Development of a New Strategy to Treat Locally Advanced Pancreatic Cancer

胰腺癌（PC）是美国癌症死亡的第三大常见原因， 年总生存率为8%。有有限的治疗方案，个人诊断为PC，即使 及早发现。因此，迫切需要改进现有疗法或开发新的策略， 提高PC患者的总体生存率。一种称为立体定向体部放射治疗（SBRT）的新兴策略， 其中在短时间内提供较高剂量的辐射，已经证明了上级肿瘤 与常规放疗相比，本应用程序将扩展这些发现， 在SBRT中纳入新的范式转变，压倒性地证明了免疫系统的关键作用 介导这种方式的抗肿瘤作用。因此，我们的总体假设是SBRT 可以通过调节PC中的免疫应答来增强功效。为了验证这一点，我们开发了两个 创新方法：首先，我们通过递送免疫刺激细胞因子来激活抗肿瘤免疫细胞， 白细胞介素-12（IL-12）使用称为微球（MS）的尖端技术。这些聚合物包裹 IL-12，并且当瘤内注射时，提供细胞因子的缓慢、连续释放10-14天。第二、 建立了PC的临床前原位模型，其中胰腺肿瘤用临床上可接受的药物治疗。 使用最近获得的小动物辐射研究平台（SARRP）的SBRT相关时间表; 与临床放射肿瘤学中使用的器械非常相似的器械。当SBRT与 在2个不同的患者中观察到IL-12 MS前所未有地降低了肿瘤负荷，甚至治愈了肿瘤 原位PC模型。这项建议将以这些令人鼓舞的研究为基础， 在原发肿瘤（Aim 1）和PC转移的主要部位，即肝脏（Aim 2）。目标1： 将确定SBRT + IL-12 MS是否可以转化典型的免疫抑制肿瘤微环境（TME） 使用2个单独的原位PC模型和一个自发PC模型将其转化为免疫刺激性PC模型。我们预测 SBRT + IL-12 MS增强了CD 8 + T细胞的抗肿瘤能力，沿着复极化抑制性肿瘤， 相关巨噬细胞（TAM）转化为直接或间接支持肿瘤破坏的细胞。在目标2中， 我们将探讨胰腺的局部SBRT + IL-12 MS治疗是否调节肝脏的 微环境破坏转移。我们预测，局部SBRT + IL-12 MS增强全身性 抗肿瘤免疫，这反过来又通过上调细胞因子IFNγ调节肝脏微环境， 防止转移的建立。这将具有重要的临床意义，因为许多PC 患者死于转移性疾病。总而言之，这里提出的赠款将获得必要的预- 临床数据，最终将告知在研究者中使用这种令人兴奋的新PC疗法SBRT + IL-12 MS， 领导临床试验。

Pancreatic cancer (PC) is the 3rd most common cause of cancer deaths in the United States with a dismal 5- year overall survival of 8%. There are limited treatment options for individuals diagnosed with PC even if detected early. As a result, there is a vital need to improve existing therapies or develop new strategies to increase the overall survival of PC patients. An emerging strategy called stereotactic body radiotherapy (SBRT), where higher doses of radiation are delivered over a short period of time, has demonstrated superior tumor control when compared to conventional radiotherapy. This application will expand on these findings and incorporate a new paradigm shift in SBRT that overwhelmingly demonstrates a crucial role of the immune system in mediating the anti-tumor effects of this modality. Therefore, our overarching hypothesis is that SBRT efficacy can be enhanced by modulating the immune response in PC. To test this, we developed two innovative approaches: First, we activated antitumor immune cells by delivering the immunostimulatory cytokine interleukin-12 (IL-12) using a cutting-edge technology called microspheres (MS). These polymers encapsulate IL-12, and when injected intratumorally, provide a slow, continuous release of cytokine for 10-14 days. Second, a preclinical orthotopic model of PC was established where pancreatic tumors were treated with a clinically relevant schedule of SBRT using a recently acquired Small Animal Radiation Research Platform (SARRP); an instrument that closely resembles those used in clinical radiation oncology. When SBRT was combined with IL-12MS, an unprecedented decrease of tumor burden, and even cure, was observed in 2 different orthotopic PC models. This proposal will build on these encouraging studies and address mechanisms of action both at the primary tumor (Aim 1) and at the predominate site of PC metastases, the liver (Aim 2). In Aim 1, we will determine if SBRT + IL-12MS can convert a typically immunosuppressive tumor microenvironment (TME) into one that is immunostimulatory using 2 separate orthotopic and one spontaneous PC model. We predict that SBRT + IL-12MS augments the antitumor capacity of CD8+ T cells along with repolarizing suppressive tumor- associated macrophages (TAMs) into cells that either directly or indirectly bolster tumor destruction. In Aim 2, we will explore whether localized SBRT + IL-12MS therapy to the pancreas modulates the hepatic microenvironment to destroy metastases. We predict that localized SBRT + IL-12MS potentiates systemic antitumor immunity, which in turn conditions the hepatic microenvironment by upregulating the cytokine IFNγ and protects against the establishment of metastases. This would have important clinical significance as many PC patients succumb to metastatic disease. In summary, the grant proposed here will obtain the necessary pre- clinical data that will ultimately inform the use of this exciting new PC therapy, SBRT + IL-12MS, in an investigator led clinical trial.