个体化异源黑猩猩腺病毒与自扩增mRNA新抗原疫苗用于晚期转移性实体瘤：1期试验中期结果
Individualized, heterologous chimpanzee adenovirus and self-amplifying mRNA neoantigen vaccine for advanced metastatic solid tumors: phase 1 trial interim results
检查点抑制剂对免疫反应低的肿瘤获益有限，诱导T细胞的疫苗有望与检查点抑制剂联用实现长期疾病控制。该1/2期研究评估个体化异源黑猩猩腺病毒（ChAd68）和自扩增mRNA（samRNA）新抗原疫苗联合nivolumab和ipilimumab的安全性和推荐2期剂量。疫苗方案安全耐受，无剂量限制毒性；诱导了持久的新抗原特异性CD8 T细胞反应，部分微卫星稳定结直肠癌患者总生存改善，且循环肿瘤DNA下降。研究规模小，需更大随机试验验证。
为什么推荐给您：首次人体使用异源ChAd68加自扩增mRNA新抗原疫苗平台，安全且诱导持久CD8 T细胞，属新模态早期阳性结果。
不需要生物学背景，多打比方
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摘要Abstract
Checkpoint inhibitor (CPI) therapies provide limited benefit to patients with tumors of low immune reactivity. T cell-inducing vaccines hold promise to exert long-lasting disease control in combination with CPI therapy. Safety, tolerability and recommended phase 2 dose (RP2D) of an individualized, heterologous chimpanzee adenovirus (ChAd68) and self-amplifying mRNA (samRNA)-based neoantigen vaccine in combination with nivolumab and ipilimumab were assessed as primary endpoints in an ongoing phase 1/2 study in patients with advanced metastatic solid tumors (NCT03639714). The individualized vaccine regimen was safe and well tolerated, with no dose-limiting toxicities. Treatment-related adverse events (TRAEs) >10% included pyrexia, fatigue, musculoskeletal and injection site pain and diarrhea. Serious TRAEs included one count each of pyrexia, duodenitis, increased transaminases and hyperthyroidism. The RP2D was 10^12 viral particles (VP) ChAd68 and 30 µg samRNA. Secondary endpoints included immunogenicity, feasibility of manufacturing and overall survival (OS). Vaccine manufacturing was feasible, with vaccination inducing long-lasting neoantigen-specific CD8 T cell responses. Several patients with microsatellite-stable colorectal cancer (MSS-CRC) had improved OS. Exploratory biomarker analyses showed decreased circulating tumor DNA (ctDNA) in patients with prolonged OS. Although small study size limits statistical and translational analyses, the increased OS observed in MSS-CRC warrants further exploration in larger randomized studies.