An integrated polymeric carrier for subunit cancer vaccines

用于亚单位癌症疫苗的集成聚合物载体

• 批准号: 10229292
• 负责人: Suzie H. Pun
• 金额: $ 42.97万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-05 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10229292
• 关键词: Address; Adjuvant; Amino Acid Sequence; Antigen Presentation; Antigen Targeting; Antigen-Presenting Cells; Antigens; Binding; Bioinformatics; Biological Assay; Breast Cancer Model; CAR T cell therapy; CD4 Positive T Lymphocytes; CD8B1 gene; Cancer Vaccines; Cancerous; Chemistry; Clinical; Clinical Trials; Cross Presentation; Cytosol; Dendritic Cells; Dendritic cell activation; ERBB2 gene; Engineering; Epitopes; Evaluation; Excretory function; Formulation; Goals; Immune; Immune checkpoint inhibitor; Immune response; Immune system; Immunity; Immunization; Immunologics; Immunooncology; Immunosuppression; Immunotherapy; In Situ; In Vitro; Intravenous; Kinetics; Lead; Ligands; Malignant Neoplasms; Mammary Neoplasms; Mediating; Modeling; Mus; Nucleic Acids; Pathway interactions; Peptide Vaccines; Peptides; Polymers; Preclinical Testing; Prevention therapy; Prodrugs; Proteins; Recombinant Cytokines; Research; Risk; Safety; Structure; System; T cell response; T-Lymphocyte Epitopes; Testing; Therapeutic; Time; Tissues; Toxic effect; Transgenic Mice; Translations; Tumor Antigens; Vaccination; Vaccine Adjuvant; Vaccines; anti-cancer; base; cancer immunotherapy; cancer prevention; cancer type; clinical development; clinical efficacy; combat; controlled release; density; design; efficacy evaluation; extracellular; immunogenic; improved; in vivo; innovation; interest; lymph nodes; lymphatic vessel; melanoma; monomer; neoantigens; peptide based vaccine; polymerization; prevent; prophylactic; research clinical testing; resiquimod; subcutaneous; success; systemic toxicity; trafficking; tumor; tumor growth; vaccine access; vaccine delivery; vaccine development; vaccine efficacy

PROJECT SUMMARY Cancer vaccines are a promising immuno-oncology approach that can elicit highly tumor-specific responses from the immune system, resulting in prolonged anti-cancer protection. Peptide-based vaccines are especially attractive because they have low toxicity risk and can be produced easily at large scale with good storage stability. However, peptide antigens are inherently poorly immunogenic and susceptible to rapid degradation and excretion after administration. Thus, the success of peptide-based cancer vaccines are critically tied to their effective formulation and delivery. The ideal peptide vaccine formulation would replicate each of these critical aspects: recognition and internalization by dendritic cells, activation of these dendritic cells, and antigen delivery to both MHC I (called cross-presentation) and MHC II molecules. In this application, we propose to develop a polymer-based peptide antigen carrier that uniquely addresses all of the aforementioned delivery needs in a well-controlled, scalable system through the integration of targeting ligands, controlled release adjuvants, and cytosolic and lysosomal antigen delivery mechanisms. Our main objectives are to 1) optimize polymer structure and synthesis through material engineering, 2) assess peptide and adjuvant delivery and characterize in vitro and in vivo trafficking and delivery, 3) optimize formulations for vaccine efficacy in a murine melanoma model and 4) evaluate efficacy and safety in a murine breast cancer model for cancer prevention and therapy. Successful completion of these aims will lead to a formulation poised for GMP manufacturing and the IND pathway toward clinical testing.

项目概要 癌症疫苗是一种有前途的免疫肿瘤学方法，可以引发高度肿瘤特异性 免疫系统的反应，从而产生持久的抗癌保护。基于肽的 疫苗特别有吸引力，因为它们毒性风险低且易于生产 规模化生产，储存稳定性好。然而，肽抗原本身的性能较差。 具有免疫原性，给药后易于快速降解和排泄。因此， 基于肽的癌症疫苗的成功与其有效的配方和 送货。理想的肽疫苗配方将复制以下每个关键方面： 树突状细胞的识别和内化、这些树突状细胞的激活和抗原 递送至 MHC I（称为交叉呈递）和 MHC II 分子。在这个应用程序中，我们 建议开发一种基于聚合物的肽抗原载体，该载体可以独特地解决所有问题 通过集成，在一个良好控制的、可扩展的系统中满足上述交付需求 靶向配体、控释佐剂以及胞质和溶酶体抗原递送 机制。我们的主要目标是 1) 通过以下方式优化聚合物结构和合成 材料工程，2) 评估肽和佐剂的递送并表征体外和体内 运输和递送，3) 优化小鼠黑色素瘤模型中疫苗功效的配方 4) 评估小鼠乳腺癌模型对于癌症预防和治疗的有效性和安全性 治疗。成功完成这些目标将导致制剂符合 GMP 制造和通往临床测试的 IND 途径。