Relative Immunological Effectiveness (RIE) of Carbon Ion Radiation Therapy for Pancreatic Cancer

碳离子放射治疗胰腺癌的相对免疫有效性（RIE）

基本信息

批准号：
10544737
负责人：
Chandan Guha
金额：
$ 47.31万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-14 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10544737
关键词：
Ablation Address Anti-CD40 Antibodies Antigen Presentation Biological C57BL/6 Mouse Cancer Etiology Cancer Patient Carbon Carbon ion Cell surface Cells Cessation of life Characteristics Clinical Coculture Techniques Combination immunotherapy Combined Modality Therapy Complex DNA DNA Damage DNA Double Strand Break DNA Viruses Disease Disseminated Malignant Neoplasm Distant Metastasis Dose Effectiveness Engineering Epigenetic Process Event Experimental Designs Exposure to Fire - disasters Genetically Engineered Mouse Goals Heavy Ions High-LET Radiation Histocompatibility Antigens Class I Histone Deacetylase Histone Deacetylase Inhibitor Immune Immune Evasion Immune response Immunity Immunocompetent Immunologics Immunosuppression Immunotherapeutic agent Immunotherapy In Vitro Infiltration Interferon Type I Irradiated tumor Linear Energy Transfer Local Therapy MHC Class I Genes Malignant Neoplasms Malignant neoplasm of pancreas Measurement Measures Methods Modality Modeling Molecular Mus Myeloid Cells Natural Immunity Nature Neoplasm Metastasis Normal tissue morphology Organ Outcome Patients Pattern Photons Phototherapy Prediction of Response to Therapy Proteins Protons Quality of life Radiation Radiation therapy Radio Relative Biological Effectiveness Reporting Roentgen Rays Role Signal Transduction Solid Neoplasm Splenocyte Survival Rate System T-Cell Activation T-Lymphocyte TNFRSF5 gene Techniques Testing Therapeutic Travel Treatment Protocols Treatment outcome Tumor Antigens Tumor Cell Line Tumor Immunity Tumor Tissue Unresectable Vaccinated Viral X-Ray Therapy absorption adaptive immunity anti-PD-1 anti-PD1 antibodies antigen processing chemoradiation clinical efficacy clinically relevant compare effectiveness design dosimetry epigenetic silencing exhaust fighting immunodeficient mouse model immunogenic immunoregulation improved in vivo indexing inhibitor interest ionization irradiation kinetic model member mouse model neoplastic cell pancreas radiation therapy pancreatic cancer cells pancreatic cancer model pancreatic cancer patients pancreatic neoplasm particle particle beam prognostic of survival programmed cell death protein 1 programs proton therapy randomized trial repaired response standard of care success tumor tumor microenvironment tumor xenograft tumor-immune system interactions

项目摘要

Abstract Pancreatic cancer is the leading cause of cancer-related death with less than 5% (5-year) survival rate with current treatment regimen involving chemo-radiation therapy. Almost all patients with pancreatic cancer eventually develop metastatic disease with poor prognosis for survival. There remains a significant opportunity for breakthrough strategies to improve the quality of life and outcomes for pancreatic cancer patients. Recent studies have shown some success with proton therapy and the interest in proton RT has grown progressively with increasing evidence indicating substantial benefit over photons (XRT). The success of proton therapy relies on precise delivery of high dose in tumor tissue, sparing normal tissue due to the nature of its Bragg’s peak, while maintaining similar therapeutic advantages as XRT. Carbon ion radiation therapy (CIRT) offers steep Bragg’s peak and less scatter but also higher LET (Linear Energy Transfer), resulting in greater ionizing events and greater biological damage. We hypothesize that greater complex DNA damage also defined as relative biological effect (RBE) of CIRT can induce stronger immune response. In the current proposal, we are testing the hypothesis that high-LET CIRT has unique ability of enhancing tumor immune response, when applied alone or combine with other immunotherapeutic agents. Our goal is to determine the immunomodulation effectiveness of CIRT compared to XRT in pancreatic cancer mouse model. We will test the effect of high LET-CIRT on tumor cells as well as the immune cells at local and systemic level. We will correlate biological end points such as DNA double strand breaks (DSB), complex DNA damage and clonogenic survival in XRT/CIRT-irradiated cells with their ability to induce immune response under aim 1. We will also determine whether HDAC inhibition enhances antigen presentation by pancreatic tumor cells in aim 2. Under aim 3, we will enhance the efficacy of CIRT by reprogramming tumor microenvironment (TME) using concurrent treatment with check point inhibitors and antigen presentation activators. Relevance. Successful completion of these studies could establish the significance and help us design unique combination therapy of immunotherapy with CIRT for solid tumors.

抽象的胰腺癌是癌症相关死亡的主要原因，其 5 年生存率低于 5% 目前的治疗方案几乎所有胰腺癌患者都采用化学放射治疗。最终发展为预后不良的转移性疾病，仍有很大的生存机会。寻求改善胰腺癌患者生活质量和预后的突破性策略。研究表明质子治疗取得了一些成功，人们对质子放疗的兴趣逐渐增长越来越多的证据表明质子治疗的成功依赖于光子治疗 (XRT) 的巨大益处。在肿瘤组织中精确输送高剂量，由于其布拉格峰的性质而不会影响正常组织，同时保持与 XRT 类似的治疗优势。布拉格峰值和较少的散射，但也具有较高的 LET（线性能量转移），从而导致更大的电离事件我们认为更大的复杂 DNA 损伤也被定义为相对的。 CIRT的生物效应（RBE）可以诱导更强的免疫反应，在目前的提案中，我们正在测试。假设高 LET CIRT 单独应用时具有增强肿瘤免疫反应的独特能力或与其他免疫治疗药物联合使用我们的目标是确定免疫调节的有效性。我们将在胰腺癌小鼠模型中测试高 LET-CIRT 对肿瘤的影响。我们将在局部和全身水平上关联细胞以及免疫细胞。 XRT/CIRT 照射细胞中的双链断裂 (DSB)、复杂 DNA 损伤和克隆存活它们在目标 1 下诱导免疫反应的能力。我们还将确定 HDAC 抑制是否增强目标 2 中胰腺肿瘤细胞的抗原呈递。根据目标 3，我们将通过以下方式增强 CIRT 的功效：使用检查点抑制剂同时治疗来重新编程肿瘤微环境（TME）抗原呈递激活剂。成功完成这些研究可以确定其重要性并帮助我们设计独特的产品。免疫治疗与 CIRT 联合治疗实体瘤。