Bioprinting Plant Virus Nanoparticles for Immunotherapy and Relapse Prevention of Ovarian Cancer

生物打印植物病毒纳米颗粒用于卵巢癌的免疫治疗和复发预防

基本信息

批准号：
10180921
负责人：
SHAOCHEN CHEN
金额：
$ 57.66万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10180921
关键词：
3-Dimensional 3D Print Adjuvant Antigens Antitumor Response Biocompatible Materials Biological Testing Biopolymers C57BL/6 Mouse Cancer Vaccines Cells Cessation of life Clinical Trials Complex Data Development Devices Disease Disease remission Dose Formulation Future Geometry Hour Image Immune Immunity Immunologics Immunosuppression Immunotherapy Implant Investigation Irradiated tumor Left Location Lytic Malignant neoplasm of ovary Mechanics Medicine Memory Methods Modeling Modification Nature Oncogenic Viruses Oncology Operative Surgical Procedures Optics Patients Pattern recognition receptor Peptides Plant Viruses Plants Printing Process Prognosis Proteins Publishing Quality Control Recurrence Relapse Reproducibility Resolution Scanning Electron Microscopy Serous Source Stimulus Structure Surrogate Markers System Techniques Testing Therapeutic Treatment Efficacy Tumor Antigens Tumor Debulking Tumor Immunity Vaccines Virus-like particle Woman Work X ray spectroscopy adaptive immune response base bioprinting cancer cell cancer immunotherapy chemotherapy clinically significant design disorder later incidence prevention efficacy evaluation electron energy engineering design immune activation in situ vaccination innovation insight intraperitoneal mouse model nano nanoparticle neoantigens neoplastic cell novel ovarian cancer prevention photopolymerization prevent prophylactic recruit scaffold subcutaneous translational approach tumor tumor microenvironment vaccination schedule

项目摘要

Summary Bioprinting plant virus nanoparticles for immunotherapy and relapse prevention of ovarian cancer High grade serous ovarian cancer (HGSOC) is the most common and severe form of ovarian cancer and women with HGSOC have a poor prognosis. Immunotherapy approaches that induce systemic antitumor immunity, in particular those that prevent relapse, are urgently needed for HGSOC. We propose to employ plant virus-like nanoparticles (VLPs) combined with slow release antigen depots as a cancer vaccine approach to launch sys- temic antitumor immunity during remission to block relapse. Our data indicate that intraperitoneal (IP) admin- istration of plant VLPs in a mouse model of ovarian cancer modulates the tumor microenvironment to relieve immunosuppression and generate adaptive anti-tumor immunity and memory against tumor antigens. The VLPs are non-infectious, non-cytotoxic, and non-cytolytic, but the highly repetitive nature of the proteinaceous VLPs triggers innate immune activation and associated adaptive immune response. Building on this, we will develop a VLP biopolymer formulation to enable effective immunotherapy following surgical debulking in HGSOC. We will incorporate irradiated tumor cells as source for patient specific tumor antigens; the cells will be delivered together with the VLPs which act as adjuvant to launch long-lasting anti-tumor immunity. The proposed immu- notherapy implant will be produced through an innovative 3D bioprinting technique; specifically, rapid, microscale continuous optical bioprinting (µCOB). This platform offers control over both the topographical complexity and the cellular and material composition of the scaffold at micron-level resolution. Our rapid 3D bioprinting process allows for photopolymerization of multiple biocompatible materials, and facilitates incorporation of VLPs and/or cells. The engineering design space and tunability of this approach is impeccable; in particular the implant will be designed so that therapeutic doses are released in programmed intervals (prime/boost) vs. continuous slow release. We will fulfill three specific aims: 1) Bioprint VLP biopolymer implants and test various configurations to optimize slow, continuous release vs. staged, e.g. weekly release of the therapeutic VLPs. The implants will undergo rigorous quality control and reproducibility testing and released VLPs will undergo structural analysis and biological testing. 2) Evaluate efficacy of the immunotherapy implants vs. soluble VLPs will be evaluated using mouse model of ovarian cancer (ID8vegf/defb29). Immunological investigation will provide insights into the mechanism of the immunotherapy. 3) To further explore vaccine parameters and model very low endogenous patient antigen loads during remission, we will bioprint biopolymer implants to deliver VLPs and antigen (from irradiated cells) prior to challenge with ID8vegf/defb29 cells. For future translational approaches, patient tumor from surgical debulking and/or patient neoantigen peptides would be used. The clinical significance is high: we envision a simple modification to the current treatment work-flow, where small degradable vaccine implants are left in the intraperitoneal (IP) cavity during surgery or administered subcutaneously (SC) post-surgery, or both.

概括生物构图植物病毒纳米颗粒可用于免疫疗法和预防卵巢癌高级浆液卵巢癌（HGSOC）是卵巢癌和女性最常见和最严重的形式 HGSOC的预后不佳。在特别是那些迫切需要HGSOC的人。我们建议采用类似植物病毒的样子纳米颗粒（VLP）与缓慢释放的抗原沉积物作为癌症疫苗的方法结合起来缓解过程中的技术抗肿瘤免疫以阻止救济。我们的数据表明腹膜内（IP）管理在卵巢癌小鼠模型中渗透植物VLP会调节肿瘤微环境以营救免疫抑制并产生适应性抗肿瘤免疫学和对肿瘤抗原的记忆。 VLP 是非感染，非胞毒性和非溶解性的，但蛋白质VLP的高度重复性触发先天免疫激活和相关的适应性免疫响应。在此基础上，我们将发展 VLP生物聚合物公式可在HGSOC中进行手术缓解后有效的免疫疗法。我们将纳入辐照的肿瘤细胞作为患者特定肿瘤抗原的来源；细胞将传递与VLP一起进行调整以发射长期的抗肿瘤免疫。提议的immmu- 通过创新的3D生物打印技术可以生产任何植入物。具体而言，快速，微观连续光学生物打印（µCOB）。该平台可以控制地形复杂性和在微分辨率下支架的细胞和材料组成。我们快速的3D生物打印过程允许对多种生物相容性材料进行光聚合，并促进VLP和/或的基础设施细胞。这种方法的工程设计空间和可可的可线性是无可确定的；特别是植入物将设计以使治疗剂量以编程间隔（Prime/Boost）与连续慢释放发布。我们将实现三个具体目标：1）生物报vlp生物聚合物incrans incomans inspans ins to 优化慢速，连续的释放与上演，例如每周发布治疗VLP。即将进行严格的质量控制和可重复性测试和释放的VLP将进行结构分析和生物测试。 2）评估免疫疗法的效率将对可溶性VLP进行评估使用卵巢癌的小鼠模型（ID8VEGF/DEFB29）。免疫学调查将为您提供有关免疫疗法的机制。 3）进一步探索疫苗参数和模型非常低的内源性患者抗原负荷在缓解过程中，我们将生物聚集物生物聚合物意味着提供VLP和抗原（来自辐照细胞）在挑战ID8VEGF/DEFB29细胞之前。对于将来的翻译方法，患者肿瘤可以使用手术延伸和/或患者的新抗原辣椒。临床意义很高：我们设想对当前治疗工作流的简单修改，在该工作流中，可降解的疫苗工具是在手术期间或皮下施用（SC）手术后或两者兼皮。