Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, OR, United States of America.
Oregon Health and Sciences University, Portland, OR, United States of America.
PLoS One. 2019 Jan 2;14(1):e0209153. doi: 10.1371/journal.pone.0209153. eCollection 2019.
Dysregulated signaling via the epidermal growth factor receptor (EGFR)-family is believed to contribute to the progression of a diverse array of cancers. The most common variant of EGFR is EGFRvIII, which results from a consistent and tumor-specific in-frame deletion of exons 2-7 of the EGFR gene. This deletion generates a novel glycine at the junction and leads to constitutive ligand-independent activity. This junction forms a novel shared tumor neo-antigen with demonstrated immunogenicity in both mice and humans. A 21-amino acid peptide spanning the junctional region was selected, and then one or five copies of this 21-AA neo-peptide were incorporated into live-attenuated Listeria monocytogenes-based vaccine vector. These vaccine candidates demonstrated efficient secretion of the recombinant protein and potent induction of EGFRvIII-specific CD8+ T cells, which prevented growth of an EGFRvIII-expressing squamous cell carcinoma. These data demonstrate the potency of a novel cancer-specific vaccine candidate that can elicit EGFRvIII-specific cellular immunity, for the purpose of targeting EGFRvIII positive cancers that are resistant to conventional therapies.
通过表皮生长因子受体 (EGFR)-家族的失调信号被认为有助于多种癌症的进展。EGFR 的最常见变体是 EGFRvIII，它是由 EGFR 基因外显子 2-7 的一致和肿瘤特异性框内缺失产生的。这种缺失在连接处产生一个新的甘氨酸，导致组成性配体非依赖性活性。这个连接处与在小鼠和人类中均表现出免疫原性的新型共享肿瘤新抗原形成。选择跨越连接区的 21 个氨基酸肽，然后将该 21-AA 新肽的一个或五个拷贝掺入活减毒李斯特菌单核细胞增生症疫苗载体中。这些候选疫苗表现出重组蛋白的有效分泌和 EGFRvIII 特异性 CD8+T 细胞的强烈诱导，从而阻止了表达 EGFRvIII 的鳞状细胞癌的生长。这些数据证明了一种新型的癌症特异性候选疫苗的效力，该疫苗能够引发 EGFRvIII 特异性细胞免疫，用于靶向对传统疗法有抗性的 EGFRvIII 阳性癌症。
