Use of a Nano-Enabled Platform for Pancreatic Cancer Immunotherapy

纳米化疗在胰腺导管腺癌免疫治疗中的应用 (PDAC)推出了一种新的方法来克服免疫治疗的强大障碍，包括穷人 免疫原性、低新抗原负荷、基质干扰(“T细胞排斥”)、高表达 吲哚胺2，3-双加氧酶(IDO-1)与肝脏有利于转移的免疫特权环境 散开。我们的初步数据显示，脂质双层包覆的介孔二氧化硅纳米颗粒(硅酶体) 为诱导免疫原性细胞死亡(ICD)提供有效的平台 化疗药物进入PDAC部位。ICD促进内源性肿瘤抗原的呈递 细胞，提出了这样一种假设，即ICD提供了一种很有前途的内源性疫苗接种方法来产生一种“热”。 肿瘤微环境(TME)可通过区域干扰药物共给药而传播 过度表达的免疫抑制途径。这些通路可以被IDO-1、CXCR4的抑制剂靶向 (T细胞除外)和糖原合成酶激酶3(控制PD-1表达)。我们还建议 ICD诱导的记忆T细胞和“干扰素刺激物”可减少转移扩散 基因“(刺痛)激动剂对肝脏中的耐受性抗原提呈细胞。我们的长期目标是 跨学科的努力是开发一个化学免疫治疗平台，通过 硅酶体与免疫检查点和T细胞排斥途径的抑制物(CXCR4)同时存在。 目标包括使用创新的载药和胆固醇结合的前药来合成 可用于在ICD刺激物和血管紧张素转换酶抑制剂之间获得最佳协同作用的硅酶体 原位和基因工程PDAC模型中的免疫抑制途径。这需要研究 发现ICD和区域免疫逃逸途径协同作用的机制基础。我们会 使用整合素靶向、肿瘤穿透的IRGD多肽通过跨细胞途径增强药物传递。 我们还将构建聚合物纳米载体来运送刺痛激动剂，以防止转移到 肝脏。其基本原理是，使用ICD方法来产生“热”的肿瘤环境将促进 免疫治疗与提高PDAC死亡率相结合。我们计划通过以下方式来检验我们的假设 具体目标如下：目标1：开发一种用于PDAC的纳米启用的化疗免疫治疗平台 利用内源性(ICD介导的)治疗方法加上对区域性过度表达的干预 免疫检查点途径产生一个“热”的肿瘤环境。目的2：加强免疫治疗 使用整合素靶向、肿瘤穿透性IRGD多肽和开发一种 通过递送CXCR4抑制剂干扰基质中T细胞排斥的硅酶体。目标3：达到 通过刺激纳米粒促进肝APC的免疫抑制作用的重新编程 ICD诱导的硅酶体产生的记忆T细胞的PDAC转移。

The use of nano-enabled chemotherapy to trigger an immune response to pancreatic ductal adenocarcinoma (PDAC) introduces a novel approach for overcoming robust barriers to immunotherapy, including poor immunogenicity, low neoantigen burden, stromal interference (“T-cell exclusion”), overexpression of indoleamine 2,3-dioxygenase (IDO-1), and the immune privileged environment of the liver favoring metastatic spread. Our preliminary data show that lipid-bilayer coated mesoporous silica nanoparticles (silicasomes) provide an effective platform for inducing immunogenic cell death (ICD) by delivering prescreened chemotherapeutic agents to the PDAC site. ICD promotes the presentation of endogenous tumor antigens cells, raising the hypothesis that ICD offers a promising endogenous vaccination approach to generate a “hot” tumor microenvironment (TME) that can be propagated by co-delivery of drugs interfering in regionally overexpressed immunosuppressive pathways. These pathways can be targeted by inhibitors of IDO-1, CXCR4 (T-cell exclusion) and glycogen synthase kinase 3 (which controls PD-1 expression). We also propose that metastatic spread can be reduced by ICD-induced memory T-cells and delivery of “stimulator of interferon genes” (STING) agonists to tolerogenic antigen presenting cells in the liver. The long-term goal of our interdisciplinary efforts is to develop a chemo-immunotherapy platform for delivery of ICD stimuli by the silicasome contemporaneous with inhibitors of immune checkpoint and T-cell exclusion pathways (CXCR4). The objectives include the use of innovative drug loading and cholesterol-conjugated prodrugs to synthesize silicasomes that can be used to obtain the best synergy between ICD stimuli and inhibitors of immunosuppressive pathways in orthotopic and genetic engineered PDAC models. This requires research discovery into the mechanistic basis of synergy between ICD and regional immune escape pathways. We will use an integrin-targeting, tumor-penetrating iRGD peptide to enhance drug delivery by a transcytosis pathway. We will also construct polymeric nanocarriers to deliver STING agonists for preventing metastatic spread to the liver. The rationale is that the use of an ICD approach to generate a “hot” tumor environment will facilitate combination immunotherapy with improvement of PDAC mortality. We plan to test our hypothesis by pursuing the following specific aims: Aim 1: To develop a nano-enabled chemo-immunotherapy platform for PDAC that utilizes an endogenous (ICD-mediated) treatment approach plus interference in regionally overexpressed immune checkpoint pathways to generate a “hot” tumor environment. Aim 2: To enhance the immunotherapy impact of the ICD platform by using integrin-targeting, tumor-penetrating iRGD peptides and developing a silicasome that interferes in T-cell exclusion in the stroma through the delivery of CXCR4 inhibitors. Aim #3: To reprogram the immune suppressive effects of liver APC by STING nanoparticles that promote eradication of PDAC metastases by the memory T-cells generated by ICD-inducing silicasomes.