Engineered Ensemble Nanoimmunotherapies for Cancer

项目摘要 免疫检查点抑制剂已经彻底改变了癌症的治疗，因为它们产生了显着的 在以前无法治疗的癌症（例如转移性黑色素瘤）中的反应和持久的治疗益处。 尽管有这样的前景，但对免疫检查点抑制剂的反应仅限于小的亚群。 并且与毒性和潜在致命的免疫相关不良事件相关。针对这一 迫切需要设计新的治疗策略，大大提高免疫应答率， 检查点抑制剂，我们已经设计了一种集成纳米免疫疗法，它结合了联合收割机的优点， 纳米技术和免疫疗法。具体来说，我们的系综包括： 用免疫佐剂生物功能化的PBNP，并与全身性给药组合施用。 检查点抑制剂。我们利用PBNP进行光热治疗，其消融肿瘤细胞， 释放肿瘤抗原和增加肿瘤免疫原性的损伤相关分子模式。的 免疫原性的丧失是癌症中关键的免疫逃逸机制之一。此外，PBNP还 生物功能化以用作外源性免疫佐剂，特别是Toll样免疫佐剂的局部递送的储库 受体激动剂在破坏对肿瘤抗原的耐受性和改善肿瘤免疫中起重要作用， 抗原呈递，其在免疫抑制性肿瘤中受损。这些影响得到补充， 全身给予检查点抑制剂（抗PD-1和抗CTLA-4）， 免疫细胞（特别是T细胞）的反应，并释放其强大的抗肿瘤作用。我们认为这 靶向肿瘤细胞、抗原呈递细胞和T细胞的整体方法可能是治疗肿瘤的关键。 将无反应的“冷”肿瘤转化为有反应的“热”肿瘤。在目标1中，我们试图确定是否 用Toll样受体激动剂生物功能化并用于光热治疗的PBNP 免疫原性细胞死亡并改善抗原呈递。在目标2中，我们测试了集成的有效性 纳米免疫疗法对肿瘤根除和预防复发的作用。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为 关键洞察使用多功能纳米粒子与免疫疗法相结合，以克服 肿瘤免疫逃避机制和改善治疗结果。重要的是，它将提供动力， 我们的纳米免疫疗法的临床翻译，从而扩大其持久的好处，以更大的比例， 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.