Development of a New Strategy to Treat Locally Advanced Pancreatic Cancer

开发治疗局部晚期胰腺癌的新策略

• 批准号: 10377966
• 负责人: Scott Andrew Gerber
• 金额: $ 39.22万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10377966
• 关键词: Address; Animals; Antitumor Response; Breast; CD8-Positive T-Lymphocytes; Cancer Burden; Cancer Etiology; Cells; Cessation of life; Clinical; Clinical Data; Clinical Trials; Colorectal; Development; Diagnosis; Disease; Distal; Encapsulated; Excision; Grant; Hepatic; Immune; Immune response; Immune system; Immunosuppression; Immunotherapy; Individual; Interferon Type II; Interleukin-12; Laboratories; Liver; Local Therapy; Lung; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Metastatic Neoplasm to the Liver; Metastatic to; Microspheres; Modality; Modeling; Myelogenous; Myeloid Cells; Nature; Neoplasm Metastasis; Operative Surgical Procedures; Organ; Pancreas; Patients; Polymers; Primary Neoplasm; Prognosis; Quality of life; Radiation; Radiation Dose Unit; Radiation Oncology; Radiation Tolerance; Radiation therapy; Research; Research Personnel; Role; Schedule; Site; T-Lymphocyte; Technology; Testing; Time; Toxic effect; Treatment Protocols; Tumor Burden; Tumor Immunity; Tumor-associated macrophages; United States; advanced disease; advanced pancreatic cancer; anti-tumor immune response; antitumor effect; arm; cancer therapy; clinical effect; clinical translation; clinically relevant; clinically significant; combinatorial; controlled release; curative treatments; cytokine; cytotoxicity; effective therapy; efficacy evaluation; improved; in vivo; infancy; innovation; instrument; neoplastic cell; novel strategies; novel therapeutics; palliative; pancreatic cancer model; pancreatic cancer patients; pancreatic neoplasm; pre-clinical; radioresistant; therapy development; tool; tumor; tumor microenvironment; tumor-immune system interactions

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.

胰腺癌（PC）是美国癌症死亡的第三个最常见原因，5-- 年总生存期8％。对于被诊断为PC的人的治疗选择有限，即使 提早检测到。结果，至关重要的是改善现有疗法或制定新策略以 增加PC患者的总体存活率。一种称为立体定向身体放射疗法（SBRT）的新兴策略， 如果在短时间内递送较高剂量的辐射，则表现出上肿瘤 与常规放疗相比，控制。此应用程序将扩展这些发现，并 在SBRT中纳入新的范式转移，绝大多数表现出免疫系统的关键作用 在介导这种方式的抗肿瘤作用时。因此，我们的总体假设是SBRT 可以通过调节PC中的免疫反应来增强功效。为了测试这一点，我们开发了两个 创新方法：首先，我们通过递送免疫刺激性细胞因子激活了抗肿瘤免疫力 白介素12（IL-12）使用称为微球（MS）的尖端技术。这些聚合物封装 IL-12，当肿瘤内注射时，可以缓慢，连续释放细胞因子10-14天。第二， 建立了PC的临床前矫置模型，在胰腺肿瘤中用诊所处理 SBRT的相关时间表使用最近获得的小型动物辐射研究平台（SARRP）；一个 与临床辐射肿瘤学中使用的仪器相似。当SBRT与 在2种不同 原位PC型号。该提议将基于这些令人鼓舞的研究并解决行动机制 在原发性肿瘤（AIM 1）和PC转移的主要位点，肝脏（AIM 2）。在AIM 1中，我们 将确定SBRT + IL-12MS是否可以转换典型的免疫抑制肿瘤微环境（TME） 使用2种独立的原位和一个发起的PC模型进行免疫刺激性。我们预测 SBRT + IL-12MS增强了CD8 + T细胞的抗肿瘤能力以及重新极化抑制性肿瘤 相关的巨噬细胞（TAM）直接或间接增强肿瘤破坏的细胞。在AIM 2中， 我们将探索胰腺局部化SBRT + IL-12ms治疗是否可以调节肝 微环境破坏转移。我们预测局部的SBRT + IL-12MS电势系统性 抗肿瘤免疫学，进而通过上调细胞因子IFNγ和 防止建立转移。这将具有重要的临床意义，因为很多PC 患者屈服于转移性疾病。总而言之，此处提出的赠款将获得必要的前 最终将在研究人员中最终告知这种令人兴奋的新PC疗法SBRT + IL-12MS的临床数据 LED临床试验。