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.

增强对肿瘤免疫响应的一种策略是放疗（RT）。最近的数据支持诱导的微核（MN）是本质上免疫刺激的，因为MN破裂释放双链DNA （dsDNA）引发循环GMP-AMP合酶（CGA）和干扰素基因（STING）途径的刺激剂。尽管在将免疫切口封锁（ICB）与RT结合在一起方面取得了进展，但相对较少的IS 知道引起免疫刺激信号的RT的物理机制以及它们如何构成在DNA损伤和DNA修复抑制作用的背景下，在临床上嵌套。辐射高电离密度（或线性能量转移，）与相比低电子辐射。 α粒子的特征是它们的高率与照片和质子形成对比，并且可能是创建高水平的MN和下游增强免疫刺激信号激活的理想选择穿过CGAS刺道。最近成功地传递了α粒子的新型方式使用称为扩散α发射剂辐射疗法（DART）的方法在I期临床试验中进行了验证。镖由涂有radium-224（α-粒子发射极辐射的放射性种子）组成。 radium-224衰减链的独特之处在于衰减产物还会发出α粒子和扩散，使α粒子的剂量为距离种子超过2-3毫米。这是植入肿瘤的多种种子允许高LETα颗粒将剂量沉积在整个肿瘤体积中。除了辐射，DNA的药物口语抑制维修会影响MN的存在。这种对DNA修复的抑制作用可以用诸如telan- telan- telan-的药物产生 gioctia and rad3相关（ATR）抑制剂（ATRI）。 ATRI与α-颗粒诱导的簇的组合 DSB病变可能会协同增强MN的积累，最终增强免疫刺激性SIG- 纳尔。这些将与ICB一起研究，以确定如何协同增强RT诱导的抗肿瘤免疫。我们假设α粒子与Atri结合产生更多的Mn，导致更多的CGA 与dsDNA结合，因此潜在的鲁棒抗肿瘤免疫。我们建议：1）阐明机甲 - CGA在粒子+Atri处理的细胞中与dsDNA结合的障碍； 2）阐明了该机制 粒子+ATRI诱导免疫信号传导； 3）评估来自粒子+attri体内的抗肿瘤免疫史。我们的研究有可能定义粒子作为增强抗肿瘤免疫激素的工具，尤其是对于已知对ICB无反应的肿瘤。我们提出的研究至关重要，以解决与免疫学上的多种晚期固体癌症相关的预后不良。我们提出的工作是创新的，因为它旨在定义颗粒引起的聚类DNA损伤对肿瘤中肿瘤的影响抗肿瘤免疫的背景。我们的发现将通过高LET辐射，最终可能指导使用高LET辐射的方式合理使用合理使用 ation（包括发射α的放射性药物），DNA修复抑制剂和ICB用于侵袭性癌症。