Cai et al. Molecular Cancer (2021) 20:164 https://doi.org/10.1186/s12943-021-01467-8 RESEARCH Personalized neoantigen vaccine prevents postoperative recurrence in hepatocellular carcinoma patients with vascular invasion Zhixiong Cai1,2,3†, Xiaoping Su4,5†, Liman Qiu1,2,3†, Zhenli Li1,2,3†, Xiaolou Li1,2,3, Xiuqing Dong1,2,3, Fuqun Wei1,2,3, Yang Zhou1,2,3, Liuping Luo1,2,3, Geng Chen1,2,3, Hengkai Chen1,2,3, Yingchao Wang1,2,3, Yongyi Zeng1,2,3* and Xiaolong Liu1,2,3* Abstract Background: Clinically, prophylactic anti-recurrence treatments for hepatocellular carcinoma (HCC) patients after radical surgery are extremely limited. Neoantigen based vaccine can generate robust anti-tumor immune response in several solid tumors but whether it could induce anti-tumor immune response in HCC and serve as a safe and effec- tive prophylactic strategy for preventing postoperative HCC recurrence still remain largely unclear. Methods: Personalized neoantigen vaccine was designed and immunized for 10 HCC patients with high risk of post - operative recurrence in a prime-boost schedule. The safety and immune response were assessed through adverse events, tissue sequencing, ELISpot, TCR sequencing. The clinical response was evaluated by recurrence-free survival (RFS) and personalized circulating tumor DNA (ctDNA) sequencing. Results: In the 10 enrolled patients, no obvious adverse events were observed during neoantigen vaccinations. Until the deadline of clinical trial, 8 of 10 patients were confirmed with clinical relapse by imaging, the other 2 patients remained relapse-free. From receiving first neoantigen vaccination, the median RFS of 10 patients were 7.4 months. Among 7 patients received all planned neoantigen vaccinations, 5 of them demonstrated neoantigen-induced T cell responses and have significantly longer RFS after radical surgery than other 5 patients without responsive neoanti- gens or only with prime vaccination and propensity scores matching control patients (p = 0.035). Moreover, tracking personalized neoantigen mutations in ctDNA could provide real-time evaluation of clinical response in HCC patients during neoantigen vaccination and follow up. Conclusion: Personalized neoantigen vaccine is proved as a safe, feasible and effective strategy for HCC anti-recur - rence, and its progression could be sensitively monitored by corresponding neoantigen mutations in ctDNA, and thus provided solid information for individualized medicine in HCC. Trial registration: This study was registered at Chinese Clinical Trial Registry; Registration number: ChiCT R1900 020990.