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: 10366085
• 负责人: Suzie H. Pun
• 金额: $ 44.05万
• 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/10366085
• 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; vaccine formulation

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.

项目摘要 癌症疫苗是一种有希望的免疫肿瘤方法，可以引起高度肿瘤特异性的 免疫系统的反应，导致较长的抗癌保护。基于肽的 疫苗特别有吸引力，因为它们的毒性风险低，并且可以轻松生产 大规模的存储稳定性。但是，肽抗原本质上很差 免疫原性，容易受到给药后快速降解和排泄的影响。因此， 基于肽的癌症疫苗的成功与其有效配方息息相关， 送货。理想的肽疫苗配方将复制这些关键方面： 树突状细胞识别和内在化，这些树突细胞的激活和抗原 传递到MHC I（称为跨呈递）和MHC II分子。在此应用程序中，我们 建议开发基于聚合物的肽抗原载体，该抗原载体唯一解决所有 通过集成，在良好控制的可扩展系统中的上述交付需求 靶向配体，受控释放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 材料工程，2）评估肽和辅助输送，并在体外和体内表征 贩运和交付，3）优化鼠类黑色素瘤模型中疫苗功效的制剂 4）评估用于预防癌症和预防癌乳腺癌模型的功效和安全性 治疗。这些目标的成功完成将导致为GMP准备的配方 制造和IND途径通往临床测试。