A Cobalt Porphyrin Nanoliposome Adjuvant for MHC-I-Restricted Cancer Peptide Vaccines

用于 MHC-I 限制性癌症肽疫苗的钴卟啉纳米脂质体佐剂

• 批准号: 10320831
• 负责人: Scott I. Abrams
• 金额: $ 37.09万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10320831
• 关键词: Address; Adjuvant; Algorithms; Antibody Response; Antigen-Presenting Cells; Antigens; Antitumor Response; Binding; Biochemical; Biological; Biological Assay; CD44 gene; CD8-Positive T-Lymphocytes; CD8B1 gene; Cancer Vaccines; Cancer cell line; Cells; Chemicals; Clinical; Cobalt; Cyclophosphamide; Data; Dendritic Cells; Development; Dose; Environment; Epitopes; Frequencies; Generations; Goals; Histocompatibility; Immune; Immune Targeting; Immunization; Immunize; Immunosuppression; Immunotherapy; Inbred BALB C Mice; Laboratories; Length; Liposomes; Malignant Neoplasms; Mediating; Memory; Metastatic Neoplasm to the Lung; Modeling; Molecular; Mouse Strains; Murine leukemia virus; Mus; Nanotechnology; Nature; Neoplasm Metastasis; Oncogenes; Peptide Vaccines; Peptides; Phagosomes; Phospholipids; Porphyrins; Primary Neoplasm; QS21; SELL gene; Safety; Screening procedure; Serum; System; T cell response; T-Lymphocyte; T-Lymphocyte Epitopes; Techniques; Testing; Therapeutic; Time; Toll-like receptors; Toxic effect; Tumor Antigens; Tumor Cell Biology; Tumor Immunity; Tumor-infiltrating immune cells; Vaccinated; Vaccination; Vaccine Adjuvant; Vaccine Clinical Trial; Viral Antigens; anti-cancer; antigen-specific T cells; base; cancer cell; cancer therapy; cell killing; cost; cytokine; density; design; draining lymph node; high throughput screening; immune checkpoint blockade; immunogenic; improved; in vivo; insight; nanoliposome; neoantigens; next generation sequencing; particle; peptide I; peptide vaccination; prophylactic; recruit; response; screening; self assembly; stem; synthetic peptide; therapeutic immunization; therapeutic vaccine; tumor; tumor microenvironment; vaccine efficacy

PROJECT SUMMARY MHC class I (MHC-I) -restricted peptide cancer vaccines hold the minimal amount of biochemical information required for generating antigen-specific T cells to elicit anti-tumor responses. On their own, immunization with minimal peptide epitopes does not provide a satisfactory response, so typically long peptides or conjugated delivery systems are necessitated. However, such approaches defeat the directness of short synthetic peptide vaccines. A new peptide vaccine immunization paradigm will be introduced, based on combining (via simple mixing) MHC-I peptide epitopes with a vaccine adjuvant that induces spontaneous nanoliposome-antigen particleization (SNAP). Liposomes that contain small amounts of cobalt porphyrin-phospholipid (CoPoP) rapidly bind short his-tagged peptides (8-9mers) via spontaneous insertion of the his-tag into the bilayer. This gives rise to particleization that is stable in biological media. His-tagged peptides are simply mixed with CoPoP liposomes at the time of vaccination (without further purification) to convert these well-characterized peptides into a 100 nm particle. This approach is potently effective in generating antigen-specific CD8+ T cells. AH1 is a MHC-I H-2Ld model CD8+ epitope derived from the gp70 murine leukemia virus antigen. An AH1-derived peptide can be used with SNAP immunization to generate high numbers of antigen specific CD8+ T cells. SNAP immunization with low nanogram doses peptides completely protects mice from subsequent tumor challenge, and eradicates 100% of lung metastases in a therapeutic vaccine model. Varying components of SNAP immunization will be assessed, including the his-tag length, the density and dose of co-incorporated (MPLA and QS-21; both part of GSK’s vaccine adjuvant AS01) to determine their impact the Ag-specific CD8+ response. Generation of Ag-specific CD44+ CD62L+ cells will be assessed to determine whether such central memory cells are more effective in eradicating tumors. Vaccine efficacy will be tested in multiple prophylactic and therapeutic local and metastasis tumor models. Therapeutic treatment of large tumors will be assessed with the impact of cyclophosphamide and checkpoint blockade. Mechanistic insights will be probed by assessing how the delivered peptide reaches MHC- I. It is hypothesized that his-tag peptides bind to CoPoP liposomes, and undergo serum-stable transit to draining lymph nodes. There, they are phagocytosed by dendritic cells where the reductive environment of phagosomes is also suspected to induce the release of the peptide from the CoPoP liposomes. Toll-like receptor in the bilayer are hypothesized to upregulate the expression of MHC-I within the phagosome. Further studies will assess the viability of SNAP immunization and antigen multiplexing as an in vivo screening tool for peptide microlibraries using established tumor-associated antigens and neoantigens that will be identified with next-generation sequencing. Finally, the safety and cobalt response of the system will be assessed. These studies will provide substantial advancement for short, MHC-I-restricted peptide-based cancer vaccines for cancer therapy and immunogenic epitope screening.

项目摘要 MHC I类（MHC -I）限制性肽癌疫苗的生化信息量最小 产生抗原特异性T细胞以引起抗肿瘤反应所必需的。独自与免疫 最小的肽表位不能提供令人满意的反应，因此通常是长肽或共轭的 运输系统是必要的。但是，这种方法打败了短合成肽的直接性 疫苗。基于组合，将引入一种新的肽疫苗免疫范例（通过简单 混合）MHC-I肽表位与疫苗调节，可诱导自发的纳米脂体 - 抗原 颗粒化（快照）。含有少量钴卟啉磷脂（Copop）的脂质体迅速 通过将HIS标签插入双层，将短的His标签肽（8-9mers）绑定。这产生了 在生物学培养基中稳定的颗粒化。用他的标签肽与Copop脂质体混合 在接种疫苗接种时（无需进一步纯化）将这些特征良好的胡椒粉转化为100 nm 粒子。这种方法可能有效地产生抗原特异性CD8+ T细胞。 AH1是MHC-I H-2LD CD8+表位源自GP70鼠白血病病毒抗原。可以使用AH1衍生的肽 通过SNAP免疫产生大量抗原特异性CD8+ T细胞。使用 低纳图剂量petides完全保护小鼠免受随后的肿瘤挑战，而放射线100％ 治疗性疫苗模型中的肺转移。将评估快速免疫的不同组成部分， 包括His-Tag长度，共同结合的密度和剂量（MPLA和QS-21； GSK的一部分都是 疫苗调整AS01）以确定其影响Ag特异性CD8+响应的影响。 Ag特异性产生 将评估CD44+ CD62L+细胞，以确定此类中央记忆细胞是否更有效 根除肿瘤。疫苗效率将在多种预防性和治疗性局部和转移中进行测试 肿瘤模型。将通过环磷酰胺和 检查点封锁。通过评估递送的肽如何达到MHC-将探讨机械洞察力 I.假设His-Tag Pepperides与Copop脂质体结合，并经过血清稳定的过渡到排水 淋巴结。在那里，它们是由树突状细胞吞噬的，其中吞噬体的环境减少了 还怀疑还会诱导辣椒脂质体的辣椒释放。双层中的Toll样受体 假设可以上调吞噬体中MHC-I的表达。进一步的研究将评估 快照免疫和抗原多路复用的生存能力，作为胡椒微纤维的体内筛选工具 使用已建立的肿瘤相关抗原和新抗原，将与下一代鉴定 测序。最后，将评估系统的安全性和钴响应。这些研究将提供 用于癌症治疗和 免疫原性表位筛查。