Lymph node-targeted codelivery of albumin-binding peptide antigens and di-adjuvant for melanoma combination immunotherapy

用于黑色素瘤联合免疫治疗的白蛋白结合肽抗原和双佐剂的淋巴结靶向共递送

• 批准号: 10522591
• 负责人: Guizhi Zhu
• 金额: $ 46.07万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2023-06-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10522591
• 关键词: Address; Adjuvant; Albumins; Antigen-Presenting Cells; Antigens; Benchmarking; Binding; CD4 Positive T Lymphocytes; CD8B1 gene; Cells; Chemicals; Chemistry; Clinical; Combination immunotherapy; Combined Modality Therapy; Combined Vaccines; Conjugate Vaccines; DNA Binding; Engineering; Epigenetic Process; Evans blue stain; Future; Genetically Engineered Mouse; Goals; HLA Antigens; Heterogeneity; Human; Immune; Immune response; Immune system; Immunity; Immunologic Adjuvants; Immunologic Memory; Immunosuppression; Immunotherapy; Lead; Length; Location; MEL Gene; Major Histocompatibility Complex; Malignant Neoplasms; Measures; Metastatic Melanoma; Modeling; Molecular Vaccines; Mus; Natural Immunity; Outcome; Pathway interactions; Patients; Peptide Vaccines; Peptides; Pharmacologic Substance; Public Health; Recovery; Safety; Series; Site; Skin Cancer; Structure; Survival Rate; System; T cell response; T-Lymphocyte; TLR7 gene; Testing; Therapeutic; Toxicology; Treatment Efficacy; Tumor Antigens; Tumor Immunity; Up-Regulation; Vaccine Antigen; Vaccines; Validation; Work; anti-cancer; clinical practice; clinical translation; design; exhaust; humanized mouse; immune cell checkpoints; immune checkpoint; immune checkpoint blockade; immunogenic; immunogenicity; immunoregulation; improved; innovation; lymph nodes; melanoma; melanoma-associated antigen; mouse model; nanovaccine; neoantigens; neoplastic cell; pre-clinical; research clinical testing; scaffold; spatiotemporal; success; synergism; treatment response; tumor; tumor growth; tumor heterogeneity; tumor microenvironment; vaccine delivery; vaccine formulation; vaccine platform

Project Summary Advanced melanoma is a highly aggressive cancer. While immunotherapy such as immune checkpoint blockade (ICB) has benefited some patients, most melanoma patients do not respond to ICB. This is largely due to a lack of preexisting target cells and checkpoints for ICB, tumor antigenic heterogeneity, and tumor immunosuppression. ICB therapeutic efficacy can be promoted by vaccine formulations that deliver tumor antigens to induce new antitumor cells for ICB to target and reduce tumor immunosuppression. Chemically defined peptide vaccines are attractive for relatively easy manufacturing and good pharmaceutical stability. The success of peptide vaccines relies on efficient delivery. Despite clinical testing of various peptide vaccine formulations, their therapeutic efficacy has been limited due to delivery and immunomodulation issues including 1) poor vaccine delivery to the sites of action (lymph nodes and antigen-presenting cells), 2) poor immunostimulant adjuvant efficacy due to restricted target cell subsets in human, 3) limited adjuvant/antigen codelivery to enhance antigen immunogenicity, 4) limited ability to overcome tumor antigenic heterogeneity, and 5) limited ability to deliver heterogeneous antigens. Our strategy is to develop a high efficiency and spatiotemporally targeted peptide vaccine platform that addresses each of these deficiencies to improve ICB therapy: 1) albumin hitchhiking delivers peptide vaccines to lymph nodes and antigen-presenting cells, 2) a di-adjuvant targets a broad spectrum of cell subsets across species, 3) potent di-adjuvant and adjuvant/antigen codelivery enhance antigen immunogenicity, and 4) a modular system delivers heterogeneous multi-antigens to overcome tumor antigenic heterogeneity. In our preliminary studies, we developed albumin-binding vaccines (AlbiVax) to enhance vaccine delivery 100-fold in mice, promote anticancer T cell responses 14-fold, and improve melanoma therapeutic efficacy relative to a clinical benchmark. Moreover, by codelivering a di-adjuvant and antigens using a nanoscaffold, AlbiVax further potentiated antigen immunogenicity and promoted melanoma therapeutic efficacy. Our objective in this study is to engineer multi-antigen/di-adjuvant codelivery AlbiVax (mADC-AlbiVax) as an efficient platform that codelivers a di-adjuvant and multiple heterogenous peptide antigens to lymph nodes and antigen-presenting cells to elicit a potent, broad, and long-lasting immunity for ICB melanoma combination immunotherapy. Aim 1 is to optimize the modular structure of model mADC-AlbiVax for targeted multi-antigen/di-adjuvant codelivery to lymph nodes, antigen-presenting cells, and subcellular locations for optimal antitumor immunomodulation; Aim 2 is to synthesize melanoma mADC-AlbiVax using multiple tumor antigens and measure vaccine codelivery and immunomodulation; Aim 3 is to evaluate the melanoma therapeutic efficacy and safety of melanoma mADC- AlbiVax combined with ICB in multiple mouse models. A significant deliverable of this work will be preclinical validation of an innovative system to codeliver chemically-defined vaccines using clinically tested or used agents for future clinical evaluation. 1

项目摘要 晚期黑色素瘤是一种高度侵袭性的癌症。虽然免疫治疗，如免疫检查点阻断， (ICB)虽然ICB使一些患者受益，但大多数黑色素瘤患者对ICB没有反应。这主要是由于缺乏 预先存在的靶细胞和ICB检查点，肿瘤抗原异质性和肿瘤免疫抑制。 ICB治疗功效可以通过递送肿瘤抗原以诱导新的免疫应答的疫苗制剂来促进。 ICB靶向并降低肿瘤免疫抑制的抗肿瘤细胞。化学上确定的肽疫苗是 由于相对容易的制造和良好的药物稳定性而具有吸引力。肽疫苗的成功 依赖于高效的交付。尽管对各种肽疫苗制剂进行了临床测试，但它们的治疗效果仍然不佳。 由于递送和免疫调节问题，效力受到限制，包括：1）向 作用部位（淋巴结和抗原呈递细胞），2）由于免疫刺激剂佐剂的不良功效， 限制的人靶细胞亚群，3）限制的佐剂/抗原共递送以增强抗原免疫原性， 4)克服肿瘤抗原异质性的能力有限，和5）递送异质性的能力有限， 抗原我们的策略是开发一种高效的时空靶向肽疫苗平台， 解决了这些缺陷中的每一个，以改善ICB治疗：1）白蛋白搭便车递送肽疫苗 2）双佐剂靶向广泛的细胞亚群， 3）有效的双佐剂和佐剂/抗原共递送增强抗原免疫原性，和4） 模块化系统递送异质性多抗原以克服肿瘤抗原异质性。在我们 在初步研究中，我们开发了白蛋白结合疫苗（AlbiVax）， 小鼠，促进抗癌T细胞应答14倍，并改善黑素瘤治疗功效， 临床基准此外，通过使用纳米支架共同递送双佐剂和抗原，AlbiVax还 增强抗原免疫原性，提高黑色素瘤治疗效果。本研究的目的是 将多抗原/双佐剂共递送AlbiVax（mADC-AlbiVax）作为一种有效的平台， 将双佐剂和多种异源肽抗原结合至淋巴结和抗原呈递细胞， ICB黑色素瘤联合免疫疗法的有效、广泛和持久免疫。目标1：优化 用于靶向多抗原/双佐剂共递送至淋巴结的模型mADC-AlbiVax的模块化结构， 抗原呈递细胞和亚细胞位置，以实现最佳抗肿瘤免疫调节;目的2是 使用多种肿瘤抗原合成黑素瘤mADC-AlbiVax并测量疫苗共递送， 目的3是评估黑素瘤mADC的黑素瘤治疗功效和安全性。 AlbiVax联合ICB用于多种小鼠模型。这项工作的一个重要成果将是临床前 使用临床测试或使用的试剂共同递送化学定义的疫苗的创新系统的验证 用于将来的临床评价。 1