Engineered Ensemble Nanoimmunotherapies for Cancer

工程集成癌症纳米免疫疗法

基本信息

批准号：
10443229
负责人：
Rohan Fernandes
金额：
$ 45.15万
依托单位：
GEORGE WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10443229
关键词：
Adjuvant Agonist Antigen Presentation Antigen-Presenting Cells Antigens Cancer Etiology Cancer Patient Cells Clinical Combination immunotherapy Combined Modality Therapy 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 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 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 relapse prevention 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.

项目摘要免疫检查点抑制剂已经彻底改变了癌症的治疗以前无法治疗的癌症（例如转移性黑色素瘤）的反应和持久的治疗益处。尽管有这样的承诺，但对免疫抑制剂的反应仍仅限于患者并与有毒和潜在的致命免疫相关不良事件有关。为此回应迫切需要设计新颖的治疗策略，以显着提高对免疫的反应率检查点抑制剂，我们设计了一种合奏纳米免疫疗法，结合了优势纳米技术和免疫疗法。具体来说，我们的合奏包括：普鲁士蓝色纳米颗粒（PBNP）与免疫调节器生物功能化，并与全身施用管理检查点抑制剂。我们利用PBNP进行光热疗法，这消灭了肿瘤细胞，释放肿瘤抗原和与损伤相关的分子模式，以增加肿瘤免疫原性。这免疫原性的丧失是癌症中的关键免疫扫描机制之一。另外，PBNP是生物官能化可用作局部输送外源性免疫调节器的仓库，尤其是类似Toll样的仓库受体激动剂在破坏对肿瘤抗原的耐受性和改善肿瘤方面发挥重要作用抗原表现，在免疫抑制肿瘤中受损。这些效果由全身施用的检查点抑制剂（抗PD-1和抗CTLA-4）反向抑制免疫细胞反应（部分为T细胞），并释放其潜在的抗肿瘤作用。我们相信这个靶向肿瘤细胞，抗原呈递细胞和T细胞的合奏方法可能会持有关键将无反应性的“冷”肿瘤转化为反应迅速的“热”肿瘤。在AIM 1中，我们试图确定是否 PBNP用Toll样受体激动剂生物功能化，用于光热治疗免疫原性死亡并改善抗原表现。在AIM 2中，我们测试合奏的效率纳米免疫疗法对肿瘤洗脱并预防继电器。在AIM 3中，我们评估了纳米免疫疗法治疗传播癌症。该项目的成功完成将提供对使用多功能纳米颗粒与免疫疗法相结合的批判性洞察力以克服肿瘤免疫进化机制并改善治疗结果。重要的是，它将提供动力对于我们的纳米免疫疗法的临床翻译，将其持久益处扩展到更大的比例癌症患者。