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。晚期黑色素瘤侵袭性很强，尽管 在治疗方面的进步，存活率仍然很低。免疫检查点等免疫疗法 阻滞剂(ICB)使许多黑色素瘤患者受益。虽然令人鼓舞，但仍有许多需求没有得到满足 患者对ICB没有反应。ICB的治疗效果可以通过以下疫苗配方来提高 肿瘤相关抗原和新抗原。化学定义的多肽疫苗具有相对的吸引力 制造容易，药物稳定性好。多肽疫苗的成功取决于效率 送货上门。尽管对各种多肽疫苗配方进行了临床测试，但它们的治疗效果一直很差。 由于一些交付问题而受到限制，包括：1)向行动地点交付疫苗较差；2)合作有限 提供免疫刺激佐剂和抗原以增强抗原的免疫原性，3)有限的能力 克服肿瘤的异质性，以及4)传递物理化学异质性抗原的能力有限。 我们的战略是开发高效、靶向的ICB联合治疗多肽疫苗平台 这解决了这些不足：1)白蛋白搭便车将被用来将多肽疫苗运送到 淋巴结和抗原提呈细胞(APC)，2)有效佐剂和佐剂/抗原联合递送将 用来增强抗原的免疫原性，3)模块化系统将输送多种抗原以克服肿瘤 异质性，以及4)广泛适用的系统将递送各种多肽抗原。在我们的初步研究中， 我们开发了白蛋白结合疫苗(AlbiVax)，以增强向淋巴结和APC 100- 在小鼠身上折叠，相对于临床基准。AlbiVax可将抗癌免疫反应提高14倍， 提高了黑色素瘤的治疗效果。此外，通过使用一种有效的二佐剂和抗原共同传递 白蛋白搭便车纳米支架，进一步增强了抗原免疫原性，促进了黑色素瘤的发生 治疗效果。我们在这项研究中的目标是设计多抗原/双佐剂共传递白蛋白Vax (MADC-AlbiVax)作为共递送强效佐剂和异源多肽抗原的高效平台 到淋巴结和APC，从而引发对ICB黑色素瘤的强大、广泛和持久的免疫 联合免疫疗法。目标1将优化MADC-AlbiVax型号的模块化结构，以共同交付 针对淋巴结、APC和APC中的亚细胞位置的疫苗，以实现最佳的抗肿瘤免疫调节； Aim 2将合成黑色素瘤MadC-AlbiVax，并研究疫苗共传递和免疫调节； 将单独或联合评估该疫苗递送系统的黑色素瘤治疗效果和安全性。 在小鼠模型中，使用ICB。该项目由独立的、富有成效的ESI领导，并得到广泛的支持 初步数据和补充小组。这项工作的一个重要成果将在临床前建立一个 使用化学定义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 评估。 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