Department of Medical Imaging, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, China.
Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering, NIH, Bethesda, MD 20892, USA.
Sci Adv. 2020 Mar 18;6(12):eaaw6071. doi: 10.1126/sciadv.aaw6071. eCollection 2020 Mar.
Neoantigen vaccines have been enthusiastically pursued for personalized cancer immunotherapy while vast majority of neoantigens have no or low immunogenicity. Here, a bi-adjuvant neoantigen nanovaccine (banNV) that codelivered a peptide neoantigen (Adpgk) with two adjuvants [Toll-like receptor (TLR) 7/8 agonist R848 and TLR9 agonist CpG] was developed for potent cancer immunotherapy. Specifically, banNVs were prepared by a nanotemplated synthesis of concatemer CpG, nanocondensation with cationic polypeptides, and then physical loading with hydrophobic R848 and Adpgk. The immunogenicity of the neoantigen was profoundly potentiated by efficient codelivery of neoantigen and dual synergistic adjuvants, which is accompanied by reduced acute systemic toxicity. BanNVs sensitized immune checkpoint programmed death receptor 1 (PD-1) on T cells, therefore, a combination of banNVs with aPD-1 conspicuously induced the therapy response and led to complete regression of 70% neoantigen-specific tumors without recurrence. We conclude that banNVs are promising to optimize personalized therapeutic neoantigen vaccines for cancer immunotherapy.
新型抗原疫苗在个性化癌症免疫治疗中受到了热烈的追捧，而绝大多数新型抗原的免疫原性低或无。在这里，我们开发了一种双佐剂新型抗原纳米疫苗（banNV），该疫苗共递呈一种肽新型抗原（Adpgk）和两种佐剂[Toll 样受体（TLR）7/8 激动剂 R848 和 TLR9 激动剂 CpG]，用于有效的癌症免疫治疗。具体来说，banNV 是通过串联 CpG 的纳米模板合成、阳离子多肽的纳米缩合，然后物理加载疏水性 R848 和 Adpgk 制备而成。新型抗原的免疫原性通过新型抗原和双协同佐剂的有效共递呈得到显著增强，同时伴随急性全身毒性降低。BanNVs 敏化了 T 细胞上的免疫检查点程序性死亡受体 1（PD-1），因此，banNVs 与 aPD-1 的联合治疗显著诱导了治疗反应，并导致 70%的新型抗原特异性肿瘤完全消退且无复发。我们得出结论，banNVs 有望优化用于癌症免疫治疗的个性化治疗新型抗原疫苗。
