mRNA疫苗诱导胃肠道癌症患者产生新抗原特异性T细胞免疫
mRNA vaccine-induced neoantigen-specific T cell immunity in patients with gastrointestinal cancer
晚期胃肠道癌症缺乏有效治疗性疫苗。研究者将患者肿瘤中验证过的新抗原、预测的新表位及驱动基因突变拼接成单一mRNA构建体，用于转移性胃肠道癌症患者。疫苗安全，并诱发了针对预测新表位的突变特异性T细胞反应，还分离出靶向KRASG12D突变的T细胞受体。但4例接受治疗的患者均未出现客观临床缓解。提示该疫苗可能需与检查点抑制剂或过继T细胞疗法联用。
为什么推荐给您：个体化mRNA新抗原疫苗首次在胃肠道癌症患者中验证安全性和免疫原性，属新模态早期人体阳性结果。
不需要生物学背景，多打比方
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摘要Abstract
BACKGROUNDTherapeutic vaccinations against cancer have mainly targeted differentiation antigens, cancer-testis antigens, and overexpressed antigens and have thus far resulted in little clinical benefit. Studies conducted by multiple groups have demonstrated that T cells recognizing neoantigens are present in most cancers and offer a specific and highly immunogenic target for personalized vaccination.METHODSWe recently developed a process using tumor-infiltrating lymphocytes to identify the specific immunogenic mutations expressed in patients' tumors. Here, validated, defined neoantigens, predicted neoepitopes, and mutations of driver genes were concatenated into a single mRNA construct to vaccinate patients with metastatic gastrointestinal cancer.RESULTSThe vaccine was safe and elicited mutation-specific T cell responses against predicted neoepitopes not detected before vaccination. Furthermore, we were able to isolate and verify T cell receptors targeting KRASG12D mutation. We observed no objective clinical responses in the 4 patients treated in this trial.CONCLUSIONThis vaccine was safe, and potential future combination of such vaccines with checkpoint inhibitors or adoptive T cell therapy should be evaluated for possible clinical benefit in patients with common epithelial cancers.TRIAL REGISTRATIONPhase I/II protocol (NCT03480152) was approved by the IRB committee of the NIH and the FDA.FUNDINGCenter for Clinical Research, NCI, NIH.