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Engineered Ensemble Nanoimmunotherapies for Cancer

癌症综合纳米免疫疗法

基本信息

批准号：
10302277
负责人：
Rohan Fernandes
金额：
$ 40.15万
依托单位：
GEORGE WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-12-03 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10302277
关键词：
Adjuvant Agonist Antigen Presentation Antigen-Presenting Cells Antigens Cancer Etiology Cancer Patient Cells Clinical Complement Development Disease Distal Electrostatics Engineering Exhibits HMGB1 gene Immune Immune Cell Suppression Immune checkpoint inhibitor Immunologic Adjuvants Immunologic Memory Immunologics Immunotherapy Impairment In Vitro Lasers Malignant Neoplasms Metastatic Melanoma Modeling Molecular Monitor Mus Nanoimmunotherapy Nanotechnology Neuroblastoma Nivolumab Oligonucleotides Oncolytic viruses Pattern Phenotype Play Primary Neoplasm Prussian blue Public Health Radiation therapy Radiofrequency Interstitial Ablation Regimen Relapse Role T cell response T-Lymphocyte Testing Therapeutic Toll-like receptors Treatment Protocols Tumor Antigens Tumor Escape Tumor Immunity anti-CTLA-4 therapy anti-CTLA4 anti-PD-1 antitumor effect base calreticulin cancer immunotherapy cancer therapy checkpoint inhibition childhood cancer mortality clinical translation efficacy evaluation efficacy testing immune-related adverse events immunogenic cell death immunogenicity improved in situ vaccine in vivo insight ipilimumab mouse model nanoparticle neoplastic cell novel novel therapeutic intervention particle patient subsets photothermal therapy prevent response therapy outcome treatment response tumor tumor ablation tumor eradication tumor progression

项目摘要

PROJECT SUMMARY Immune checkpoint inhibitors have revolutionized the treatment of cancer because they yield dramatic responses and long-lasting therapeutic benefits in previously untreatable cancers (e.g. metastatic melanoma). Despite this promise, the responses to immune checkpoint inhibitors have been restricted to small subsets of patients and are associated with toxic, and potentially fatal immune-related adverse events. In response to this urgent need to devise novel therapeutic strategies that dramatically increase the response rate to immune checkpoint inhibitors, we have engineered an ensemble nanoimmunotherapy that combine the advantages of nanotechnology and immunotherapy. Specifically, our ensemble comprises: Prussian blue nanoparticles (PBNPs) biofunctionalized with immune adjuvants and administered in combination with systemically administered checkpoint inhibitors. We utilize the PBNPs for photothermal therapy, which ablates tumor cells, releasing tumor antigens, and damage-associated molecular patterns that increase tumor immunogenicity. The loss of immunogenicity is one of the key immune escape mechanisms in cancer. Additionally, the PBNPs are biofunctionalized to serve as a depot for local delivery of exogenous immune adjuvants, particularly toll-like receptor agonists that play an important role in breaking tolerance to tumor antigens and improving tumor antigen presentation, which is impaired in immunosuppressive tumors. These effects are complemented by systemically administered checkpoint inhibitors (anti-PD-1 and anti-CTLA-4) that reverse suppression of immune cell responses (particularly T cells) and unleash their potent antitumor effects. We believe that this ensemble approach of targeting tumor cells, antigen presenting cells, and T cells may hold the key in converting a non-responsive “cold” tumor to a responsive “hot” tumor. In Aim 1, we seek to determine whether the PBNPs biofunctionalized with toll-like receptor agonists and used for photothermal therapy elicits immunogenic cell death and improves antigen presentation. In Aim 2, we test the efficacy of the ensemble nanoimmunotherapy on tumor eradication and preventing relapse. In Aim 3, we evaluate the efficacy of the nanoimmunotherapy in treating disseminated cancer. The successful completion of the project will provide critical insight into the use of multifunctional nanoparticles in combination with immunotherapies to overcome tumor immune evasion mechanisms and improve therapeutic outcomes. Importantly, it will provide the impetus for clinical translation of our nanoimmunotherapy, thereby extending its lasting benefits to a larger proportion of cancer patients.

项目总结