来自杜克大学医学院的一个研究小组设计出一种致命武器，利用一种人造蛋白促进机体天然免疫系统对抗癌症，杀死了小鼠的脑肿瘤。如果能够证实在人体中同样起作用，它将克服影响免疫治疗效力的一个主要障碍。研究结果发表在12月17日的美国《国家科学院院刊》（PNAS）上。
这一蛋白由两部分构成——一个专门与肿瘤细胞结合，另一个负责抓住机体的斗士T细胞，对肿瘤发起攻击。治疗使得8只具有脑肿瘤的小鼠其中6只获得治愈。
“这一研究代表了一种古老概念的复兴：靶向带有肿瘤特异性抗原的癌症，或许是一种无毒副作用治疗癌症的最有效的途径，”论文的资深作者、杜克大学Preston Robert Tisch脑肿瘤中心神经外科医生John H. Sampson博士说：“这种方法一直存在一些问题，尤其是治疗脑肿瘤时。我们的治疗是令人感到兴奋的，因为它像魔术贴（Velcro）一样起作用使T细胞结合到肿瘤细胞上，诱导它们杀死肿瘤，而不会对邻近的正常组织产生任何负面效应。”
Sampson和同事们将研究焦点放在胶质母细胞瘤的免疫疗法上。众所周知，这种脑瘤非常难以医治。即便接受手术、放疗和化疗，胶质母细胞瘤仍普遍致命，平均生存期为15个月。
免疫治疗是指通过触发机体的B细胞和T细胞来攻击肿瘤的方法，其在治疗脑癌和其他癌症研究中显示出前景，然而在临床应用中却存在一些问题：一是很难达到治疗剂量，二是免疫系统会攻击健康组织和器官，从而造成副作用。
为了克服这些缺陷，杜克大学研究人员设计出了一种连接体——一种名为双特异性T细胞衔接器（BiTE）的人造蛋白质，它能够将肿瘤与它的杀伤细胞连接到一起。新工程蛋白包括两个独立的抗体部分，一个负责招募吸引机体的斗士T细胞，一个负责专门导向追踪癌症上的EGFRvIII抗原。
一旦通过新双特异性抗体连接，T细胞会将肿瘤识别为入侵物，发动攻击。而没有携带肿瘤抗原的正常组织则不受损伤。
“这种疗法一个主要的优点是可由静脉给予，能通过血脑屏障。当我们对小鼠给予全身性治疗时，它成功地定位到肿瘤，甚至治疗了中枢神经系统中体积大的侵袭性肿瘤。(生物谷Bioon.com)
doi: 10.1073/pnas.1219817110
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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.
