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: 10305629
• 负责人: David J Mooney
• 金额: $ 41.73万
• 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/10305629
• 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; vaccine 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着的抗- 肿瘤免疫反应，但存在显着的实际局限性。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即可产生抗肿瘤反应的替代方法， 但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，使用可植入生物材料，可以将大量树突状细胞（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 方法在几个预治疗中证明了前所未有的促进已形成肿瘤消退的能力 临床模型，我们最近启动了这种治疗 IV 期黑色素瘤新方法的 I 期试验 患者。然而，这种疫苗中的抗原来自活组织检查，因此需要每个 疫苗是针对特定患者制造的，并且疫苗需要手术植入。这个项目是 基于将传统化疗药物与生物材料相结合的递送的前提—— 基于疫苗接种的疫苗将通过在体内产生患者特异性抗原来导致治疗性免疫反应 原位，避免了在放入体内之前识别抗原或将抗原加载到疫苗上的需要。我们的 将使用以下目标来检验假设：（1）开发能够注射到体内和/或 瘤周通过 GM-CSF 释放招募 DC，并控制纳米粒子的释放时间 (NP) 含有来自生物材料疫苗的 Toll 样受体配体，用于浓缩和激活 DC 肿瘤内，并增强它们向引流淋巴结的运输。 (2) 确定影响 将免疫刺激化疗剂定位于肿瘤以抑制癌细胞死亡的方法，以及 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) 检查原发肿瘤处接种疫苗产生治疗效果的能力 体内远处的肿瘤，并将基于生物材料的疫苗策略与检查点封锁相结合 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策略，该策略不会 需要个性化制造。我们预计该疫苗策略将与检查点产生协同作用 封锁疗法，产生强大和系统性的治疗效果。

项目成果

Cryogel vaccines effectively induce immune responses independent of proximity to the draining lymph nodes.

Cryogel 疫苗可有效诱导免疫反应，而与是否接近引流淋巴结无关。

• 发表时间: 2022-02
• 影响因子: 14
• 作者: Najibi, Alexander J;Shih, Ting;Mooney, David J
• 通讯作者: Mooney, David J

Chemotherapy Dose Shapes the Expression of Immune-Interacting Markers on Cancer Cells.

化疗剂量影响癌细胞上免疫相互作用标记物的表达。

• DOI: 10.1007/s12195-022-00742-y
• 发表时间: 2022-10-01
• 期刊: Cellular and molecular bioengineering
• 作者: Ale;er J. Najibi;er;K. Larkin;Zhaoqianqi Feng;Nicholas Jeffreys;Mason T Dacus;Yashika Rustagi;F. Hodi;D. Mooney
• 通讯作者: D. Mooney

Viscoelastic Biomaterials for Tissue Regeneration.

用于组织再生的粘弹性生物材料。

• DOI: 10.1089/ten.tec.2022.0040
• 发表时间: 2022-04-20
• 期刊: Tissue engineering. Part C, Methods
• 作者: David T. Wu;Nicholas Jeffreys;M. Diba;D. Mooney
• 通讯作者: D. Mooney

Biomaterial-assisted targeted modulation of immune cells in cancer treatment.

癌症治疗中生物材料辅助免疫细胞的靶向调节。

• 发表时间: 2018
• 影响因子: 41.2
• 作者: Wang, Hua;Mooney, David J
• 通讯作者: Mooney, David J

Cell and tissue engineering in lymph nodes for cancer immunotherapy.

用于癌症免疫治疗的淋巴结细胞和组织工程。

• DOI: 10.1016/j.addr.2020.07.023
• 发表时间: 2020
• 期刊: Advanced drug delivery reviews
• 影响因子: 16.1
• 作者: Najibi AJ;Mooney DJ
• 通讯作者: Mooney DJ