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/年轻人和狗身上，年发病率为 450 和 25,000 个病例，使狗成为开发有用的比较肿瘤学模型 OSA 治疗。不幸的是，过去三年 OSA 患者的治疗结果已趋于稳定 几十年。因此，超越护理标准（SOC）手术的新治疗方法和 迫切需要化疗。作为 OSA 的新型疗法，我们团队正在开发磁力疗法 磁共振成像 (MRI) 引导的冷冻治疗与图像引导的瘤内注射相结合 免疫佐剂。为此，我们将进行一项犬类临床试验，比较 MRI 引导的 单独冷冻疗法或联合瘤内免疫佐剂给药 发生的、非转移性的犬阑尾 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重要见解 治疗的影响来指导未来的改进。虽然冷冻疗法直接杀死 OSA 肿瘤细胞， 我们的目的是激活患者针对出现的肿瘤抗原的适应性免疫系统 来自垂死的肿瘤细胞，并添加免疫佐剂的瘤内递送。下列的 局部控制手术，我们假设启动的适应性免疫反应可以延迟或预防 转移性疾病的发生，这都是致命的。使用 MRI，人们可以精确地确定 在不暴露于电离辐射的情况下通过冷冻疗法冷冻和杀死肿瘤组织的范围。 其他人已经证明冷冻消融后巨噬细胞和骨髓细胞大量涌入。通过 瘤内注射，我们将提供一种新型干扰素基因刺激剂（STING）激动剂 冷冻疗法激活浸润的先天免疫细胞。 STING 通路激活导致 广泛的细胞因子诱导、抗原呈递细胞的激活以及随后 T 细胞的启动 细胞。我们的具体目标是： 1. 确定 MRI 引导的 OSA 冷冻消融是否会产生 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，从而提高整体 与 SOC 治疗相比的生存率。 2. 表征CT引导下的免疫反应和安全性 STING 激动剂在犬 OSA 中进行瘤内给药。 3. 判断是否MRI引导 冷冻消融联合 CT 引导下瘤内 STING 激动剂给药可预防转移 与 OSA 的 SOC 治疗相比，可以减少疾病进展并延长生存期。发病率高 患有高转移性疾病的狗中 OSA 的发生提供了一个理想的动物模型来研究 这种使用临床相关成像系统的新型图像引导治疗 OSA 的潜力 用于其他实体瘤的快速翻译和应用。