Engineered Ensemble Nanoimmunotherapies for Cancer

项目总结 免疫检查点抑制剂已经彻底改变了癌症的治疗，因为它们产生了戏剧性的 对以前无法治疗的癌症(如转移性黑色素瘤)的反应和长期治疗效果。 尽管有这样的承诺，但对免疫检查点抑制剂的反应仅限于一小部分 并与有毒的、可能致命的免疫相关不良事件有关。作为对此的回应 迫切需要设计新的治疗策略，显著提高对免疫的应答率 检查点抑制剂，我们已经设计出一种整体纳米免疫疗法，它结合了 纳米技术和免疫疗法。具体地说，我们的整体包括：普鲁士蓝纳米颗粒 (PBNPs)用免疫佐剂生物功能化，并与系统联合给药 使用检查点抑制剂。我们利用PBNPs进行光热疗法，这种疗法可以去除肿瘤细胞， 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。这个 免疫原性丧失是肿瘤免疫逃逸的关键机制之一。此外，这些多国核电厂是 生物功能化，作为外源性免疫佐剂本地输送的仓库，特别是Toll样 受体激动剂在打破对肿瘤抗原的耐受性和改善肿瘤方面发挥重要作用 抗原提呈，这在免疫抑制肿瘤中是受损的。这些影响还得到了以下补充 全身应用的检查点抑制剂(抗PD-1和抗CTLA-4)逆转抑制 免疫细胞反应(特别是T细胞)，并释放其强大的抗肿瘤作用。我们相信这一点 靶向肿瘤细胞、抗原提呈细胞和T细胞的整体方法可能是 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 用Toll样受体激动剂生物功能化的PBNPs用于光热治疗 免疫原性细胞死亡，并改善抗原提呈。在目标2中，我们测试了合奏的效果 纳米免疫疗法在肿瘤根除和预防复发中的作用。在目标3中，我们评估了 纳米免疫疗法在治疗播散性癌症中的应用。该项目的成功完成将提供 对多功能纳米颗粒与免疫疗法结合使用的关键洞察力 肿瘤免疫逃逸机制和改善治疗结果。重要的是，它将提供动力 用于我们的纳米免疫疗法的临床翻译，从而将其持久的好处扩展到更大比例的 癌症患者。

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.