Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee 37235, United States.
Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, Tennessee 37235, United States.
ACS Nano. 2024 Mar 5;18(9):6845-6862. doi: 10.1021/acsnano.3c04471. Epub 2024 Feb 22.
Immune checkpoint blockade (ICB) has revolutionized cancer treatment and led to complete and durable responses, but only for a minority of patients. Resistance to ICB can largely be attributed to insufficient number and/or function of antitumor CD8 T cells in the tumor microenvironment. Neoantigen targeted cancer vaccines can activate and expand the antitumor T cell repertoire, but historically, clinical responses have been poor because immunity against peptide antigens is typically weak, resulting in insufficient activation of CD8 cytotoxic T cells. Herein, we describe a nanoparticle vaccine platform that can overcome these barriers in several ways. First, the vaccine can be reproducibly formulated using a scalable confined impingement jet mixing method to coload a variety of physicochemically diverse peptide antigens and multiple vaccine adjuvants into pH-responsive, vesicular nanoparticles that are monodisperse and less than 100 nm in diameter. Using this approach, we encapsulated synergistically acting adjuvants, cGAMP and monophosphoryl lipid A (MPLA), into the nanocarrier to induce a robust and tailored innate immune response that increased peptide antigen immunogenicity. We found that incorporating both adjuvants into the nanovaccine synergistically enhanced expression of dendritic cell costimulatory markers, pro-inflammatory cytokine secretion, and peptide antigen cross-presentation. Additionally, the nanoparticle delivery increased lymph node accumulation and uptake of peptide antigen by dendritic cells in the draining lymph node. Consequently, nanoparticle codelivery of peptide antigen, cGAMP, and MPLA enhanced the antigen-specific CD8 T cell response and delayed tumor growth in several mouse models. Finally, the nanoparticle platform improved the efficacy of ICB immunotherapy in a murine colon carcinoma model. This work establishes a versatile nanoparticle vaccine platform for codelivery of peptide neoantigens and synergistic adjuvants to enhance responses to cancer vaccines.
免疫检查点阻断 (ICB) 彻底改变了癌症治疗方法，并导致完全和持久的反应，但只有少数患者受益。ICB 耐药性在很大程度上归因于肿瘤微环境中抗肿瘤 CD8 T 细胞的数量和/或功能不足。靶向新抗原的癌症疫苗可以激活和扩增抗肿瘤 T 细胞库，但历史上，临床反应较差，因为针对肽抗原的免疫通常较弱，导致 CD8 细胞毒性 T 细胞的激活不足。在此，我们描述了一种纳米颗粒疫苗平台，该平台可以通过多种方式克服这些障碍。首先，该疫苗可以使用可重复的规模化受限冲击射流混合方法来配制，将各种物理化学性质不同的肽抗原和多种疫苗佐剂共装入 pH 响应的、囊泡状纳米颗粒中，这些纳米颗粒粒径均一且小于 100nm。通过这种方法，我们将协同作用的佐剂 cGAMP 和单磷酰脂质 A (MPLA) 包封到纳米载体中，以诱导强烈的、定制化的固有免疫反应，从而提高肽抗原的免疫原性。我们发现，将两种佐剂都纳入纳米疫苗中具有协同作用，可增强树突状细胞共刺激标志物的表达、促炎细胞因子的分泌以及肽抗原的交叉呈递。此外，纳米颗粒的递呈增加了引流淋巴结中树突状细胞对肽抗原的淋巴结积聚和摄取。因此，纳米颗粒共递呈肽抗原、cGAMP 和 MPLA 增强了几种小鼠模型中的抗原特异性 CD8 T 细胞反应并延迟了肿瘤生长。最后，纳米颗粒平台提高了 ICB 免疫疗法在小鼠结肠癌细胞模型中的疗效。这项工作建立了一种多功能的纳米颗粒疫苗平台，用于共递呈肽新抗原和协同佐剂，以增强对癌症疫苗的反应。
