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，少于5％（5年）的生存率当前涉及化学放射治疗的治疗方案。几乎所有胰腺癌患者最终发展转移性疾病，生存预后不佳。仍然有很大的机会为了提高胰腺癌患者的生活质量和结局的突破策略。最近的研究表明，质子疗法的成功和对质子RT的兴趣逐渐增长越来越多的证据表明对照片（XRT）的巨大益处。质子疗法的成功依赖精确地递送高剂量在肿瘤组织中，由于其Bragg峰的性质而保留正常组织同时保持与XRT相似的治疗优势。碳离子辐射疗法（CIRT）提供STEMP Bragg的峰值且散射较少，但也更高的LET（线性能量传递），导致更大的电离事件和更大的生物损害。我们假设更大的复杂DNA损伤也定义为相对 CIRT的生物学作用（RBE）可以诱导更强的免疫反应。在当前的建议中，我们正在测试当单独应用时，高LOT CIRT具有增强肿瘤免疫反应的独特能力的假设或与其他免疫治疗剂结合使用。我们的目标是确定免疫调节有效性与胰腺癌小鼠模型中的XRT相比，CIRT的CIRT。我们将测试高乳清对肿瘤的影响细胞以及局部和全身水平的免疫细胞。我们将关联生物学终点（例如DNA）双链断裂（DSB），复杂的DNA损伤和XRT/CIRT辐照的细胞中的克隆生存生存率它们在目标1下诱导免疫响应的能力。我们还将确定HDAC抑制是否增强 AIM 2中胰腺肿瘤细胞的抗原表现。在AIM 3下，我们将提高CIRT的效率使用检查点抑制剂并发治疗和抗原表现激活剂。关联。这些研究的成功完成可以确定意义，并帮助我们设计独特的免疫疗法与CIRT的结合疗法用于实体瘤。