权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Alpha particles combined with ATR inhibition to activate the immune system: mechanisms and pre-clinical translation

Alpha 粒子结合 ATR 抑制激活免疫系统：机制和临床前转化

基本信息

批准号：
10636348
负责人：
Gabriel Oliveira Sawakuchi
金额：
$ 52.02万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-12 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10636348
关键词：
ATR gene Address Affect Alpha Particle Emitter Alpha Particles Antigens Binding Brachytherapy Cell Cycle Cell Cycle Arrest Cell Maturation Cells Clinical Cytoplasm Cytotoxic T-Lymphocytes DNA Damage DNA Repair DNA Repair Inhibition DNA lesion Data Dendritic Cells Deposition Diffuse Diffusion Dose Gases Gene Activation High-LET Radiation IRF3 gene Immune Response Genes Immune response Immune signaling Immune system Immunologic Stimulation Immunologics Immunotherapy Impairment Innate Immune Response Interferon Type I Ionizing radiation Lesion Linear Energy Transfer Malignant Neoplasms Malignant neoplasm of pancreas Mediator Methods Mitosis Modality Outcome Pathway interactions Patient-Focused Outcomes Pharmaceutical Preparations Phase I Clinical Trials Photons Population Predisposition Production Prognosis Protons Radiation Radiation therapy Radioactive Radiopharmaceuticals Radium-224 Radon Research Role Rupture Seed Implantation Signal Transduction Solid Solid Neoplasm Stimulator of Interferon Genes T-Cell Activation TANK-binding kinase 1 Testing Tissues Transactivation Transcriptional Activation Translations Tumor Immunity Tumor Volume Water Work anti-CTLA4 anti-tumor immune response cancer subtypes cell killing combat cytokine density ds-DNA immune activation immune cell infiltrate immune checkpoint blockade immunoregulation improved in vivo inhibitor innovation interstitial ionization meter micronucleus mouse model novel pancreatic cancer model particle pharmacologic pre-clinical recruit response tool transcription factor tumor

项目摘要

One strategy to enhance the immune response to tumors is radiotherapy (RT). Recent data support that RT- induced micronuclei (MN) are intrinsically immunostimulatory, as ruptured MN releases double stranded DNA (dsDNA) eliciting the cycling GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) pathway. Although progress has been made in combining immune checkpoint blockade (ICB) with RT, relatively little is known about the physical mechanisms of RT that elicit immunostimulatory signals and how they can be har- nessed clinically in the context of DNA damage and DNA repair inhibition. Radiation with high ionization density (or linear energy transfer, LET) induces more clustered DNA lesions, more MN and higher cell kill compared to low-LET radiation. α-particles are characterized by their high-LET in contrast to photons and protons and may be ideal for creating high levels of MN and downstream enhanced activation of immunostimulatory signals through the cGAS-STING pathway. A novel modality to deliver α-particles has recently been successfully demon- strated in a phase I clinical trial using a method called diffusing alpha-emitters radiation therapy (DaRT). DaRT consists of interstitial radioactive seeds coated with radium-224, an α-particle emitter. The radium-224 decay chain is unique in that the decay products also emit α-particles and diffuse, allowing the α-particles’ dose to be deposited over 2-3 mm from the seed. Thus, multiple seeds implanted into a tumor allow the high-LET α-particle dose to be deposited within the entire tumor volume. In addition to radiation, pharmacologic inhibition of DNA repair affects the presence of MN. This inhibition of DNA repair can be created with drugs such as Ataxia telan- giectasia and Rad3 related (ATR) inhibitors (ATRi). The combination of an ATRi with α-particle-induced clustered DSB lesions may synergistically enhance the accumulation of MN, ultimately enhancing immunostimulatory sig- nals. These will be investigated with ICB to determine how to synergistically augment RT-induced antitumor immunity. We hypothesize that α-particles combined with an ATRi produces more MN, results in more cGAS binding to dsDNA and consequently potentiate robust antitumor immunity. We propose to: 1) Elucidate the mech- anisms by which cGAS binds to dsDNA in -particles+ATRi treated cells; 2) Elucidate the mechanisms by which -particles+ATRi induces immune signaling; and 3) Evaluate antitumor immunity from -particles+ATRi in vivo. Our research has the potential to define -particles as a tool to augment antitumor immune response, especially for tumors that are known to be unresponsive to ICB. Our proposed research is of critical relevance to address the poor prognosis associated with multiple advanced solid cancers that are immunologically cold. Our proposed work is innovative, in that it aims to define the effects of -particle-induced clustered DNA damage on tumors in the context of antitumor immunity. Our findings will elucidate the mechanisms behind immune modulation by high-LET radiation, which may ultimately guide the combined rational use of modalities that use high-LET radi- ation (including α-emitting radiopharmaceuticals), DNA repair inhibitors and ICB for aggressive cancers.

增强肿瘤免疫反应的一种策略是放疗（RT）。最近的数据支持RT-