An integrated polymeric carrier for subunit cancer vaccines

项目总结 癌症疫苗是一种很有前途的免疫肿瘤学方法，可以诱导高度肿瘤特异性 来自免疫系统的反应，从而延长抗癌保护。基于多肽的 疫苗特别有吸引力，因为它们的毒性风险很低，而且生产起来很容易 规模大，储存稳定性好。然而，多肽抗原天生就不好。 免疫原性，给药后易迅速降解和排泄。因此， 基于多肽的癌症疫苗的成功与其有效的配方和 送货。理想的多肽疫苗配方将复制这些关键方面的每一个： 树突状细胞的识别和内化，这些树突状细胞的激活，以及抗原 递送到MHC I(称为交叉呈递)和MHC II分子。在此应用程序中，我们 建议开发一种基于聚合物的多肽抗原载体，它独特地解决了所有 前面提到的交付需求是通过集成以下组件实现的 靶向配体、控释佐剂、胞浆和溶酶体抗原递送 机械装置。我们的主要目标是1)优化聚合物结构和合成，通过 材料工程学，2)评估多肽和佐剂递送，并在体外和体内表征 运输和递送，3)在小鼠黑色素瘤模型中优化疫苗效力的配方 以及4)评价小鼠乳腺癌模型预防癌症的有效性和安全性。 心理治疗。这些目标的成功实现将导致GMP配方的制定 制造和临床试验的IND途径。

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.