Metabolic tagging of tumor exosomes for developing enhanced exosome vaccines

肿瘤外泌体的代谢标记用于开发增强型外泌体疫苗

• 批准号: 10645558
• 负责人: Hua Wang
• 金额: $ 16.89万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10645558
• 关键词: Adjuvant; Agonist; Antigen Presentation; Antigen-Presenting Cells; Antigens; Azides; Binding; Cancer Vaccines; Cell membrane; Chemicals; Chemistry; Clinical; Clinical Trials; Cytotoxic T-Lymphocytes; Dendritic Cells; Dendritic cell activation; Development; Endosomes; Generations; Glioblastoma; Glycoengineering; Glycolipids; Glycoproteins; Goals; Immunomodulators; Immunotherapy; Inherited; Label; Ligands; Mediating; Membrane; Membrane Glycoproteins; Metabolic; Modeling; Mus; Polysaccharides; Process; Proteins; Safety; Source; Surface; TLR3 gene; TLR7 gene; TLR8 gene; Technology; Testing; Therapeutic; Toll-like receptors; Tumor Antigens; Tumor-Derived; Vaccination; Vaccines; cancer cell; cancer therapy; cancer type; clinical translation; efficacy evaluation; exosome; extracellular vesicles; immune modulating agents; improved; malignant breast neoplasm; nanosized; neoplastic cell; pre-clinical; preclinical study; response; success; sugar; triple-negative invasive breast carcinoma; tumor; uptake

SUMMARY Immunotherapies have shifted the paradigm for cancer treatment in the past decade. Among them, therapeutic cancer vaccines, consisting of tumor antigens and adjuvants for activating antigen presenting cells (e.g., dendritic cells (DCs)), have shown the promise to elicit persistent humoral and cytotoxic T lymphocyte (CTL) response, but are limited by the modest therapeutic benefit. Hurdles for developing potent cancer vaccines include the lack of available tumor antigens and sub-optimal modulation of DCs. Tumor-derived exosomes, the nano-sized extracellular vesicles secreted by tumor cells, are a good source of tumor antigens and have been widely explored as cancer vaccines in preclinical studies and clinical trials. However, the antitumor efficacy is far from satisfactory, likely as a result of poor CTL response. The incorporation of adjuvants that can bind to the toll like receptors on DC membrane and thus activate DCs has become standard practice for improving conventional vaccines, but simple mixing with adjuvants has failed to enhance the antitumor efficacy of tumor exosome vaccines. The primary goal of this project is to develop a strategy that can well integrate tumor exosomes and adjuvants for the development of potent tumor exosome vaccines. To achieve this, we utilize a metabolic glycan labeling approach to label glycoproteins and glycolipids on the membrane of cancer cells with chemical tags (e.g., azido groups), and hypothesize that exosomes secreted by these labeled cancer cells will carry chemical tags on the surface. The chemically tagged tumor exosomes can covalently capture adjuvants and other immunomodulatory agents via efficient and bioorthogonal click chemistries, potentially resulting in improved activation and antigen presentation of DCs and enhanced CTL response. This project will be organized around two specific aims. In Aim 1, metabolic glycan labeling of various types of cancer cells for the generation of azido- labeled exosomes will be explored. Two hypotheses will be tested in this aim: (1) azido-labeled tumor cells can secrete azido-labeled exosomes; (2) the azido groups on the surface of exosomes can efficiently conjugate dibenzocyclooctyne (DBCO)-molecules via click chemistry. In Aim 2, adjuvant-conjugated tumor exosomes will be explored as therapeutic cancer vaccines, with the resulting CTL response and antitumor efficacy evaluated in murine breast cancer and glioblastoma models. Tumor exosomes conjugated with both adjuvants and DC- targeting ligands (e.g., anti-DEC205) will also be developed and evaluated. Successful completion of the proposed studies not only will provide a generalizable technology to generate chemically tagged exosomes from tumor cells for tracking and targeting purposes, but will also result in the development of potent tumor exosome vaccines with great potential for clinical translation.

概括 在过去的十年中，免疫疗法改变了癌症治疗的范例。其中，治疗性 癌症疫苗，由肿瘤抗原和佐剂组成，用于激活抗原呈递细胞（例如，树突状 细胞（DC））表现出了引起持续的体液和细胞毒性T淋巴细胞（CTL）反应的希望， 但受到适度的治疗益处的限制。开发有效癌症疫苗的障碍包括缺乏 可用的肿瘤抗原和DC的亚最佳调节。肿瘤衍生的外泌体，纳米大小 由肿瘤细胞分泌的细胞外囊泡是肿瘤抗原的良好来源，已广泛 在临床前研究和临床试验中作为癌症疫苗探索。但是，抗肿瘤功效远非 令人满意的，可能是由于CTL响应差而导致的。可以与收费一样结合的佐剂掺入 DC膜上的受体并因此激活DC已成为改善常规的标准实践 疫苗，但与佐剂的简单混合未能增强肿瘤外泌体的抗肿瘤功效 疫苗。该项目的主要目标是制定可以很好地整合肿瘤外泌体和 佐剂开发有效的肿瘤外泌体疫苗。为了实现这一目标，我们利用了代谢性聚糖 用化学标签在癌​​细胞膜上标记糖蛋白和糖脂的标记方法 （例如，氮杂组），并假设这些标记的癌细胞分泌的外泌体将携带化学 表面上的标签。化学标记的肿瘤外泌体可以共价捕获佐剂和其他 通过有效和生物正交点击化学剂的免疫调节剂，有可能改善 DCS的激活和抗原表现和增强的CTL响应。这个项目将在周围组织 两个具体的目标。在AIM 1中，各种类型的癌细胞的代谢性聚糖标记，用于产生叠氮 将探索标记的外泌体。在此目的中将检验两个假设：（1）氮杂标记的肿瘤细胞可以 分泌Azido标记的外泌体； （2）外泌体表面上的氮杂组可以有效地结合 通过点击化学，二苯并杂志（DBCO） - 分子。在AIM 2中，佐剂偶联的肿瘤外泌体将 被探讨为治疗性癌症疫苗，评估了CTL的反应和抗肿瘤功效 在鼠乳腺癌和胶质母细胞瘤模型中。肿瘤外泌体与佐剂和DC-结合 还将开发和评估靶向配体（例如，抗DEC205）。成功完成 拟议的研究不仅会提供可推广的技术，以产生从化学标记的外泌体中 用于跟踪和靶向目的的肿瘤细胞，但也会导致有效的肿瘤外泌体的发展 具有很大潜力进行临床翻译的疫苗。