Lymph Node-Targeted Codelivery of Albumin-Binding Peptide Antigens and Di-Adjuvant for Melanoma Combination Immunotherapy

项目摘要 黑色素瘤是最严重的皮肤癌类型。晚期黑色素瘤非常具有侵袭性，尽管 治疗方法的进步，仍然有很低的存活率。免疫检查点（Immune Checkpoint） 阻断（ICB）使许多黑色素瘤患者受益。虽然令人鼓舞，但仍有一个未满足的需求， 患者对ICB无反应。ICB治疗功效可通过递送免疫抑制剂的疫苗制剂来促进。 肿瘤相关抗原和新抗原。化学上确定的肽疫苗对于相对较弱的免疫系统是有吸引力的。 制备容易，药物稳定性好。肽疫苗的成功依赖于 的交付。尽管对各种肽疫苗制剂进行了临床测试，但其治疗功效仍不确定。 由于许多递送问题，包括：1）向作用部位递送的疫苗较差，2）有限的共 递送免疫刺激剂佐剂和抗原以增强抗原免疫原性，3） 克服肿瘤异质性，和4）递送物理化学异质性抗原的能力有限。 我们的策略是开发一种高效、靶向性的肽疫苗平台用于ICB联合治疗 解决了这些缺陷中的每一个：1）白蛋白搭便车将用于将肽疫苗递送到 淋巴结和抗原呈递细胞（APC），2）有效的佐剂和佐剂/抗原共递送， 用于增强抗原免疫原性，3）模块化系统将递送多抗原以克服肿瘤 异质性，以及4）广泛适用的系统将递送各种肽抗原。在我们的初步研究中， 我们开发了白蛋白结合疫苗（AlbiVax），以增强疫苗向淋巴结和APC的递送， 倍，相对于临床基准。AlbiVax促进抗癌免疫应答14倍， 提高了黑色素瘤的治疗效果。此外，通过使用免疫球蛋白共递送有效的双佐剂和抗原， 白蛋白搭便车纳米支架，我们进一步增强抗原免疫原性，促进黑色素瘤 疗效我们在这项研究中的目标是设计多抗原/双佐剂共递送AlbiVax （mADC-AlbiVax）作为共递送有效佐剂和异源肽抗原的有效平台 淋巴结和APC，从而引发对ICB黑色素瘤的有效，广泛和持久的免疫力 联合免疫疗法目标1将优化mADC-AlbiVax型号的模块化结构， 针对淋巴结、APC和APC中的亚细胞位置的疫苗，用于最佳的抗肿瘤免疫调节; 目的2合成黑色素瘤mADC-AlbiVax，研究疫苗共递送和免疫调节作用; 3将评估这种疫苗输送系统单独或联合使用的黑色素瘤治疗效果和安全性 在小鼠模型中，该项目由一个独立的、富有成效的ESI领导， 初步数据和一个辅助团队。这项工作的一个重要成果将在临床前建立一个 使用化学确定的疫苗和临床测试或使用的试剂的疫苗递送系统，用于未来的临床 评价 1

Project Summary Melanoma is the most serious type of skin cancer. Advanced melanoma is very aggressive and, despite advances in therapeutics, continues to have a low survival rate. Immunotherapy such as immune checkpoint blockade (ICB) benefited many melanoma patients. While encouraging, there remains an unmet need as most patients do not respond to ICB. ICB therapeutic efficacy can be promoted by vaccine formulations that deliver tumor-associated antigens and neoantigens. Chemically-defined peptide vaccines are attractive for relatively easy manufacturing and good pharmaceutical stability. The success of peptide vaccines relies on the efficiency of delivery. Despite clinical testing of various peptide vaccine formulations, their therapeutic efficacy has been limited due to a number of delivery issues including: 1) poor vaccine delivery to the site of action, 2) limited co- delivery of immunostimulant adjuvants and antigens to enhance antigen immunogenicity, 3) the limited ability to overcome tumor heterogeneity, and 4) the limited ability to deliver physicochemically heterogeneous antigens. Our strategy is to develop a high efficiency and targeted peptide vaccine platform for ICB combination therapy that addresses each of these deficiencies: 1) albumin hitchhiking will be used to deliver peptide vaccines to lymph nodes and antigen-presenting cells (APCs), 2) potent adjuvants and adjuvant/antigen co-delivery will be employed to enhance antigen immunogenicity, 3) a modular system will deliver multi-antigens to overcome tumor heterogeneity, and 4) a widely applicable system will deliver various peptide antigens. In our preliminary studies, we developed albumin-binding vaccines (AlbiVax) to enhance vaccine delivery to lymph nodes and APCs 100- fold in mice, relative to a clinical benchmark. AlbiVax promoted anticancer immune responses 14-fold, and improved melanoma therapeutic efficacy. Moreover, by co-delivering a potent di-adjuvant and antigens using an albumin-hitchhiking nanoscaffold, we further potentiated antigen immunogenicity and promoted melanoma therapeutic efficacy. Our objective in this study is to engineer multi-antigen/di-adjuvant co-delivery AlbiVax (mADC-AlbiVax) as an efficient platform that co-delivers potent adjuvants and heterogenous peptide antigens to lymph nodes and APCs, whereby eliciting potent, broad, and long-lasting immunity for ICB melanoma combination immunotherapy. Aim 1 will optimize the modular structure of model mADC-AlbiVax to co-deliver vaccines to lymph nodes, APCs, and subcellular locations in APCs for optimal antitumor immunomodulation; Aim 2 will synthesize melanoma mADC-AlbiVax, and study vaccine co-delivery and immunomodulation; and Aim 3 will evaluate the melanoma therapeutic efficacy and safety of this vaccine delivery system, alone or combined with ICB, in mouse models. This project led by an independent, productive ESI is supported by extensive preliminary data and a complementary team. A significant deliverable from this work will preclinically establish a vaccine delivery system using chemically-defined vaccines and clinically tested or used agents for future clinical evaluation. 1