Overcoming the immune-suppressive tumor microenvironment through in situ vaccination nanotechnology.

通过原位疫苗接种纳米技术克服免疫抑制肿瘤微环境。

基本信息

批准号：
10227062
负责人：
STEVEN FIERING
金额：
$ 58.33万
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：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10227062
关键词：
Animal Model Antibodies Antigen-Presenting Cells Antigens Antitumor Response Applications Grants Benchmarking Canis familiaris Cells Characteristics Clinical Trials Communities Companions Cowpea Mosaic Viruses Cytokine Signaling Data Development Disease Disseminated Malignant Neoplasm Dose Drug resistance Engineering Equilibrium FDA approved Frequencies Future Generations Goals Herpesviridae Human Immune Immune Targeting Immune Tolerance Immune checkpoint inhibitor Immune response Immune system Immunization Immunologic Memory Immunologics Immunology Immunosuppression Immunotherapeutic agent Injectable Knockout Mice Malignant Neoplasms Malignant neoplasm of ovary Measures Mediating Metastatic Melanoma Modeling Molecular Molecular Probes Mus Nanotechnology Nature Neoplasm Metastasis Oral Pathway interactions Patients Phenotype Plant Viruses Plants Price Primary Neoplasm Reagent Recruitment Activity Recurrence Research Personnel Signal Pathway Site T-Lymphocyte Technology Tenuate Testing Therapeutic Time Toxic effect Treatment Efficacy Tumor Burden Tumor Immunity Tumor-infiltrating immune cells Tumorigenicity Virus Virus-like particle anti-tumor immune response antigen-specific T cells base cancer therapy clinical development cytokine engineering design experience falls immune activation immune clearance immune function improved in situ vaccination insight malignant breast neoplasm man melanoma mouse model nano nanoengineering neoantigens neutrophil novel personalized medicine programs standard of care success tumor tumor microenvironment

项目摘要

Summary The immune-suppressive microenvironment generated by tumors is a key barrier to immune clearance and thereby, enables cancer to manifest. We propose to overcome this barrier using a plant virus-like nanopar- ticle (VLP) platform technology for in situ vaccination, to eliminate local immunosuppression and generate ef- fective local and systemic anti-tumor immunity. We recently demonstrated that plant-produced, engineered VLP-based nanotechnologies stimulate a potent anti-tumor immune response in mouse models of metastatic melanoma, ovarian cancer, and breast cancer. Data indicate that the effect is systemic and durable, resulting in immune-memory and protection from recurrence. Preliminary studies in companion dogs with metastatic melanoma indicate that the potent anti-tumor efficacy can be replicated in the canine model, which has high relevance to human melanoma. In situ vaccination provides a personalized treatment approach by relieving the patient's tumor-mediated immunosuppression and potentiating anti-tumor immunity against antigens ex- pressed by their own tumor. The proposed nanoengineering approach using plant VLPs would improve the standard of care in several ways. First, in situ vaccination will increase the frequency of antigen-specific T cells, leading to long-lasting immunologic memory; this is in contrast to checkpoint inhibitors, which are not an- tigen specific, activate all antigen-experienced T cells and result in off-target immune toxicities. Second, FDA- approved in situ vaccination using T-VEC demonstrates the approach but is limited because of the use of at- tenuated herpes virus, which can be infectious, has poor stability and an extraordinary price per dose. While our supporting data indicate potent efficacy in various tumor models, the underlying immunology is quite unique and not yet completely understood. Therefore, the essence of this proposal is to decipher the engineering design space of the potent nanotechnology and to delineated the underlying mecha- nism of action. Therefore, this proposal sets out to fulfill the following aims: 1) To decipher the VLP's molecu- lar features triggering the potent efficacy. 2) To delineate the underlying mechanisms of immune activation primed by the VLPs. 3) To gain further insights into the mechanism of action and efficacy through study of companion dogs with oral melanoma. A multi-PI partnership and collaborating investigators will contribute to the success of the program. Together, data will provide detailed mechanisms of anti-tumor immune activation by engineered VLP nanotechnologies and will inform nanoengineering to further improve the approach and begin the effort to test it in human patients.

概括肿瘤产生的免疫抑制微环境是免疫清除的关键障碍从而使癌症得以显现。我们建议使用类似植物病毒的纳米颗粒来克服这一障碍 Ticle（VLP）平台技术用于原位疫苗接种，消除局部免疫抑制并产生效果有效的局部和全身抗肿瘤免疫。我们最近证明，植物生产的、工程设计的基于 VLP 的纳米技术可在转移性小鼠模型中刺激有效的抗肿瘤免疫反应黑色素瘤、卵巢癌和乳腺癌。数据表明，这种影响是系统性的、持久的，免疫记忆和防止复发。患有转移性伴侣犬的初步研究黑色素瘤表明，有效的抗肿瘤功效可以在犬模型中复制，该模型具有很高的抗肿瘤效果。与人类黑色素瘤的相关性。原位疫苗接种提供了一种个性化的治疗方法，可减轻患者的肿瘤介导的免疫抑制和增强针对抗原的抗肿瘤免疫被自己的肿瘤压迫。所提出的使用植物 VLP 的纳米工程方法将改善护理标准有多种方式。首先，原位疫苗接种会增加抗原特异性T的出现频率细胞，产生持久的免疫记忆；这与检查点抑制剂相反，检查点抑制剂不是抗原特异性，激活所有经历过抗原的 T 细胞并导致脱靶免疫毒性。其次，FDA—— 批准使用 T-VEC 进行原位疫苗接种证明了该方法，但由于使用了 at- 减毒疱疹病毒具有传染性，稳定性差，每剂价格昂贵。尽管我们的支持数据表明在各种肿瘤模型中具有强大的功效，潜在的免疫学是相当独特且尚未完全理解。因此，本提案的实质是破译强大的纳米技术的工程设计空间，并描绘出底层的机械结构行动主义。因此，该提案旨在实现以下目标：1）破译VLP的分子 lar 的特点触发了强大的功效。 2）描绘免疫激活的潜在机制由 VLP 启动。 3）通过研究进一步了解作用机制和功效患有口腔黑色素瘤的伴侣犬。多 PI 伙伴关系和合作研究人员将有助于该计划的成功。总之，数据将提供抗肿瘤免疫激活的详细机制通过工程化 VLP 纳米技术，并将为纳米工程提供信息，以进一步改进该方法和开始在人类患者身上进行测试。

项目成果

期刊论文数量（14）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Endosomal toll-like receptors play a key role in activation of primary human monocytes by cowpea mosaic virus.

内体 Toll 样受体在豇豆花叶病毒激活原代人单核细胞中发挥关键作用。

DOI：
发表时间：
2020-02
期刊：
影响因子：
6.4
作者：
Albakri, Marwah M;Veliz, Frank A;Fiering, Steven N;Steinmetz, Nicole F;Sieg, Scott F
通讯作者：
Sieg, Scott F

Transcriptomics of Canine Inflammatory Mammary Cancer Treated with Empty Cowpea Mosaic Virus Implicates Neutrophils in Anti-Tumor Immunity.

用空豇豆花叶病毒治疗犬炎症性乳腺癌的转录组学表明中性粒细胞参与抗肿瘤免疫。

DOI：
发表时间：
2023-09-13
期刊：
影响因子：
5.6
作者：
Barreno, Lucia;Sevane, Natalia;Valdivia, Guillermo;Alonso;Suarez;Alonso;Fiering, Steven;Beiss, Veronique;Steinmetz, Nicole F;Perez;Peña, Laura
通讯作者：
Peña, Laura

Alfalfa mosaic virus nanoparticles-based in situ vaccination induces antitumor immune responses in breast cancer model.

基于苜蓿花叶病毒纳米颗粒的原位疫苗接种可在乳腺癌模型中诱导抗肿瘤免疫反应。