Ciesielski Michael J, Kazim A Latif, Barth Rolf F, Fenstermaker Robert A
Department of Neurosurgery, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
Cancer Immunol Immunother. 2005 Feb;54(2):107-19. doi: 10.1007/s00262-004-0576-y. Epub 2004 Aug 31.
Human malignant gliomas contain epidermal growth factor receptor (EGFR) gene mutations that encode tumor-associated antigens (TAAs) that can be targeted using immunological techniques. One EGFR mutant gene (EGFRvIII) encodes a protein with an epitope that is not found in normal tissues. A number of studies have focused on this unique epitope as a potential target for tumor vaccines. In the present study, we examined the cellular immune effects of a peptide containing multiple copies of the unique EGFRvIII epitope linked together by way of a lysine bridge. Fischer rats were vaccinated with an EGFRvIII multiple antigenic peptide (MAP). While vaccination produced a humoral immune response, anti-MAP antibody production was not accompanied by expression of the Th2 response cytokine IL-4. In MAP/GM-CSF vaccinated animals, a cellular immune response was detected in association with the appearance of CD4+ and CD8+ T cells at the tumor site. Splenocytes and CD8+ T cells from vaccinated rats produced the Th1 cytokine IFN-gamma in vitro in response to stimulation by rat glioma cells expressing EGFRvIII, but not by those expressing wild-type EGFR. MAP vaccine also induced a specific lytic antitumor CTL immune response against F98 glioma cells expressing EGFRvIII, but not against F98 cells expressing either wild-type EGFR or no receptor. The in vivo growth of F98(EGFRvIII) cells was attenuated in vaccinated rats; whereas, growth of F98(EGFR) cells was not. The median survival of vaccinated rats was increased 72% over that of unvaccinated controls challenged with intracerebral F98(EGFRvIII) tumor implants. Therefore, MAP vaccination produced a predominantly cellular antitumor immune response directed against F98 gliomas expressing the EGFRvIII target antigen. The potent immunosuppressive effects of F98 glioma cells mimic the human disease and make this particular tumor model useful for studying immunotherapeutic approaches to malignant gliomas.
人类恶性胶质瘤含有表皮生长因子受体（EGFR）基因突变，这些突变编码肿瘤相关抗原（TAA），可通过免疫技术进行靶向治疗。一种EGFR突变基因（EGFRvIII）编码一种在正常组织中不存在表位的蛋白质。许多研究都聚焦于这个独特的表位，将其作为肿瘤疫苗的潜在靶点。在本研究中，我们检测了一种通过赖氨酸桥连接在一起的含有多个独特EGFRvIII表位拷贝的肽的细胞免疫效应。用EGFRvIII多抗原肽（MAP）对Fischer大鼠进行疫苗接种。虽然接种疫苗产生了体液免疫反应，但抗MAP抗体的产生并未伴随Th2反应细胞因子IL-4的表达。在接种MAP/GM-CSF的动物中，在肿瘤部位检测到与CD4+和CD8+T细胞出现相关的细胞免疫反应。接种大鼠的脾细胞和CD8+T细胞在体外受到表达EGFRvIII的大鼠胶质瘤细胞刺激时产生Th1细胞因子IFN-γ，但受到表达野生型EGFR的细胞刺激时则不产生。MAP疫苗还诱导了针对表达EGFRvIII的F98胶质瘤细胞的特异性溶细胞抗肿瘤CTL免疫反应，但对表达野生型EGFR或不表达受体的F98细胞则无此反应。接种大鼠体内F98(EGFRvIII)细胞的生长受到抑制；而F98(EGFR)细胞的生长则不受影响。接种疫苗的大鼠的中位生存期比接受脑内F98(EGFRvIII)肿瘤植入物攻击的未接种对照延长了72%。因此，MAP疫苗接种产生了主要针对表达EGFRvIII靶抗原的F98胶质瘤的细胞抗肿瘤免疫反应。F98胶质瘤细胞强大的免疫抑制作用模拟了人类疾病，使这个特定的肿瘤模型对于研究恶性胶质瘤的免疫治疗方法很有用。
