫瘤生長是有效的: (1)CTLA-4或CTLA-4加PD-1 DNA疫苗可以增強放射在B16(圖1B)和CT26模型(圖2B)的抗癌效果; (2)CTLA-4-PD-L1融合基因DNA和CTLA-4加PD-L1 DNA疫苗在CT26模型中與放射治療組合使用時也都表現出優異的抗癌效果(圖3B); (3)當使用脂質體遞送CTLA-4-PD-L1 DNA疫苗並與放射組合時,也觀察到正面的抗CT26效果(圖4B); (4)荷CT26腫瘤小鼠的放射增強存活不僅可藉由CTLA-4-PD-1 DNA疫苗實現,而且也可藉由其蛋白疫苗實現(圖5B); (5)CTLA-4-PD-L1 DNA疫苗可在小鼠體內對未經照射的B16腫瘤產生遠位效應(圖6B);類似地,與放射治療組合,CTLA-4加PD-1 DNA疫苗在未經照射的CT26上實現最明顯的遠位效應(圖7D); (6)此外,與單獨J43相比,CTLA-4-PD-L1 DNA疫苗與抗PD1抗體J43組合表現出更好的抗B16效果(圖8B); (7)與單獨J43相比,CTLA-4-PD-L1或PD-1片段DNA疫苗都顯示更好的抗LLC效果(圖9B);以及 (8)CTLA-4-PD-L1 DNA疫苗也對小鼠體內的肝癌細胞BNL的生長表現出抑制效果(圖10B)。
所屬技術領域中具有通常知識者將理解的是,在不偏離廣義的發明概念下,可以對上述具體實施例進行改變。因此,應當理解的是,本發明不限於揭示的特定具體實施例,而是意圖涵蓋在所附申請專利範圍界定的、本發明的精神和範圍內的修改。
無
為了說明本發明的目的,在圖式中圖示出具體實施例。然而,應當理解的是,本發明並不限於圖示的較佳具體實施例。
在圖式中:
圖1A提供實施例1和2中使用的實驗和治療時間表之簡圖。
圖1B圖示實施例1中用放射治療處理的荷B16腫瘤小鼠之體重變化。
圖1C圖示實施例1中荷B16腫瘤小鼠之體重變化。
圖2A提供實施例2的實驗和治療時間表之簡圖。
圖2B圖示實施例2的荷CT26腫瘤小鼠之體重變化。
圖2C圖示實施例2中藉由各種治療策略的CT26腫瘤抑制。
圖3A圖示實施例3中對CT26腫瘤抑制的實驗和治療時間表之簡圖。
圖3B圖示實施例3中藉由各種治療策略的CT26腫瘤抑制,其中就腫瘤抑制效果而言,與用放射治療聯合pVAC1的疫苗治療的小鼠相比,用放射治療聯合CTLA4(pVAC1-mCTLA4)的DNA疫苗與PDL1(pVac1-mPDL1)的DNA疫苗的組合治療的小鼠達到統計顯著性+RT。
圖4A圖示實施例4中對CT26腫瘤抑制的實驗和治療時間表之簡圖。
圖4B圖示實施例4中藉由各種治療策略的CT26腫瘤抑制,其中就腫瘤抑制效果而言,與僅用RT治療的對照組相比,用CTLA4-PLL1(pVAC1-mCTLA4-mPDL1)疫苗與放射治療(在第16天和第22天10 Gy x2)的組合治療的小鼠達到統計顯著性。
圖5A圖示實施例5中對CT26腫瘤抑制的實驗和治療時間表之簡圖。
圖5B圖示就腫瘤抑制效果而言,與pVAC1+RT和其他的疫苗相比,藉由與各種疫苗(包括藉由電穿孔遞送的CTLA4-PDL1(pVAC1-mCTLA4-PDL1)的DNA疫苗)組合的放射與放射治療的組合的CT26腫瘤抑制達到統計顯著性。
圖5C圖示在實施例5中使用放射與各種疫苗的組合治療的小鼠之Kapln-Meier存活曲線。
圖6A圖示實施例6中對B16腫瘤抑制的實驗和治療時間表之簡圖。
圖6B圖示CTLA-4-PD-L1的DNA疫苗的效果,在右側腫瘤接受照射之後,CTLA-4-PD-L1的DNA疫苗能夠誘導遠位效應,如未經照射的左側腫瘤的抑制生長所證(右圖)。
圖7A圖示實施例7中對CT26腫瘤抑制的實驗和治療時間表之簡圖。
圖7B圖示用DNA疫苗治療的組中的體重變化,其中在注射指定的抗CTLA-4(mCTLA)及/或抗PD-1(mPD1)DNA疫苗後,在Balb/c小鼠的兩條腿上接種CT26結腸腫瘤,並照射右腿的腫瘤。
圖7C圖示實施例7中在小鼠的經照射腫瘤上的遠位效應。
圖7D圖示實施例7中在小鼠的未經照射腫瘤上的遠位效應。
圖8A圖示實施例8中使用DNA或蛋白疫苗與抗PD1抗體J43的組合治療B16腫瘤的實驗和治療時間表之簡圖。
圖8B圖示實施例8中J43與CTLA-4-PD-L1 DNA疫苗的組合之抗癌效果。
圖9A圖示在實施例9中用與抗PD1抗體(J43)組合的DNA疫苗治療鼠Lewis肺癌(LLC)的實驗和治療時間表之簡圖。
圖9B圖示藉由單獨、或與J43或PD-1 DNA片段疫苗組合的CTLA-4-PD-L1 DNA疫苗、或單獨J43的LLC生長抑制的效果。
圖10A圖示在實施例10中用 mCTLA4-mPDL1 DNA 疫苗治療鼠肝細胞癌( BNL )
的實驗和治療時間表之簡圖。
圖10B圖示實施例10中mCTLA4-PDL1 DNA疫苗對BNL肝癌細胞生長的效果。
無
Claims (14)
- 一種用於治療一個體的一惡性病變的方法,包含對該個體投予一疫苗與一抗癌治療的組合,其中該疫苗為一醫藥組合物,該醫藥組合物包含一DNA構築體或融合蛋白,該DNA構築體或融合蛋白包含一細胞毒性T淋巴細胞抗原-4(CTLA-4)、及一程式性死亡-1(PD-1)或一程式性細胞死亡1配體1(PD-L1)、或上述之組合。
- 如申請專利範圍第1項之方法,其中該疫苗為包含CTLA-4和PD-L1的DNA疫苗或CTLA-4-PD-L1的疫苗。
- 如申請專利範圍第1項之方法,其中該疫苗為包含CTLA-4和PD-1的DNA疫苗或CTLA-4-PD-1的疫苗。
- 如申請專利範圍第1項之方法,其中該疫苗為針對PD-1片段(PD1 Frag)、CTLA-4-PD-L1(CTLA4-PD-L1 Elec)、或CTLA-4-PD-L1融合蛋白的疫苗。
- 一種用於治療一個體的一惡性病變的方法,包含對該個體投予一抗癌治療與一疫苗的組合,其中該疫苗為一醫藥組合物,該醫藥組合物包含含有編碼細胞毒性T淋巴細胞抗原-4(CTLA-4)的多核苷酸序列的DNA構築體或融合蛋白、及含有程式性死亡-1(PD-1)或程式性細胞死亡1配體1(PD-L1)、或上述之組合的DNA構築體。
- 如申請專利範圍第5項之方法,其中該抗癌治療為放射或抗癌抗體治療。
- 一種用於在接受惡性病變治療的個體體內增強免疫反應的醫藥組合物,包含含有CTLA-4和PD-1的DNA疫苗或含有CTLA-4和PD-L1的DNA疫苗。
- 如申請專利範圍第7項之醫藥組合,包含針對CTLA-4和PD-1的疫苗。
- 如申請專利範圍第7項之醫藥組合,包含針對CTLA-4和PD-L1的疫苗。
- 如申請專利範圍第7項之醫藥組合,包含PD-1片段(PD1 Frag)、CTLA-4-PD-L1(CTLA4-PDL1 Elec)、或CTLA-4-PD-L1融合蛋白。
- 一種用於治療一個體的一惡性病變的方法,包含聯合含有編碼CTLA-4的多核苷酸序列的DNA構築體與含有PD-1或PD-L1的DNA構築體的組合對該個體投予放射治療。
- 如申請專利範圍第11項之方法,包含對該個體投予放射治療與針對CTLA-4和PD-1的疫苗或針對CTLA-4-PD-1的疫苗的組合。
- 如申請專利範圍第11項之方法,包含對該個體投予放射治療與針對CTLA-4和PD-L1的疫苗或針對CTLA-4-PD-L1的疫苗的組合。
- 如上述申請專利範圍之方法或醫藥組合,其中該惡性病變係選自由轉移性黑色素瘤、胰腺癌、結腸直腸癌、肝細胞癌、淋巴瘤、激素難治的前列腺癌、卵巢癌、急性骨髓性白血病、及肺癌所組成之群組。
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