Toward translation of a plant virus-based in situ vaccination nanotechnology

基于植物病毒的原位疫苗接种纳米技术的转化

基本信息

批准号：
10688114
负责人：
STEVEN FIERING
金额：
$ 60.85万
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：
2022
资助国家：
美国
起止时间：
2022-08-22 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10688114
关键词：
Abscopal effect Antigens Antitumor Response Applications Grants Award Biodistribution Biological Biological Markers Biopsy Biotechnology Blood Cancer Intervention Canis familiaris Cells Chemistry Chromatography Chronic Clinical Clinical Trials Collaborations Companions Cowpea Mosaic Viruses Data Development Disease remission Dose Enrollment Environment Evaluation Fabaceae Farm Feces Formulation Foundations Funding Future Genomics Goals Good Manufacturing Process Human Image Immune Immune system Immunologic Memory Immunologic Stimulation Immunologics Immunosuppression Immunotherapy Industry Standard Inflammation Injections Innate Immune System Intellectual Property Investigation Investigational Therapies Leadership Licensing Malignant Neoplasms Mammals Mast Cell Neoplasm Mediating Methodology Methods Modeling Molecular Monitor Mosaic Viruses Mus Nanotechnology Nanovirus Neoplasm Metastasis Oncogenic Viruses Oncology Organ Patients Pharmacology Pharmacology and Toxicology Phase 0 Clinical Trial Plant Viruses Plants Positioning Attribute Production Protocols documentation Recurrence Safety Site Structure Techniques Technology Time Toxic effect Toxicology Translating Translational Research Translations Tumor Antigens Tumor Burden Tumor Immunity Tumor Markers Urine Vaccine Therapy anti-tumor immune response arm cancer immunotherapy cell killing clinical practice drug candidate experience immunoengineering immunotherapy trials improved in situ vaccination in situ vaccine intervention program malignant breast neoplasm manufacture manufacturing facility melanoma method development mosaic mouse model nanoparticle neoantigens neoplastic cell oncology trial patient subsets personalized approach prevent programs recruit residence sarcoma success systemic toxicity treatment response tumor tumor immunology tumor microenvironment vaccine candidate

项目摘要

Summary This R01, submitted to the Toward Translation of Nanotechnology Cancer Interventions (TTNCI) program, is a continuation of our successful U01 CA218292 (09/2017-07/2022), funded through the NCI Alliance for Nanotechnology in Cancer program. During the U01 project period, we demonstrated that our nanoparticles derived from the plant virus cowpea mosaic virus (CPMV) stimulate a potent antitumor immune response against multiple tumor mouse models. Additionally, trials in companion dogs with melanoma, sarcoma, and breast cancer demonstrate potent antitumor efficacy with our unique immunotherapy approach. CPMV is an intratumoral injected in situ vaccine (ISV) technology, with an ability to induce durable immune-mediated antitumor efficacy against treated and untreated tumors as well as immunological memory against recurrence. Mechanistically, CPMV activates the innate immune system to improve processing of tumor-associated and neoantigens, thereby resulting in a more functional adaptive antitumor immunity against antigens expressed by the tumor. This results in remissions of treated and untreated malignant tumors, and protection from recurrence via the adaptive arm and immune memory. Building on this strong foundation of data as well as intellectual property, this project will focus on optimizing GMP manufacturing and pharmacology in murine tumor models and canine patients to provide the foundational basis of future human oncology trials. The multi-PI leadership team Steinmetz (UC San Diego), Fiering (Dartmouth) and Ranjan (OSU) brings complimentary expertise in plant virus-based CPMV nanotechnology, cancer immunology, and veterinary oncology/immunotherapy trials. Our team is also supported by a group of consultants with expertise in regulatory (Garnick, Mosaic IE Inc.), pharmacology/toxicology (Luksic, Intrinsik), clinical (Garovoy, Mosaic IE Inc.) affairs, as well as experience in vertical farming (Eisenberg, OPO). We believe that our strong team of collaborators can help establish the future manufacture of the plant-derived biologic. We will fulfil the following Specific Aims: (1) Chemistry, Manufacturing, and Control (CMC) method development for scalable manufacture and QAC of the CPMV- ISV, (2) Pharmacology: Determine biodistribution, dosing, and toxicology of the CPMV-ISV drug candidate in orthotopic and metastatic mouse models of melanoma; and (3) Canine trials: establish dosing and safety in canine oncology trials in varying tumor types amenable for in situ vaccination (melanoma, sarcoma, and mast- cell tumor). Through parallel trials in murine tumor models and dog patients, we will identify biopsy or blood biomarkers for longitudinal monitoring of treatment response. Successful completion would position us for good manufacturing practice (GMP) production of this plant virus-based biologic nanotechnology and to continue the developmental path, e.g. through the NCI Experimental Therapeutics (NExT) program, thereby translating the CPMV-based drug candidate into a human clinical trial and practice.

概括此 R01 已提交给纳米技术癌症干预 (TTNCI) 计划的转化，是我们成功的 U01 CA218292 (09/2017-07/2022) 的延续，由 NCI 联盟资助癌症计划中的纳米技术。在 U01 项目期间，我们证明了我们的纳米颗粒源自植物病毒豇豆花叶病毒 (CPMV)，可刺激有效的抗肿瘤免疫反应多种肿瘤小鼠模型。此外，还对患有黑色素瘤、肉瘤和乳腺癌的伴侣犬进行了试验通过我们独特的免疫治疗方法证明了有效的抗肿瘤功效。 CPMV 是一种瘤内原位注射疫苗（ISV）技术，能够诱导持久的免疫介导抗肿瘤对已治疗和未治疗肿瘤的功效以及针对复发的免疫记忆。从机制上讲，CPMV 激活先天免疫系统，改善肿瘤相关和免疫系统的处理。新抗原，从而产生针对由新抗原表达的抗原的功能更强的适应性抗肿瘤免疫肿瘤。这可以缓解已治疗和未治疗的恶性肿瘤，并防止复发通过适应性臂和免疫记忆。建立在数据和知识的坚实基础之上该项目将重点优化小鼠肿瘤模型中的 GMP 生产和药理学和犬类患者，为未来的人类肿瘤学试验提供基础。多 PI 领导力 Steinmetz（加州大学圣地亚哥分校）、Fiering（达特茅斯）和 Ranjan（俄勒冈州立大学）团队带来了以下领域的免费专业知识：基于植物病毒的 CPMV 纳米技术、癌症免疫学和兽医肿瘤学/免疫治疗试验。我们的团队还得到了一组具有监管专业知识的顾问（Garnick、Mosaic IE Inc.）的支持，药理学/毒理学（Luksic、Intrinsik）、临床（Garovoy、Mosaic IE Inc.）事务以及经验垂直农业（Eisenberg，OPO）。我们相信，我们强大的合作团队可以帮助建立植物源性生物制品的未来制造。我们将实现以下具体目标：（1）化学，用于 CPMV- 的可扩展制造和 QAC 的制造和控制 (CMC) 方法开发 ISV，(2) 药理学：确定 CPMV-ISV 候选药物的生物分布、剂量和毒理学黑色素瘤的原位和转移性小鼠模型； (3) 犬类试验：确定剂量和安全性对适合原位疫苗接种的不同肿瘤类型（黑色素瘤、肉瘤和乳腺瘤）进行犬肿瘤学试验细胞瘤）。通过对小鼠肿瘤模型和狗患者进行平行试验，我们将鉴定活检或血液用于纵向监测治疗反应的生物标志物。成功完成将为我们奠定良好的基础这种基于植物病毒的生物纳米技术的生产实践（GMP）生产，并继续发展路径，例如通过 NCI 实验治疗 (NExT) 计划，从而将基于CPMV的候选药物进入人体临床试验和实践。