Biomaterial Cancer Vaccines that Generate Patient-Specific Antigen In Situ

利用患者自身细胞的体外操纵的癌症免疫疗法可以产生显著的抗肿瘤效应 肿瘤免疫反应，但存在重大的实际限制。基于纳米颗粒的抗原提呈 系统提供了一种无需体外细胞操作即可产生抗肿瘤反应的替代方法， 但确定的抗原很可能需要针对每个患者进行个性化。我们已经展示了一种新的 概念，使用可植入的生物材料，可以定位大量树突状细胞(DC)从 宿主，并有效地激活这些细胞，同时负载来自肿瘤活检的抗原。这 方法显示了前所未有的能力，以促进已建立的肿瘤消退在几个前期 临床模型，我们最近启动了这种治疗IV期黑色素瘤的新方法的I期试验 病人。然而，这种疫苗中的抗原来自活组织检查，导致要求每个疫苗 疫苗是为特定的患者生产的，疫苗需要手术植入。这个项目是 基于将传统化疗药物和生物材料相结合的前提- 基于疫苗的接种将导致治疗性免疫反应，通过在 在原位，不需要在疫苗植入体内之前识别或将抗原装载到疫苗上。我们的 假设将通过以下目标进行检验：(1)开发能够在体内和/或注射的冷冻机 瘤周通过GM-CSF的释放来招募DC，并控制纳米粒的释放时间 (NPS)含有来自生物材料疫苗的Toll样受体配体，以浓缩和激活DC 在肿瘤内，并加强它们向引流淋巴的运输。(2)确定 根据癌细胞死亡对肿瘤定位免疫刺激化疗药物的方法 确定联合化疗和疫苗接种对肿瘤生长和肿瘤特异性宿主的影响 免疫反应。(3)检查原发肿瘤接种疫苗的治疗效果 并将基于生物材料的疫苗策略与检查点封锁相结合 心理治疗。这些研究将利用可移植肿瘤模型和转基因黑色素瘤模型。这 该项目将导致开发一种新的、针对患者的疫苗接种战略，该战略不会 要求个性化制造。我们预计这一疫苗策略将与检查站协同工作 阻断疗法，产生强大和系统的治疗效益。

Cancer immunotherapies that exploit ex vivo manipulation of a patient's own cells can generate significant anti- tumor immune responses, but present significant practical limitations. Nanoparticle-based antigen presenting systems provide an alternative approach to generate anti-tumor responses without ex vivo cell manipulation, but the defined antigens will likely need to be personalized to each patient. We have demonstrated a new concept, the use of implantable biomaterials that can localize large numbers of dendritic cells (DCs) from the host, and efficiently activate these cells while loading with antigens derived from a tumor biopsy. This approach demonstrated unprecedented ability to promote regression of established tumors in several pre- clinical models, and we have recently initiated a Phase I trial of this new approach to treat stage IV melanoma patients. However, the antigen in this vaccine is derived from a biopsy, leading to the requirement that each vaccine be manufactured for a specific patient, and the vaccine requires surgical implantation. This project is based on the premise that combining delivery of traditional chemotherapeutic agents and biomaterial- based vaccination will lead to therapeutic immune responses, by generating patient-specific antigen in situ, obviating the need to identify or load antigen onto vaccines prior to placement in the body. Our hypothesis will be tested using the following Aims: (1) Develop cryogels capable of being injected intra and/or peritumorally that recruit DCs through GM-CSF release, and control the timing of release of nanoparticles (NPs) containing toll like receptor ligands from the biomaterial vaccine in order to concentrate and activate DCs within the tumor, and enhance their trafficking to the draining lymph node. (2) Determine the impact of an approach to localize immunostimulatory chemotherapeutic agents to tumors on cancer cell death, and determine the impact of combined chemotherapy and vaccination on tumor growth and the tumor-specific host immune response. (3) Examine the ability of vaccination at the primary tumor to yield therapeutic effects on distant tumors in the body, and combine the biomaterial-based vaccine strategy with checkpoint blockade therapy. These studies will utilize both transplantable tumor models and a transgenic melanoma model. This project will result in the development of a new, patient-specific vaccination strategy that does not require personalized manufacturing. We expect this vaccine strategy will synergize with checkpoint blockade therapy, yielding robust and systemic therapeutic benefit.