來(lái)自杜克大學(xué)醫(yī)學(xué)院的一個(gè)研究小組設(shè)計(jì)出一種致命武器,，利用一種人造蛋白促進(jìn)機(jī)體天然免疫系統(tǒng)對(duì)抗癌癥，殺死了小鼠的腦腫瘤,。如果能夠證實(shí)在人體中同樣起作用,，它將克服影響免疫治療效力的一個(gè)主要障礙。研究結(jié)果發(fā)表在12月17日的美國(guó)《國(guó)家科學(xué)院院刊》（PNAS）上,。
這一蛋白由兩部分構(gòu)成——一個(gè)專(zhuān)門(mén)與腫瘤細(xì)胞結(jié)合,，另一個(gè)負(fù)責(zé)抓住機(jī)體的斗士T細(xì)胞，對(duì)腫瘤發(fā)起攻擊,。治療使得8只具有腦腫瘤的小鼠其中6只獲得治愈,。
“這一研究代表了一種古老概念的復(fù)興：靶向帶有腫瘤特異性抗原的癌癥，或許是一種無(wú)毒副作用治療癌癥的最有效的途徑,，”論文的資深作者,、杜克大學(xué)Preston Robert Tisch腦腫瘤中心神經(jīng)外科醫(yī)生John H. Sampson博士說(shuō)：“這種方法一直存在一些問(wèn)題，尤其是治療腦腫瘤時(shí),。我們的治療是令人感到興奮的,，因?yàn)樗衲g(shù)貼（Velcro）一樣起作用使T細(xì)胞結(jié)合到腫瘤細(xì)胞上，誘導(dǎo)它們殺死腫瘤,，而不會(huì)對(duì)鄰近的正常組織產(chǎn)生任何負(fù)面效應(yīng),。”
Sampson和同事們將研究焦點(diǎn)放在膠質(zhì)母細(xì)胞瘤的免疫療法上。眾所周知,，這種腦瘤非常難以醫(yī)治,。即便接受手術(shù)、放療和化療,，膠質(zhì)母細(xì)胞瘤仍普遍致命,，平均生存期為15個(gè)月。
免疫治療是指通過(guò)觸發(fā)機(jī)體的B細(xì)胞和T細(xì)胞來(lái)攻擊腫瘤的方法,，其在治療腦癌和其他癌癥研究中顯示出前景,，然而在臨床應(yīng)用中卻存在一些問(wèn)題：一是很難達(dá)到治療劑量，二是免疫系統(tǒng)會(huì)攻擊健康組織和器官,，從而造成副作用,。
為了克服這些缺陷，杜克大學(xué)研究人員設(shè)計(jì)出了一種連接體——一種名為雙特異性T細(xì)胞銜接器（BiTE）的人造蛋白質(zhì),，它能夠?qū)⒛[瘤與它的殺傷細(xì)胞連接到一起,。新工程蛋白包括兩個(gè)獨(dú)立的抗體部分，一個(gè)負(fù)責(zé)招募吸引機(jī)體的斗士T細(xì)胞,，一個(gè)負(fù)責(zé)專(zhuān)門(mén)導(dǎo)向追蹤癌癥上的EGFRvIII抗原,。
一旦通過(guò)新雙特異性抗體連接，T細(xì)胞會(huì)將腫瘤識(shí)別為入侵物,，發(fā)動(dòng)攻擊,。而沒(méi)有攜帶腫瘤抗原的正常組織則不受損傷,。
“這種療法一個(gè)主要的優(yōu)點(diǎn)是可由靜脈給予，能通過(guò)血腦屏障,。當(dāng)我們對(duì)小鼠給予全身性治療時(shí),，它成功地定位到腫瘤，甚至治療了中樞神經(jīng)系統(tǒng)中體積大的侵襲性腫瘤,。(生物谷Bioon.com)
doi: 10.1073/pnas.1219817110
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PMID:
Systemic administration of a bispecific antibody targeting EGFRvIII successfully treats intracerebral glioma
Bryan D. Choia,b, Chien-Tsun Kuanb,c, Mingqing Caid, Gary E. Archera,b,c, Duane A. Mitchella,b,c, Patrick C. Gedeona,e, Luis Sanchez-Pereza,c, Ira Pastanf,1, Darell D. Bignera,b,c, and John H. Sampsona,b,c,1
Bispecific antibodies (bscAbs), particularly those of the bispecific T-cell engager (BiTE) subclass, have been shown to effectively redirect T cells against cancer. Previous efforts to target antigens expressed in both tumors and normal tissues have produced significant toxicity, however. Moreover, like other large molecules, bscAbs may be restricted from entry into the “immunologically privileged” CNS. A tumor-specific mutation of the epidermal growth factor receptor, EGFRvIII, is a constitutively activated tyrosine kinase not found in normal tissues but frequently expressed in glioblastomas and many other neoplasms. Because it is localized solely to tumor tissue, EGFRvIII presents an ideal target for immunotherapy. Here we report the preclinical evaluation of an EGFRvIII-targeted BiTE, bscEGFRvIIIxCD3. Our results show that bscEGFRvIIIxCD3 activates T cells to mediate potent and antigen-specific lysis of EGFRvIII-expressing gliomas in vitro (P < 0.001) at exceedingly low concentrations (10 ng/mL) and effector-to-target ratios (2.5:1). Treatment with i.v. bscEGFRvIIIxCD3 yielded extended survival in mice with well-established intracerebral tumors (P < 0.05) and achieved durable complete cure at rates up to 75%. Antitumor efficacy was significantly abrogated on blockade of EGFRvIII binding, demonstrating the need for target antigen specificity both in vitro and in vivo. These results demonstrate that BiTEs can be used to elicit functional antitumor immunity in the CNS, and that peptide blockade of BiTE-mediated activity may greatly enhance the safety profile for antibody-redirected T-cell therapies. Finally, bscEGFRvIIIxCD3 represents a unique advancement in BiTE technology given its exquisite tumor specificity, which enables precise elimination of cancer without the risk of autoimmune toxicity.
