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: 10633064
• 负责人: DARA L KRAITCHMAN
• 金额: $ 61.53万
• 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/10633064
• 关键词: Academic Medical Centers; Adaptive Immune System; Adult; Agonist; Amino Acid Sequence; Amputation; Anatomy; Animal Hospitals; Animal Model; Antigen Presentation; Antigen-Presenting Cells; Biological Assay; Biological Models; Biotechnology; Bone neoplasms; Canis familiaris; Cells; Child; Client; Clinical Trials; Cold Therapy; Collaborations; Combined Modality Therapy; Correlative Study; Cryosurgery; Disease; Disease Progression; Distant; Equipment; Exposure to; Freezing; Future; Goals; Human; Immune; Immune response; Immune system; Immunity; Immunoassay; Immunohistochemistry; Immunologic Adjuvants; Immunologics; Immunooncology; Immunosuppression; Immunotherapy; Incidence; Infiltration; Injections; Interferon Type I; Interferon-beta; Ionizing radiation; Learning; Macrophage; Magnetic Resonance Imaging; Malignant Childhood Neoplasm; Malignant Neoplasms; Maps; Metastatic/Recurrent; Modality; Modeling; Myeloid Cells; Necrosis; Nonmetastatic; Normal tissue morphology; Nucleotides; Oncology; Operative Surgical Procedures; Outcome; Pathway interactions; Patient-Focused Outcomes; Patients; Phase I Clinical Trials; Positioning Attribute; Randomized; Recording of previous events; Safety; Secondary to; Solid Neoplasm; Stimulator of Interferon Genes; System; T-Lymphocyte; Technology; Testing; Toxic effect; Translations; Tumor Antigens; Tumor Tissue; Virus Diseases; adaptive immune response; anti-tumor immune response; bone; cancer therapy; cell injury; chemotherapy; clinical outcome measures; clinically relevant; comparative; cytokine; image guided; image guided therapy; image translation; imaging system; immune activation; immune cell infiltrate; immunoregulation; improved; improved outcome; in situ vaccine; innovation; insight; medical schools; meetings; model development; neoplastic cell; non-invasive imaging; novel; novel therapeutic intervention; novel therapeutics; osteosarcoma; preservation; prevent; recruit; sarcoma; side effect; standard care; standard of care; treatment and outcome; 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/年轻人和狗身上，年发病率为450 和25,000例，使狗成为发展的有用的比较肿瘤学模型 阻塞性睡眠呼吸暂停综合症的治疗。不幸的是，在过去的三年中，阻塞性睡眠呼吸暂停综合症患者的治疗结果一直停滞不前 几十年。因此，新的治疗方法超越了标准护理(SOC)手术和 化疗是迫切需要的。作为治疗阻塞性睡眠呼吸暂停综合征的一种新疗法，我们团队正在开发磁力疗法 磁共振成像(MRI)引导的冷冻治疗联合图像引导的肿瘤内注射 一种免疫佐剂。为此，我们将进行一项犬类临床试验，比较核磁共振引导下的 冷冻治疗单独或联合瘤内免疫佐剂自发给药 发生的，非转移性的，犬的附件OSA。拟议的免疫相关研究将 为OSA肿瘤的免疫调节机制和免疫学提供了重要的见解 治疗的影响，以指导未来的改进。虽然冷冻治疗可以直接杀死OSA肿瘤细胞， 我们的目的是激活患者的适应性免疫系统，以对抗呈现的肿瘤抗原 从垂死的肿瘤细胞中分离出来，并在肿瘤内注入免疫佐剂。跟随 局部控制手术，我们假设启动的适应性免疫反应可以延迟或防止 转移性疾病的发生，这都是致命的。使用核磁共振成像，人们可以精确地确定 不暴露在电离辐射下通过冷冻治疗而被冷冻和杀死的肿瘤组织的范围。 其他研究表明，冷冻消融后巨噬细胞和髓系细胞大量涌入。通过 瘤内注射，我们将提供一种新的干扰素基因刺激物(STIN)激动剂如下 冷冻疗法激活正在渗透的先天免疫细胞。刺痛通路激活导致 广泛的细胞因子诱导，抗原提呈细胞的激活，以及随后T细胞的启动 细胞。我们的具体目标是：1.确定MRI引导下的OSA冷冻消融是否会产生 基于细胞因子分析、免疫组织化学(IHC)和免疫分析的免疫反应 通过非侵入性成像评估，防止转移进展，从而增加整体 存活率与SOC治疗相比。2.CT引导下免疫反应及安全性的研究 犬阻塞性睡眠呼吸暂停综合征瘤内注射刺激剂。3.确定MRI引导的 冷冻消融联合CT引导下瘤内注射激动剂预防转移 与SOC治疗OSA相比，OSA的疾病进展和生存期延长。高发病率 高转移率的阻塞性睡眠呼吸暂停综合征为研究提供了一个理想的动物模型 这种新的影像引导治疗阻塞性睡眠呼吸暂停综合征使用临床相关的成像系统具有潜在的 用于快速翻译和在其他实体肿瘤中应用。