Heimberger Amy B, Crotty Laura E, Archer Gary E, Hess Kenneth R, Wikstrand Carol J, Friedman Allan H, Friedman Henry S, Bigner Darell D, Sampson John H
Department of Neurosurgery, The University of Texas M. D. Anderson Cancer Center, Unit 442, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Clin Cancer Res. 2003 Sep 15;9(11):4247-54.
The epidermal growth factor receptor (EGFR) is often amplified and structurally rearranged in malignant gliomas and other tumors such as breast and lung, with the most common mutation being EGFRvIII. In the study described here, we tested in mouse models a vaccine consisting of a peptide encompassing the tumor-specific mutated segment of EGFRvIII (PEP-3) conjugated to keyhole limpet hemocyanin [KLH (PEP-3-KLH)].
C57BL/6J or C3H mice were vaccinated with PEP-3-KLH and subsequently challenged either s.c. or intracerebrally with a syngeneic melanoma cell line stably transfected with a murine homologue of EGFRvIII. Control mice were vaccinated with KLH. To test its effect on established tumors, C3H mice were also challenged intracerebrally and subsequently vaccinated with PEP-3-KLH.
S.c. tumors developed in all of the C57BL/6J mice vaccinated with KLH in Freund's adjuvant, and there were no long-term survivors. Palpable tumors never developed in 70% of the PEP-3-KLH-vaccinated mice. In the C57BL/6J mice receiving the PEP-3-KLH vaccine, the tumors that did develop were significantly smaller than those in the control group (P < 0.05). PEP-3-KLH vaccination did not result in significant cytotoxic responses in standard cytotoxicity assays; however, antibody titers against PEP-3 were enhanced. The passive transfer of sera from the immunized mice to nonimmunized mice protected 31% of the mice from tumor development (P < 0.05). In vivo depletion studies showed that the effector cell population was natural killer and CD8+ T cells, and in vitro assays showed that macrophages could lyse target tumor cells with serum from the PEP-3-KLH-vaccinated mice. Peptide vaccination was also sufficiently potent to have marked efficacy against intracerebral tumors, resulting in a >173% increase in median survival time, with 80% of the C3H mice achieving long-term survival (P = 0.014). In addition, C3H mice with established intracerebral tumor that received a single treatment of PEP-3-KLH showed a 26% increase in median survival time, with 40% long-term survival (P = 0.007).
Vaccination with an EGFRvIII-specific peptide is efficacious against both s.c. and established intracerebral tumors. The therapeutic effect of peptide vaccination may be mediated, in part, by antibody-dependent cellular cytotoxicity.
表皮生长因子受体（EGFR）在恶性胶质瘤以及其他肿瘤（如乳腺癌和肺癌）中常发生扩增和结构重排，最常见的突变是EGFRvIII。在此所述的研究中，我们在小鼠模型中测试了一种疫苗，该疫苗由与钥孔戚血蓝蛋白[KLH（PEP - 3 - KLH）]偶联的包含EGFRvIII肿瘤特异性突变片段的肽（PEP - 3）组成。
用PEP - 3 - KLH对C57BL/6J或C3H小鼠进行疫苗接种，随后通过皮下或脑内接种稳定转染有EGFRvIII鼠同源物的同基因黑色素瘤细胞系进行攻击。对照小鼠用KLH进行疫苗接种。为了测试其对已形成肿瘤的作用，也对C3H小鼠进行脑内攻击，随后用PEP - 3 - KLH进行疫苗接种。
在所有用弗氏佐剂中的KLH进行疫苗接种的C57BL/6J小鼠中均出现皮下肿瘤，且无长期存活者。在70%接种PEP - 3 - KLH的小鼠中从未出现可触及的肿瘤。在接受PEP - 3 - KLH疫苗的C57BL/6J小鼠中，确实形成的肿瘤明显小于对照组（P < 0.05）。在标准细胞毒性试验中，PEP - 3 - KLH疫苗接种未导致显著的细胞毒性反应；然而，针对PEP - 3的抗体滴度有所提高。将免疫小鼠的血清被动转移至未免疫小鼠可使31%的小鼠免受肿瘤发生（P < 0.05）。体内清除研究表明，效应细胞群体是自然杀伤细胞和CD8 + T细胞，体外试验表明巨噬细胞可以用接种PEP - 3 - KLH小鼠的血清裂解靶肿瘤细胞。肽疫苗接种对脑内肿瘤也具有足够的效力，可使中位生存时间增加>173%，80%的C3H小鼠实现长期存活（P = 0.014）。此外，对已形成脑内肿瘤的C3H小鼠进行单次PEP - 3 - KLH治疗，中位生存时间增加26%，40%长期存活（P = 0.007）。
用EGFRvIII特异性肽进行疫苗接种对皮下肿瘤和已形成的脑内肿瘤均有效。肽疫苗接种的治疗效果可能部分由抗体依赖性细胞毒性介导。
