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射治疗（RT），最近的数据支持放射治疗。诱导微核 (MN) 本质上具有免疫刺激作用，因为破裂的 MN 会释放双链 DNA (dsDNA) 引发循环 GMP-AMP 合酶 (cGAS) 和干扰素基因刺激剂 (STING) 途径。尽管免疫检查点阻断 (ICB) 与 RT 相结合方面已取得进展，但进展相对较少。了解放疗引发免疫刺激信号的物理机制以及如何利用它们临床上需要高电离密度辐射来抑制 DNA 损伤和 DNA 修复。（或线性能量转移，LET）与相比，诱导更多的聚集性 DNA 损伤、更多的 MN 和更高的细胞杀伤与光子和质子相比，低 LET 辐射的特点是其高 LET 辐射。是产生高水平 MN 和下游免疫刺激信号增强激活的理想选择最近成功地证明了一种通过 cGAS-STING 途径传递 α 粒子的新方式。在一项 I 期临床试验中，该试验使用了一种称为扩散 α 发射体放射治疗 (DaRT) 的方法。由涂有镭 224 的间隙放射性种子组成，镭 224 是一种 α 粒子发射体。链的独特之处在于衰变产物也会发射α粒子并扩散，从而使α粒子的剂量可以沉积在距离种子 2-3 毫米的地方，因此，植入肿瘤中的多个种子可以产生高 LET α 粒子。剂量沉积在整个肿瘤体积内除了放射之外，DNA 的药理学抑制。修复会影响 MN 的存在，可以使用 Ataxia telan- 等药物来抑制 DNA 修复。 giectasia 和 Rad3 相关 (ATR) 抑制剂 (ATRi) ATRi 与 α 粒子诱导的簇的组合。 DSB 损伤可能协同增强 MN 的积累，最终增强免疫刺激信号这些将与 ICB 一起进行研究，以确定如何协同增强 RT 诱导的抗肿瘤作用。我们追求 α 粒子与 ATRi 结合产生更多的 MN，从而产生更多的 cGAS。与 dsDNA 结合，从而增强强大的抗肿瘤免疫力。我们建议：1）阐明其机制。 cGAS 在 α-粒子+ATRi 处理的细胞中与 dsDNA 结合的机制 2) 阐明其机制； α-颗粒+ATRi诱导免疫信号传导；以及3)评估α-颗粒+ATRi体内的抗肿瘤免疫。我们的研究有可能将 α 粒子定义为增强抗肿瘤免疫反应的工具，特别是对于已知对 ICB 无反应的肿瘤，我们提出的研究对于解决这一问题至关重要。与免疫冷的多种晚期实体癌相关的不良预后。这项工作具有创新性，因为它的目的是确定 α 粒子诱导的簇状 DNA 损伤对肿瘤的影响我们的研究结果将阐明免疫调节背后的机制。高 LET 辐射，这可能最终指导使用高 LET 辐射的方式的综合合理使用用于治疗侵袭性癌症的药物（包括 α 发射放射性药物）、DNA 修复抑制剂和 ICB。