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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：
10158123
负责人：
Chandan Guha
金额：
$ 56.41万
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/10158123
关键词：
Ablation Address Anti-CD40 Antibodies Antigen Presentation Antiviral Agents 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 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 Immunotherapeutic agent Immunotherapy In Vitro Interferon Type I Ions Irradiated tumor Linear Energy Transfer Local Therapy MHC Class I Genes Malignant Neoplasms Malignant neoplasm of pancreas Measurement Measures Methods Modeling Molecular Mus Myeloid Cells Natural Immunity Nature Neoplasm Metastasis Normal tissue morphology Organ Outcome Patients Pattern Photons Phototherapy Prognosis 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 Tissue Unresectable Vaccinated X-Ray Therapy adaptive immunity anti-PD-1 anti-PD1 antibodies antigen processing base chemoradiation clinical efficacy clinically relevant compare effectiveness design epigenetic silencing exhaust experimental study fighting immunodeficient mouse model immunogenic immunoregulation improved in vivo indexing inhibitor/antagonist interest irradiation kinetic model member mouse model neoplastic cell pancreatic cancer cells pancreatic cancer model pancreatic cancer patients pancreatic neoplasm particle particle beam programmed cell death protein 1 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.

摘要