Dual-pronged nano-drug delivery using plant virus-like particles

使用植物病毒样颗粒的双管齐下纳米药物输送

基本信息

批准号：
10700990
负责人：
Nicole Franziska Steinmetz
金额：
$ 36.52万
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：
2022-09-15 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10700990
关键词：
4T1 Binding Biodistribution Biological Assay Blocking Antibodies Blood Breast Cancer Patient Canis familiaris Cells Clinical Clinical Trials Combined Modality Therapy Companions Cowpea Mosaic Viruses Data Development Disease Disseminated Malignant Neoplasm Distant Metastasis Dose Drug Delivery Systems Engineering Event Extracellular Matrix Female Flow Cytometry Funding Future Genomics Goals Human Immune Immune checkpoint inhibitor Immune system Immunologics Immunotherapy In Vitro Inflammation Innate Immune System Intravenous Libraries Life Link Malignant Neoplasms Mammary Neoplasms Molecular Monitor Monoclonal Antibodies Myelogenous Neoplasm Metastasis Patients Pattern Pattern recognition receptor Peptides Pharmacology Plant Viruses Prognosis Property Proteins Radiation Recurrence Research Resources S100A9 gene Safety Schedule Signal Transduction Site Spain Specificity T-Lymphocyte TLR2 gene Testing Time Tissues Toll-like receptors Toxic effect Tumor Antigens Tumor Immunity Tumor Markers Virus-like particle anti-PD-L1 biophysical properties cancer immunotherapy candidate identification candidate selection carcinogenesis checkpoint therapy chemotherapy effector T cell efficacy evaluation immune modulating agents immunoregulation in situ vaccination in vivo insight malignant breast neoplasm mouse model nanodrug nanomedicine nanoparticle neoantigens pathogen personalized approach pharmacologic preclinical development prevent programmed cell death ligand 1 receptor residence safety assessment synergism targeted treatment treatment response triple-negative invasive breast carcinoma tumor tumor growth tumor microenvironment tumorigenesis

项目摘要

Summary This R01 renewal application is focused on triple negative breast cancer (TNBC), which is an aggressive life- threatening disease with poor prognosis and increased likelihood of recurrence and distant metastasis. Advances in cancer immunotherapy have demonstrated that modulation of the patient’s immune system can result in dramatic antitumor activity. The most promising immunotherapy approaches are those that are personalized and take advantage of the unique neoantigens within each patient’s tumor. Toward this goal, we developed a plant virus nanoparticle immunotherapy approach that activates innate immune cells within the tumor microenvironment (TME) to launch adaptive, systemic, and durable antitumor immunity. Specifically, intratumorally injected cowpea mosaic virus (CPMV) demonstrates potent efficacy in multiple mouse models, incl. TNBC. Trials in companion dogs with breast cancer also demonstrate potent antitumor efficacy. During the previous funding cycle, we gained insights into the mechanism of action and demonstrated that CPMV is recognized by pathogen-associated molecular pattern (PAMP) receptors that detect danger signals and activate the innate immune system; specifically, CPMV is recognized by Toll-like receptors (TLR2, 4 and 7). Further, we developed and tested combination and dual-pronged treatment approaches: we demonstrated efficacy of CPMV as solo-treatment as well as in combination with radiation, chemotherapy, immunomodulatory drugs, and checkpoint inhibitors, amongst others. This proposal builds on this strong portfolio of data. Our first goal is to focus on dual-pronged CPMV that combines its immunomodulatory and antitumor immunity properties with checkpoint therapy (Aim 1). Checkpoint blocking antibodies are effective at removing inhibitory signals but as monotherapy have variable and limited efficacy. In situ vaccination with CPMV increases tumor antigen specific effector T cells and our preliminary data indicate that CPMV treatment synergizes with immune checkpoint therapy. Next, we seek to develop targeted approaches that effectively concentrate systemically administered CPMV in tumors and provide further therapy options to treat metastatic disease (Aim 2). S100A9- targeted CPMV will be studied: expression of S100A9 (also known as myeloid-related protein 14 [MRP-14]), is linked to inflammation and carcinogenesis. Higher S100A9 expression in breast cancer correlates with a worse prognosis. S100A9 expression is an early event in tumorigenesis, enhancing tumor aggressiveness and metastasis. In the TME, S100A9 is secreted to the extracellular matrix, making it a highly suitable target for nanomedicine. Recognizing the potential of S100A9 as a pharmacologic target, we developed S100A9-targeted CPMV that efficiently concentrates at sites of metastasis enabling potent efficacy preventing outgrowth of metastases. Here we set out to detail the mechanisms of action and understand the pharmacology of S100A9- targeted CPMV. Finally, the preclinical development will be substantially extended with veterinary clinical trials in companion dogs with mammary tumors (Aim 3).

概括此 R01 更新应用程序专注于三阴性乳腺癌 (TNBC)，这是一种侵袭性的生命- 威胁性疾病，预后不良，复发和远处转移的可能性增加。癌症免疫疗法的进展表明，调节患者的免疫系统可以最有前途的免疫治疗方法是那些具有显着抗肿瘤活性的方法。为了实现这一目标，我们进行个性化治疗并利用每位患者肿瘤内独特的新抗原。开发了一种植物病毒纳米颗粒免疫治疗方法，可激活体内的先天免疫细胞肿瘤微环境（TME）以启动适应性、系统性和持久的抗肿瘤免疫。具体来说，瘤内注射豇豆花叶病毒（CPMV）在多只小鼠中表现出有效的功效模型，包括 TNBC，在患有乳腺癌的伴侣犬中进行的试验也证明了其有效的抗肿瘤功效。在上一个融资周期中，我们深入了解了作用机制，并证明了 CPMV 被病原体相关分子模式 (PAMP) 受体识别，可检测危险信号并激活先天免疫系统；具体而言，CPMV 被 Toll 样受体（TLR2、4 和 7）识别。此外，我们开发并测试了组合和双管齐下的治疗方法：我们证明了 CPMV 单独治疗以及与放疗、化疗、免疫调节联合治疗的疗效该提案建立在我们的第一个强大数据组合的基础上。目标是专注于双管齐下的 CPMV，结合其免疫调节和抗肿瘤免疫特性检查点疗法（目标 1）可有效消除抑制信号。因为单一疗法具有可变且有限的功效，CPMV 的原位疫苗接种会增加肿瘤抗原。特异性效应 T 细胞和我们的初步数据表明 CPMV 治疗与免疫具有协同作用接下来，我们寻求开发有效系统集中注意力的有针对性的方法。在肿瘤中施用 CPMV 并提供治疗转移性疾病的进一步治疗选择（目标 2）。将研究靶向 CPMV：S100A9（也称为骨髓相关蛋白 14 [MRP-14]）的表达是乳腺癌中较高的 S100A9 表达与较差的乳腺癌相关。 S100A9 表达是肿瘤发生的早期事件，增强肿瘤的侵袭性和预后。在 TME 中，S100A9 被分泌到细胞外基质，使其成为非常适合的靶点。认识到 S100A9 作为药理学靶点的潜力，我们开发了针对 S100A9 的药物。 CPMV 可有效集中在转移部位，具有有效防止肿瘤生长的功效在这里，我们详细介绍了 S100A9- 的作用机制并了解其药理学。最后，临床前开发将通过兽医临床试验得到大幅扩展。患有乳腺肿瘤的伴侣犬（目标 3）。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Delivery of siRNA therapeutics using cowpea chlorotic mottle virus-like particles.

使用豇豆退绿斑驳病毒样颗粒进行 siRNA 治疗。

DOI：
发表时间：
2019-08-01
期刊：
影响因子：
6.6
作者：
Lam, Patricia;Steinmetz, Nicole F
通讯作者：
Steinmetz, Nicole F

CD47 Blockade and Cowpea Mosaic Virus Nanoparticle In Situ Vaccination Triggers Phagocytosis and Tumor Killing.

CD47 阻断和豇豆花叶病毒纳米颗粒原位疫苗接种可触发吞噬作用和肿瘤杀伤作用。

DOI：
发表时间：
2019
期刊：
影响因子：
10
作者：
Wang, Chao;Steinmetz, Nicole F
通讯作者：
Steinmetz, Nicole F

Development of a Virus-Like Particle-Based Anti-HER2 Breast Cancer Vaccine.

开发基于病毒样颗粒的抗 HER2 乳腺癌疫苗。

DOI：
发表时间：
2021-06-10
期刊：
影响因子：
5.2
作者：
Hu, He;Steinmetz, Nicole F
通讯作者：
Steinmetz, Nicole F

Viral nanoparticle vaccines against S100A9 reduce lung tumor seeding and metastasis.

针对 S100A9 的病毒纳米颗粒疫苗可减少肺部肿瘤的种植和转移。

DOI：
发表时间：
2023-10-24
期刊：
影响因子：
11.1
作者：
Chung, Young Hun;Ortega;Volckaert, Britney A;Jung, Eunkyeong;Zhao, Zhongchao;Steinmetz, Nicole F
通讯作者：
Steinmetz, Nicole F

Heterologous Prime-Boost Enhances the Antitumor Immune Response Elicited by Plant-Virus-Based Cancer Vaccine.

异源 Prime-Boost 增强植物病毒癌症疫苗引发的抗肿瘤免疫反应。