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.

项目概要 MHC I 类 (MHC-I) 限制性肽癌症疫苗含有最少量的生化信息 产生抗原特异性 T 细胞以引发抗肿瘤反应所需。 最小肽表位不能提供令人满意的响应，因此通常是长肽或缀合肽 然而，这种方法无法实现短合成肽的直接性。 将引入基于组合（通过简单）的新的肽疫苗免疫模式。 MHC-I 肽表位与诱导自发纳米脂质体抗原的疫苗佐剂 快速颗粒化（SNAP），含有少量钴卟啉磷脂（CoPoP）。 通过将 his 标签自发插入双层，结合带有 his 标签的短肽（8-9mers）。 只需将 His 标记的肽与 CoPoP 脂质体混合即可实现在生物介质中稳定的颗粒化。 在接种疫苗时（无需进一步纯化）将这些充分表征的肽转化为 100 nm 这种方法对于产生抗原特异性 CD8+ T 细胞非常有效，AH1 是 MHC-I H-2Ld。 可以使用源自 gp70 鼠白血病病毒抗原的模型 CD8+ 表位 AH1 衍生肽。 SNAP 免疫产生大量抗原特异性 CD8+ T 细胞。 低纳克剂量肽完全保护小鼠免受随后的肿瘤攻击，并 100% 根除 将评估治疗性疫苗模型中肺转移的不同组成部分， 包括组氨酸标签长度、共掺物的密度和剂量（MPLA 和 QS-21；均为 GSK 的一部分） 疫苗佐剂 AS01）以确定其对 Ag 特异性 CD8+ 反应的影响。 将评估 CD44+ CD62L+ 细胞以确定此类中央记忆细胞是否更有效 根除肿瘤的功效将在多种预防和治疗局部和转移中进行测试。 肿瘤模型的治疗将通过环磷酰胺和环磷酰胺的影响进行评估。 将通过评估递送的肽如何到达 MHC-来探究检查点阻断的机制。 I. 重新认识到his标签肽与CoPoP脂质体结合，并经历血清稳定转运至引流 在那里，它们被树突状细胞吞噬，其中吞噬体的还原环境。 还被怀疑诱导肽从双层 CoPoP 脂质体中的 Toll 样受体释放。 进一步的研究将评估吞噬体中 MHC-I 的表达。 SNAP 免疫和抗原多重作为肽微文库体内筛选工具的可行性 使用已建立的肿瘤相关抗原和新抗原，这些抗原将被下一代识别 最后，这些研究将评估系统的安全性和钴反应。 用于癌症治疗的短期 MHC-I 限制性肽癌症疫苗取得了重大进展 免疫原性表位筛选。