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，令人沮丧的是 一年的总体存活率为8%。被诊断为PC的患者的治疗选择有限，即使 很早就发现了。因此，迫切需要改进现有的治疗方法或开发新的战略来 提高PC患者的总体存活率。一种名为立体定向全身放射治疗(SBRT)的新兴策略， 在短时间内给予较高剂量的辐射，已显示出较好的肿瘤 对照常规放射治疗。本申请将在这些调查结果的基础上展开 在SBRT中纳入了新的范式转变，压倒性地展示了免疫系统的关键作用 在调节这种方式的抗肿瘤作用方面。因此，我们的首要假设是SBRT 可通过调节PC中的免疫反应来提高疗效。为了测试这一点，我们开发了两个 创新方法：首先，我们通过传递免疫刺激细胞因子来激活抗肿瘤免疫细胞 白介素12(IL-12)使用一种名为微球(MS)的尖端技术。这些聚合物包覆了 IL-12，当肿瘤内注射时，提供10-14天的缓慢、持续的细胞因子释放。第二, 建立了临床前胰腺癌原位移植模型，其中胰腺肿瘤被临床应用 使用最近获得的小动物辐射研究平台(SARRP)进行SBRT的相关时间表； 与临床放射肿瘤学中使用的仪器非常相似的仪器。当SBRT与 IL-12MS，前所未有的减轻了肿瘤负担，甚至治愈了，在两个不同的 正位PC模型。这项提议将以这些令人鼓舞的研究为基础，并解决行动机制问题。 原发肿瘤(目标1)和PC转移的主要部位--肝脏(目标2)。在目标1中，我们 将确定SBRT+IL-12MS是否可以转变典型的免疫抑制肿瘤微环境(TME) 用2个单独的原位PC模型和1个自发PC模型进行免疫刺激。我们预测 SBRT+IL-12MS增强CD8+T细胞的抗肿瘤能力 相关的巨噬细胞(TAM)转化成细胞，直接或间接地支持肿瘤的破坏。在目标2中， 我们将探讨胰腺局部SBRT+IL-12MS治疗是否对肝脏有调节作用 破坏转移的微环境。我们预测局部SBRT+IL-12MS增强全身性 抗肿瘤免疫，进而通过上调细胞因子干扰素γ和 防止肿瘤转移。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，这里建议的赠款将获得必要的预先- 临床数据，最终将在研究人员中使用这种令人兴奋的新PC疗法，SBRT+IL-12MS 主导临床试验。

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.