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: 10610324
• 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/10610324
• 关键词: Address; Animals; Antitumor Response; Breast; CD8-Positive T-Lymphocytes; Cancer Burden; Cancer Etiology; Cells; Cessation of life; Clinical; Clinical Trials; Colorectal; Data; Development; Diagnosis; Disease; Distal; Early Diagnosis; 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; 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 Efficacy; Treatment Protocols; Tumor Burden; Tumor Immunity; Tumor Promotion; Tumor-associated macrophages; Tumor-infiltrating immune cells; United States; advanced disease; advanced pancreatic cancer; anti-tumor immune response; antitumor effect; arm; cancer therapy; carcinogenesis; clinical effect; clinical translation; clinically relevant; clinically significant; combinatorial; controlled release; curative treatments; cytokine; cytotoxicity; effective therapy; efficacy evaluation; immunoregulation; improved; in vivo; infancy; innovation; instrument; neoplastic cell; novel strategies; novel therapeutics; palliative; pancreatic cancer model; pancreatic cancer patients; pancreatic neoplasm; pre-clinical; programs; 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) 是美国第三大最常见的癌症死亡原因，死亡率高达 5- 即使诊断患有 PC 的患者的年总生存率也有限。 因此，迫切需要改进现有疗法或开发新策略。 一种称为立体定向放射治疗 (SBRT) 的新兴策略可提高 PC 患者的总体生存率。 在短时间内提供更高剂量的辐射，已证明具有优越的肿瘤效果 与传统放射治疗相比，该应用将扩展这些发现和 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 因此，我们的首要假设是 SBRT。 可以通过调节 PC 中的免疫反应来增强疗效。为了测试这一点，我们开发了两种。 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) 使用一种称为微球 (MS) 的尖端技术封装这些聚合物。 IL-12 在瘤内注射时可缓慢、连续释放细胞因子 10-14 天。 建立了 PC 的临床前原位模型，其中胰腺肿瘤采用临床治疗 使用最近收购的小动物辐射研究平台（SARRP）进行 SBRT 的相关时间表； 与 SBRT 结合时临床放射肿瘤学中使用的仪器非常相似。 IL-12MS 在 2 个不同的国家中观察到前所未有的肿瘤负荷降低甚至治愈 该提案将建立在这些令人鼓舞的研究的基础上并解决作用机制。 在原发肿瘤（目标 1）和 PC 转移的主要部位（目标 2）中，我们。 将确定 SBRT + IL-12MS 是否可以改变典型的免疫抑制肿瘤微环境 (TME) 我们预测，使用 2 个独立的原位模型和一个自发 PC 模型将其转化为免疫刺激模型。 SBRT + IL-12MS 增强 CD8+ T 细胞的抗肿瘤能力，同时复极抑制肿瘤 - 在目标 2 中，相关巨噬细胞 (TAM) 进入细胞，直接或间接促进肿瘤破坏。 我们将探讨胰腺局部 SBRT + IL-12MS 治疗是否会调节肝脏 我们预测局部 SBRT + IL-12MS 会增强全身性。 抗肿瘤免疫，进而通过上调细胞因子 IFNγ 和 防止转移的形成，这对于许多 PC 具有重要的临床意义。 总之，这里提出的补助金将获得必要的预先准备。 临床数据最终将为研究人员使用这种令人兴奋的新型 PC 疗法（SBRT + IL-12MS）提供信息 主导临床试验。

项目成果

Development of Terahertz Imaging Markers for Pancreatic Ductal Adenocarcinoma using Maximum A Posteriori Probability (MAP) Estimation.

• DOI: 10.1021/acsomega.2c07080
• 发表时间: 2023-03-21
• 期刊: ACS OMEGA
• 影响因子: 4.1
• 作者: Chakraborty, Debamitra;Mills, Bradley N.;Cheng, Jing;Komissarov, Ivan;Gerber, Scott A.;Sobolewski, Roman
• 通讯作者: Sobolewski, Roman