MRI-Guided Cryoablation and Imaging-Guided Intratumoral Delivery of STING Agonist Immunotherapy to Target Localized and Metastatic Canine Osteosarcoma

MRI 引导冷冻消融和成像引导 STING 激动剂肿瘤内递送免疫疗法治疗局部和转移性犬骨肉瘤

• 批准号: 9980073
• 负责人: DARA L KRAITCHMAN
• 金额: $ 63.74万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9980073
• 关键词: Academic Medical Centers; Adaptive Immune System; Adult; Agonist; Amino Acid Sequence; Amputation; Anatomy; Animal Hospitals; Animal Model; Antigen-Presenting Cells; Antigens; Biological Assay; Biological Models; Biotechnology; Bone neoplasms; Canis familiaris; Cells; Child; Client; Clinical; Clinical Trials; Cold Therapy; Collaborations; Combined Modality Therapy; Correlative Study; Cryosurgery; Cyclic Nucleotides; Disease; Disease Progression; Disease model; Distant; Equipment; Exposure to; Freezing; Future; Goals; Gold; Human; Immune; Immune response; Immune system; Immunity; Immunoassay; Immunohistochemistry; Immunologic Adjuvants; Immunologics; Immunooncology; Immunosuppression; Immunotherapy; In Situ; Incidence; Injections; Interferon Type I; Interferon-beta; Ionizing radiation; Learning; Magnetic Resonance Imaging; Malignant Childhood Neoplasm; Malignant Neoplasms; Maps; Modality; Modeling; Myeloid Cells; Necrosis; Nonmetastatic; Normal tissue morphology; Oncology; Operative Surgical Procedures; Outcome; Outcome Measure; Pathway interactions; Patient-Focused Outcomes; Patients; Phase I Clinical Trials; Positioning Attribute; Randomized; Recording of previous events; Recurrence; Safety; Secondary to; Solid Neoplasm; Stimulator of Interferon Genes; System; T-Lymphocyte; Technology; Testing; Time; Toxic effect; Translations; Treatment outcome; Tumor Antigens; Tumor Tissue; Tumor-infiltrating immune cells; Vaccines; Virus Diseases; adaptive immune response; anti-tumor immune response; base; bone; cancer therapy; cell injury; chemotherapy; clinically relevant; comparative; cytokine; ds-DNA; image guided; image guided therapy; imaging system; immune activation; immunoregulation; improved outcome; innovation; insight; macrophage; medical schools; meetings; model development; neoplastic cell; non-invasive imaging; novel; novel therapeutics; osteosarcoma; preservation; prevent; recruit; sarcoma; side effect; standard care; standard of care; treatment strategy; trial comparing; tumor; tumor ablation; young adult

Osteosarcoma (OSA) occurs in both children/young adults and in dogs, with an annual incidence of 450 and 25,000 cases, respectively, making dogs a useful comparative oncology model for the development of OSA treatments. Unfortunately, outcomes for patients with OSA have plateaued over the past three decades. Thus, new treatment approaches beyond the standard of care (SOC) surgery and chemotherapy are sorely needed. As a novel therapy for OSA, our group is developing Magnetic Resonance Imaging (MRI)-guided cryotherapy in conjunction with image-guided intratumoral injection of an immune adjuvant. To this end, we will perform a canine clinical trial comparing MRI-guided cryotherapy alone or in conjunction with intratumoral immune adjuvant administration in spontaneously occurring, non-metastatic, canine appendicular OSA. The proposed immune correlative studies will provide crucial insights into the mechanisms of immune regulation in OSA tumors and the immunologic impact of the therapies to guide future improvements. While cryotherapy directly kills OSA tumor cells, our intent is to activate the patient’s adaptive immune system against tumor antigens that are presented from the dying tumor cells, with the addition of intratumoral delivery of an immune adjuvant. Following local control surgery, we hypothesize that the primed adaptive immune response can delay or prevent the occurrence of metastatic disease, which is uniformly fatal. Using MRI, one can precisely determine the extent of tumor tissue that is frozen and killed by cryotherapy without exposure to ionizing radiation. Others have demonstrated an influx of macrophage and myeloid cells following cryoablation. Via intratumoral injection, we will deliver a novel Stimulator of Interferon Gene (STING) agonist following cryotherapy to activate the infiltrating innate immune cells. STING pathway activation results in extensive cytokine induction, the activation of antigen presenting cells, and subsequent priming of T cells. Our specific aims are: 1. To determine whether MRI-guided cryoablation of OSA generates an immune response based on cytokine assays, immunohistochemistry (IHC), and immunoassays that can prevent metastatic progression, as assessed by non-invasive imaging and thereby increase overall survival compared to SOC treatment. 2. To characterize the immune response and safety of CT-guided STING agonist intratumoral administration in canine OSA. 3. To determine whether MRI-guided cryoablation combined with CT-guided intratumoral STING agonist administration prevents metastatic disease progression and prolongs survival compared with SOC treatment for OSA. The high incidence of OSA in dogs with a high rate of metastatic disease provides an ideal animal model with which to study this novel image-guided treatment of OSA using clinically relevant imaging systems with the potential for rapid translation and application in other solid tumors.

骨肉瘤（OSA）发生在儿童/年轻人和狗中，年发病率为450 和25,000例病例，使狗成为开发的有用的比较肿瘤学模型 OSA治疗。不幸的是，OSA患者的结果在过去三个 几十年。这是超出护理标准（SOC）手术和 迫切需要化学疗法。作为OSA的新型疗法，我们的小组正在发展磁性 共振成像（MRI）指导的冷冻疗法与图像引导的肿瘤内注射 免疫调节。为此，我们将进行比较MRI引导的犬临床试验 单独的冷冻疗法或与肿瘤内免疫调节自发的给药 发生，非转移性的犬阑尾OSA。提出的免疫相关研究将 提供有关OSA肿瘤免疫调节机制和免疫学的重要见解 疗法指导未来改进的影响。冷冻疗法直接杀死OSA肿瘤细胞，但 我们的目的是激活患者针对肿瘤抗原的适应性免疫系统 从垂死的肿瘤细胞中加入免疫调节的肿瘤内递送。下列的 局部控制手术，我们假设启动的适应性免疫响应可以延迟或防止 使用MRI，可以精确确定 通过冷冻疗法冷冻和杀死的肿瘤组织的程度，而不会暴露于电离辐射。 其他人在冷冻化后显示出巨噬细胞和髓样细胞的影响。通过 肿瘤内注射，我们将提供一个新型的干扰素基因（Sting）激动剂的刺激剂 冷冻疗法激活浸润的先天免疫细胞。刺激途径激活导致 广泛的细胞因子诱导，抗原呈递细胞的激活以及随后的T启动 细胞。我们的具体目的是：1。确定MRI指导的OSA的冷冻化是否会产生 基于细胞因子测定，免疫组织化学（IHC）和免疫测定的免疫反应 通过非侵入性成像评估，预防转移进展，从而总体上增加 与SOC治疗相比，生存。 2。表征CT引导的免疫反应和安全性 犬OSA中的刺激性激动剂内给药。 3。确定MRI引导是否 冷冻保障与CT引导的肿瘤内刺激性激动剂给药可防止转移 与OSA的SOC治疗相比，疾病进展并延长了生存。高事件 转移性疾病率高的狗的OSA提供了一个理想的动物模型来研究 这种新型图像引导的OSA使用具有潜在潜力的临床相关成像系统对OSA的处理 用于在其他实体瘤中的快速翻译和应用。