Biomaterial Cancer Vaccines that Generate Patient-Specific Antigen In Situ

原位产生患者特异性抗原的生物材料癌症疫苗

• 批准号: 10053676
• 负责人: David J Mooney
• 金额: $ 42.59万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10053676
• 关键词: Adjuvant; Adoptive Transfer; Antigen-Presenting Cells; Antigens; Antitumor Response; Biocompatible Materials; Biopsy; Cancer Model; Cancer Vaccines; Cancerous; Cell Death; Cells; Cytotoxic T-Lymphocytes; Dendritic Cells; Dendritic cell activation; Development; Distant; Down-Regulation; Doxorubicin; Generations; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Homing; Immune; Immune response; Immune system; Immunization; Immunotherapeutic agent; In Situ; Ligands; Malignant Neoplasms; Mitoxantrone; Modeling; Neoplasm Transplantation; Operative Surgical Procedures; Patients; Pharmaceutical Preparations; Pre-Clinical Model; Primary Neoplasm; Process; Site; System; T-Lymphocyte; Testing; Therapeutic; Therapeutic Effect; Time; Toll-like receptors; Transgenic Organisms; Transplantation; Vaccination; Vaccines; anti-tumor immune response; antitumor effect; base; cancer cell; cancer immunotherapy; chemotherapeutic agent; chemotherapy; cryogel; draining lymph node; immune checkpoint blockade; immunogenic; implantation; lymph nodes; melanoma; nanoparticle; neoplastic cell; novel strategies; phase I trial; prevent; recruit; response; side effect; targeted delivery; trafficking; tumor; tumor growth; vaccination strategy

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.

利用患者自身细胞的离体操作的癌症免疫疗法可以产生显著的抗肿瘤活性。 肿瘤免疫应答，但存在显著的实际局限性。基于纳米颗粒的抗原呈递 系统提供了一种无需离体细胞操作而产生抗肿瘤应答的替代方法， 但是所定义的抗原可能需要针对每个患者进行个性化。我们展示了一种新的 概念，使用可植入的生物材料，可以定位大量的树突状细胞（DC）从 宿主，并有效地激活这些细胞，同时加载来自肿瘤活检的抗原。这 这种方法显示出前所未有的能力，促进在几个预 临床模型，我们最近已经启动了一项I期试验，这种新方法治疗IV期黑色素瘤 患者然而，该疫苗中的抗原来自活组织检查，导致需要每个 疫苗是为特定的病人制造的，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的递送相结合的前提， 基于疫苗接种将导致治疗性免疫应答，通过产生患者特异性抗原， 原位，避免了在置于体内之前鉴定抗原或将抗原加载到疫苗上的需要。我们 （1）开发能够在体内和/或体内注射的冷冻凝胶， 通过GM-CSF释放募集DC，并控制纳米颗粒释放的时间 (NPs)含有来自生物材料疫苗的Toll样受体配体， 在肿瘤内，并增强它们向引流淋巴结的运输。(2)确定一个 在癌细胞死亡时将免疫刺激性化疗剂定位于肿瘤的方法，和 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)检查在原发性肿瘤处接种疫苗以产生治疗效果的能力， 并将基于生物材料的疫苗策略与检查点阻断联合收割机相结合 疗法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、针对特定患者的疫苗接种策略， 需要个性化的制造。我们预计这种疫苗策略将与检查点协同作用， 阻断治疗，产生稳健的全身治疗益处。