Vaccine Research Center (VRC), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA.
Avidea Technologies, Inc, Baltimore, MD, USA.
Nat Biotechnol. 2020 Mar;38(3):320-332. doi: 10.1038/s41587-019-0390-x. Epub 2020 Jan 13.
Personalized cancer vaccines targeting patient-specific neoantigens are a promising cancer treatment modality; however, neoantigen physicochemical variability can present challenges to manufacturing personalized cancer vaccines in an optimal format for inducing anticancer T cells. Here, we developed a vaccine platform (SNP-7/8a) based on charge-modified peptide-TLR-7/8a conjugates that are chemically programmed to self-assemble into nanoparticles of uniform size (~20 nm) irrespective of the peptide antigen composition. This approach provided precise loading of diverse peptide neoantigens linked to TLR-7/8a (adjuvant) in nanoparticles, which increased uptake by and activation of antigen-presenting cells that promote T-cell immunity. Vaccination of mice with SNP-7/8a using predicted neoantigens (n = 179) from three tumor models induced CD8 T cells against ~50% of neoantigens with high predicted MHC-I binding affinity and led to enhanced tumor clearance. SNP-7/8a delivering in silico-designed mock neoantigens also induced CD8 T cells in nonhuman primates. Altogether, SNP-7/8a is a generalizable approach for codelivering peptide antigens and adjuvants in nanoparticles for inducing anticancer T-cell immunity.
针对患者特异性新抗原的个体化癌症疫苗是一种很有前途的癌症治疗方法;然而,新抗原的理化可变性可能会给以最佳形式制造用于诱导抗癌 T 细胞的个体化癌症疫苗带来挑战。在这里,我们开发了一种基于带电荷修饰的肽-TLR-7/8a 缀合物的疫苗平台 (SNP-7/8a),这些缀合物通过化学程序自组装成均匀大小 (~20nm) 的纳米颗粒,而与肽抗原组成无关。这种方法精确地加载了与 TLR-7/8a(佐剂)连接的各种肽新抗原(n=179),这增加了抗原呈递细胞的摄取和激活,从而促进了 T 细胞免疫。使用来自三种肿瘤模型的预测新抗原(n=179)对 SNP-7/8a 进行的小鼠疫苗接种诱导了针对约 50%具有高预测 MHC-I 结合亲和力的新抗原的 CD8 T 细胞,并增强了肿瘤清除。在灵长类动物中,SNP-7/8a 递送计算机设计的模拟新抗原也诱导了 CD8 T 细胞。总之,SNP-7/8a 是一种可推广的方法,用于在纳米颗粒中共同递呈肽抗原和佐剂,以诱导抗癌 T 细胞免疫。