Pan Jing, Zhang Qi, Sei Shizuko, Shoemaker Robert H, Lubet Ronald A, Wang Yian, You Ming
Cancer Center and Department of Pharmacology & Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA.
Chemopreventive Agent Development Research Group, Division of Cancer Prevention, National Cancer Institute, Bethesda, MD, USA.
Oncotarget. 2017 Aug 1;8(47):82689-82699. doi: 10.18632/oncotarget.19831. eCollection 2017 Oct 10.
Lung cancer remains the leading cause of cancer death worldwide. Mutations in KRAS are detected in up to 30% of lung cancer cases. No effective therapies specifically targeting mutant KRAS have been developed. Vaccination against KRAS mutants is one of the venues of active exploration. The present study evaluated both immunogenicity and antitumor efficacy of a newly formulated multipeptide vaccine targeting multiple epitopes of the KRAS molecule. The formulated vaccine contained top four peptides, which elicited the strongest immunologic response and showed 100% sequence homology between human and mouse. The multipeptide KRAS vaccine was tested in an inducible CCSP-TetO-KRAS mouse model, where the vaccine was administered prior to activating the mutant KRAS protein. The KRAS peptide vaccine exhibited striking efficacy, reducing tumor number and tumor burden by >80% when compared with adjuvant alone. Splenocytes collected from vaccinated animals showed a robust immunologic response to the immunizing peptides. Furthermore, stimulation of these splenocytes by the vaccinated peptides resulted in the secretion of cytokines indicative of Th1 responses but with minimal secretion of Th2-related cytokines. The multipeptide KRAS vaccine was immunogenic and efficacious in the primary prevention of KRAS-induced lung cancer, indicating that the approach potentially can be used to prevent other KRAS-driven cancers, either alone or in combination with other modalities.
肺癌仍然是全球癌症死亡的主要原因。在高达30%的肺癌病例中检测到KRAS基因突变。目前尚未开发出专门针对突变型KRAS的有效疗法。针对KRAS突变体的疫苗接种是正在积极探索的途径之一。本研究评估了一种新配制的针对KRAS分子多个表位的多聚肽疫苗的免疫原性和抗肿瘤疗效。配制的疫苗包含排名前四位的肽段，这些肽段引发最强的免疫反应，并且在人和小鼠之间显示出100%的序列同源性。在可诱导的CCSP-TetO-KRAS小鼠模型中测试了多聚肽KRAS疫苗，在该模型中，在激活突变型KRAS蛋白之前接种疫苗。KRAS肽疫苗显示出显著疗效，与单独使用佐剂相比，肿瘤数量和肿瘤负荷减少了80%以上。从接种疫苗的动物收集的脾细胞对免疫肽表现出强烈的免疫反应。此外，接种疫苗的肽对这些脾细胞的刺激导致了指示Th1反应的细胞因子的分泌，但Th2相关细胞因子的分泌极少。多聚肽KRAS疫苗在KRAS诱导的肺癌的一级预防中具有免疫原性和疗效，表明该方法有可能单独或与其他方式联合用于预防其他KRAS驱动的癌症。
