TLR5 enhancement of liver-directed radiotherapy plus immune checkpoint blockade against irradiated liver metastasis and abscopal tumors

TLR5增强肝脏定向放疗加免疫检查点阻断治疗受照射的肝转移和远隔肿瘤

• 批准号: 10630642
• 负责人: Craig M. Brackett
• 金额: $ 72万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-09 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10630642
• 关键词: Abscopal effect; Address; Aftercare; Agonist; Antibodies; CD8-Positive T-Lymphocytes; CT26; Cancer Etiology; Cancer Patient; Cell Death; Cell surface; Cessation of life; Clinic; Clinical; Clinical Data; Colon; Colorectal Cancer; Combined Modality Therapy; Cytoplasm; Disease; Ensure; FDA approved; Flagellin; Gene Expression; Genetic; Goals; Hepatocyte; Human; Immune; Immunotherapeutic agent; Immunotherapy; Inflammasome; Injections; Innovative Therapy; Interferon Type II; Interferons; Irradiated tumor; Letters; Link; Liver; Malignant Neoplasms; Measures; Mediating; Metastatic Neoplasm to the Liver; Modeling; Mus; Neoplasm Metastasis; Normal tissue morphology; Operative Surgical Procedures; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Pre-Clinical Model; Publishing; Radiation; Radiation Toxicity; Radiation therapy; Radioimmunotherapy; Research; Rodent; Safety; Salmonella; Sampling; Shapes; Signal Transduction; Site; Source; T cell response; TLR5 gene; Testing; Time; Translating; Treatment Efficacy; Tumor Immunity; Work; anti-CTLA4; anti-PD-1; colon cancer metastasis; cytokine; effective therapy; genetic signature; healthy volunteer; immune checkpoint blockade; immunomodulatory therapies; immunoregulation; improved; innovation; melanoma; neoantigens; neutrophil; nonhuman primate; novel; novel therapeutics; pharmacologic; pre-clinical; pre-clinical therapy; response; survival outcome; therapy outcome; treatment response; tumor; tumor-immune system interactions

The liver is a frequent site of metastasis for several cancers and when this occurs, it is associated with poor response to immunotherapy. Liver-directed radiotherapy (RT) is a non-traditional immune modulating therapy that improves immune checkpoint blockade (ICB, αPD-1 or αPD-1/αCTLA-4) mediated control of liver metastasis and non-irradiated abscopal tumors. Unfortunately, enhanced tumor control following liver-directed radiotherapy and ICB is often short-lived for irradiated tumors and unpredictable for non-irradiated tumors. Thus, novel immunotherapeutic approaches that can stimulate antitumor immunity in the liver have the potential to boost liver-directed RT plus ICB mediated control of irradiated and non-irradiated abscopal tumors. Toward this goal, we are harnessing the ability of the toll-like receptor (TLR) 5 pathway to signal in the liver more so than other sites. Hepatocytes sense Salmonella flagellin and our derivative called entolimod through cell surface TLR5 and cytoplasmic NAIP5 inflammasome. Importantly, systemically administered entolimod was shown to be safe in rodents, non-human primates, and Phase I safety trials in healthy volunteers and cancer patients cumulatively involving nearly 200 subjects. Our prior work showed that entolimod protects normal tissues but not tumors from radiation toxicities and stimulates CD8+ T cell dependent antitumor immunity against preclinical models of liver metastasis. Here, we showed that entolimod enhances liver-directed RT in pre-clinical models mirroring advanced liver metastasis and that this occurs via a poorly resolved Nφ dependent mechanism. The outstanding questions that this proposal seeks to address are: 1) what is the impact of entolimod on liver-directed RT plus ICB mediated control of liver metastasis and abscopal tumors?; 2) how does the TLR5-NAIP5 pathway in Nφ support antitumor immunity post liver-directed RT and ICB?; and 3) what is the translational relevance of the TLR5-NAIP5 pathway plus RT in human tumors and Nφ? Our central hypothesis is that entolimod enhances liver-directed RT plus ICB via Nφ-dependent release of IFN-γ, a cytokine that can be released by activated Nφ to support antitumor immunity. To test our central hypothesis, we propose three interactive aims: 1) To unveil the impact of entolimod on liver-directed RT plus ICB mediated control of liver metastasis and abscopal tumors; 2) To elucidate the mechanism by which the TLR5-NAIP5 pathway in Nφ triggers antitumor immunity post liver- directed RT and ICB; and 3) To determine the translational relevance of the TLR5-NAIP5 pathway plus RT in fresh human colorectal cancer and melanoma samples and patient-matched Nφ. The impact of this work lies in the fact that all components of this therapy are in the clinic for cancer patients thereby ensuring the feasibility to combine these components into a novel and innovative therapy to improve the dire survival outcomes associated with liver metastasis.

肝脏是几种癌症的常见转移部位，当这种情况发生时，它与 对免疫治疗的反应。肝定向放射治疗是一种非传统的免疫调节疗法 这改善了免疫检查点阻断(ICb、αPD-1或αPD-1/αCTLA-4)介导的肝转移控制 和未受照射的远端肿瘤。不幸的是，肝脏定向放射治疗后肿瘤控制增强 对于受照射的肿瘤，ICB通常是短暂的，而对于未受照射的肿瘤，ICB往往是不可预测的。因此，小说 可以刺激肝脏抗肿瘤免疫的免疫治疗方法有可能增强 肝定向放射治疗加ICB介导的放射和非放射异位肿瘤的控制。为了实现这个目标， 我们正在利用Toll样受体(TLR)5途径在肝脏中更多地发出信号的能力 网站。肝细胞通过细胞表面TLR5和TLR5感觉鞭毛沙门氏菌和我们的衍生物entolimod 胞浆NAIP5炎症体。重要的是，全身给药的恩托莫特在 啮齿动物、非人类灵长类动物和I期安全试验在健康志愿者和癌症患者中的累积 涉及近200名受试者。我们先前的工作表明，恩托莫特可以保护正常组织，但不能保护肿瘤 辐射毒性和刺激CD8+T细胞依赖的抗肿瘤免疫对临床前肝脏模型的作用 转移。在这里，我们证明了恩托莫特在临床前模型中增强了肝脏导向的RT 晚期肝转移是通过未得到很好解决的N-φ依赖机制发生的。杰出的 这项提案试图解决的问题是：1)恩托莫特对肝脏导向RT Plus的影响是什么 ICB介导的肝转移和远端肿瘤的控制；2)TLR5-NAIP5通路在Nφ中是如何发挥作用的 支持肝脏导向RT和ICB后的抗肿瘤免疫？以及3)翻译上的相关性是什么 TLR5-NAIP5途径加RT在人肿瘤和N-φ？我们的中心假设是恩托莫特能增强 肝脏导向的RT+ICB通过N-φ依赖的干扰素-γ的释放，一种可由激活的N-φ释放的细胞因子 以支持抗肿瘤免疫。为了验证我们的中心假设，我们提出了三个互动目标：1)揭示 恩托莫特对肝定向放射治疗加ICB介导的肝转移和异位肿瘤控制的影响； 2)探讨N-φ中TLR5-NAIP5途径在肝移植后抗肿瘤免疫中的作用机制。 定向RT和ICB；3)确定TLR5-NAIP5途径与RT在 新鲜的人类结直肠癌和黑色素瘤样本和患者匹配的Nφ。这项工作的影响在于 事实上，这种疗法的所有组成部分都在为癌症患者提供临床服务，从而确保了 将这些成分结合到一种新颖的创新疗法中，以改善相关的可怕生存结果 有肝脏转移。