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

项目概要 黑色素瘤是最严重的皮肤癌类型。晚期黑色素瘤具有很强的侵袭性，尽管 随着治疗技术的进步，生存率仍然较低。免疫疗法，例如免疫检查点 封锁（ICB）使许多黑色素瘤患者受益。虽然令人鼓舞，但仍然存在未满足的需求，因为大多数 患者对 ICB 没有反应。 ICB 的治疗效果可以通过疫苗配方来提高 肿瘤相关抗原和新抗原。化学成分确定的肽疫苗对相对有吸引力 易于制造，药物稳定性好。肽疫苗的成功取决于效率 交货。尽管对各种肽疫苗制剂进行了临床测试，但它们的治疗效果一直未得到证实。 由于一些交付问题而受到限制，包括：1）疫苗交付到作用地点的效果不佳，2）合作有限 递送免疫刺激佐剂和抗原以增强抗原免疫原性，3）能力有限 克服肿瘤异质性，4) 递送理化异质性抗原的能力有限。 我们的策略是开发用于ICB联合治疗的高效、靶向肽疫苗平台 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输送到 淋巴结和抗原呈递细胞 (APC)，2) 有效的佐剂和佐剂/抗原共同递送将 用于增强抗原免疫原性，3）模块化系统将提供多种抗原来克服肿瘤 异质性，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 的输送 100- 相对于临床基准，小鼠中的折叠。 AlbiVax 将抗癌免疫反应促进了 14 倍，并且 提高黑色素瘤的治疗效果。此外，通过使用 白蛋白搭便车纳米支架，我们进一步增强抗原免疫原性并促进黑色素瘤 治疗功效。我们在这项研究中的目标是设计多抗原/双佐剂共同递送 AlbiVax (mADC-AlbiVax) 作为一个有效的平台，共同提供有效的佐剂和异源肽抗原 作用于淋巴结和 APC，从而引发针对 ICB 黑色素瘤的强效、广泛且持久的免疫力 联合免疫疗法。目标1将优化模型mADC-AlbiVax的模块化结构以共同交付 针对淋巴结、APC 和 APC 中亚细胞位置的疫苗，以实现最佳的抗肿瘤免疫调节； 目标2将合成黑色素瘤mADC-AlbiVax，并研究疫苗共递送和免疫调节；和目标 3 将评估该疫苗递送系统单独或组合的黑色素瘤治疗功效和安全性 在小鼠模型中使用 ICB。该项目由独立、富有成效的 ESI 领导，并得到广泛的支持 初步数据和互补团队。这项工作的一个重要成果将是建立一个临床前 使用化学定义的疫苗和经过临床测试或用于未来临床的试剂的疫苗递送系统 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