Overcoming vaccine-associated hypoxia with advanced biomaterials to enhance cancer immunotherapy

利用先进生物材料克服疫苗相关缺氧以增强癌症免疫治疗

基本信息

批准号：
10211839
负责人：
SIDI A BENCHERIF
金额：
$ 48.83万
依托单位：
NORTHEASTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10211839
关键词：
Address Adjuvant American Antigen-Presenting Cells Antitumor Response Autologous Tumor Cell Automobile Driving Biocompatible Materials Breast Cancer Model CD8B1 gene Cancer Etiology Cancer Vaccine Related Development Cancer Vaccines Cell physiology Cells Cessation of life Characteristics Clinical Cross-Priming Data Dendritic Cells Dendritic cell activation Distant Metastasis Dose Engineering Environment Exhibits Fibrinogen Future Growth Homing Human Hyaluronic Acid Hypoxia Immune Immune checkpoint inhibitor Immune response Immune system Immunologic Tests Immunosuppression Immunotherapy In Vitro Injectable Irradiated tumor Laboratories Malignant Neoplasms Malignant neoplasm of prostate Mechanics Mediating Metastatic Prostate Cancer Mus Neoplasm Transplantation Outcome Oxygen Patient-Focused Outcomes Patients Peripheral Play Positioning Attribute Primary Neoplasm Property Prostate Cancer therapy Prostatic Neoplasms Research Role Safety Site Specificity Stress Syringes T cell response T memory cell T-Lymphocyte Temperature Testing Therapeutic Toxic effect Transplantation Treatment Efficacy Tumor Immunity Vaccines anti-tumor immune response base biomaterial compatibility cancer immunotherapy cancer recurrence cancer vaccination combat cryogel draining lymph node experimental study functional restoration immune activation immunogenic immunoregulation improved in vivo innovation insight lymph nodes men migration mouse model neoplastic cell novel particle personalized cancer therapy polymerization prevent prophylactic prostate cancer model recruit response scaffold supplemental oxygen tool tumor tumor microenvironment tumor-immune system interactions vaccine efficacy

项目摘要

Project Summary Overcoming the poor efficacy of tumor cell vaccines will require enhancing activation of the immune system and preventing an immunosuppressive tumor microenvironment such as local hypoxia. In this proposal, we will address this critical need by engineering tumor cell vaccines with advanced oxygen-releasing biomaterials (O2- cryogels) to combat hypoxia-driven immunosuppression and improve antitumor immune responses in relevant mouse models of prostate cancer. Our preliminary data in mice indicate that: (i) O2-cryogels can reverse local hypoxia and restore the function of key immune cells (dendritic cells; DCs); (ii) once in the body, cryogel vaccines efficiently localize transplanted tumor cells, controllably release immunomodulatory factors, and recruit large numbers of DCs from the host; and (iii) elicit a specific and robust vaccine-induced T cell-mediated antitumor immunity. Here, we will optimize the characteristics of O2-cryogels for maximum antitumor efficacy and safety; and assess their ability to suppress the local hypoxic stress and improve DC recruitment, activation, and homing to the draining lymph nodes. Finally, we will test O2-cryogel vaccines in prophylactic and therapeutic mouse models of prostate cancer to determine their ability to induce specific, effective, and long-lasting antitumor immune responses. This proposal may have a sustained impact on the field by defining a new avenue of cancer immunotherapy that operates independently but synergizes with other therapies.

项目概要克服肿瘤细胞疫苗的低效需要增强免疫系统的激活和防止免疫抑制肿瘤微环境，例如局部缺氧。在本提案中，我们将通过使用先进的释氧生物材料（O2- 冷冻凝胶）对抗缺氧驱动的免疫抑制并改善相关的抗肿瘤免疫反应前列腺癌小鼠模型。我们在小鼠身上的初步数据表明：(i) O2-cryogels 可以逆转局部缺氧并恢复关键免疫细胞（树突状细胞；DC）的功能； (ii) 一旦进入体内，冷冻凝胶疫苗有效定位移植的肿瘤细胞，可控释放免疫调节因子，并招募大量来自主机的 DC 数量； (iii) 引发特异性且强效的疫苗诱导 T 细胞介导的抗肿瘤作用免疫。在这里，我们将优化 O2-cryogels 的特性，以实现最大的抗肿瘤功效和安全性；并评估它们抑制局部缺氧应激和改善 DC 募集、激活和归巢的能力至引流淋巴结。最后，我们将在预防性和治疗性小鼠中测试 O2-cryogel 疫苗前列腺癌模型以确定其诱导特异性、有效和持久抗肿瘤的能力免疫反应。该提案可能通过定义癌症的新途径对该领域产生持续影响独立运作但与其他疗法协同作用的免疫疗法。