Engineered Ensemble Nanoimmunotherapies for Cancer

工程集成癌症纳米免疫疗法

• 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
• 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

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.

项目概要 免疫检查点抑制剂彻底改变了癌症的治疗方法，因为它们产生了显着的效果 对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。 尽管有这样的希望，但对免疫检查点抑制剂的反应仅限于一小部分 患者，并与有毒的、可能致命的免疫相关不良事件有关。对此作出回应 迫切需要设计新的治疗策略来显着提高免疫应答率 检查点抑制剂，我们设计了一种整体纳米免疫疗法，结合了以下优点： 纳米技术和免疫疗法。具体来说，我们的整体包括： 普鲁士蓝纳米颗粒 （PBNP）与免疫佐剂进行生物功能化并与全身给药相结合 给予检查点抑制剂。我们利用 PBNP 进行光热疗法，消除肿瘤细胞， 释放肿瘤抗原，以及增加肿瘤免疫原性的损伤相关分子模式。这 免疫原性丧失是癌症中关键的免疫逃逸机制之一。此外，PBNP 是 生物功能化作为外源免疫佐剂局部递送的储存库，特别是Toll样佐剂 受体激动剂在打破肿瘤抗原耐受、改善肿瘤发生方面发挥重要作用 抗原呈递，在免疫抑制性肿瘤中受损。这些效果得到了补充 全身施用检查点抑制剂（抗 PD-1 和抗 CTLA-4），可逆转对 免疫细胞反应（特别是 T 细胞）并释放其有效的抗肿瘤作用。我们相信，这 靶向肿瘤细胞、抗原呈递细胞和 T 细胞的整体方法可能是解决这一问题的关键 将无反应的“冷”肿瘤转变为有反应的“热”肿瘤。在目标 1 中，我们试图确定是否 用 Toll 样受体激动剂进行生物功能化并用于光热疗法的 PBNP 免疫原性细胞死亡并改善抗原呈递。在目标 2 中，我们测试了集成的功效 纳米免疫疗法根除肿瘤并预防复发。在目标 3 中，我们评估了 纳米免疫疗法治疗播散性癌症。该项目的顺利完成将提供 对使用多功能纳米粒子与免疫疗法相结合来克服的关键见解 肿瘤免疫逃避机制并改善治疗结果。重要的是，它将提供动力 用于我们的纳米免疫疗法的临床转化，从而将其持久的益处扩展到更大比例的患者 癌症患者。