Optimizing Novel Immunotherapy Combinations Targeting the Tumor Microenvironment in Canine Spontaneous Osteosarcoma

优化针对犬自发性骨肉瘤肿瘤微环境的新型免疫治疗组合

• 批准号: 10260606
• 负责人: Steven W. Dow
• 金额: --
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10260606
• 关键词: Active Immunotherapy; Adjuvant; Adjuvant Study; Algorithms; Animal Model; Antibodies; Biological; Biological Assay; Biological Markers; Biological Response Modifiers; Blood; Canis familiaris; Cells; Chemoresistance; Clinical; Clinical Trials; Combination immunotherapy; Crossover Design; Data; Disease; Disease regression; Drug Combinations; Elements; Exhibits; Future; Glutamine; Goals; Human; IL6ST gene; IL8 gene; IL8RA gene; Immune; Immune Targeting; Immune checkpoint inhibitor; Immune response; Immunologic Monitoring; Immunologics; Immunosuppression; Immunotherapeutic agent; Immunotherapy; Interleukin-6; Lesion; Limb structure; Losartan; Lung; Malignant Neoplasms; Malignant neoplasm of lung; Measurement; Metastatic Osteosarcoma; Methods; Microscopic; Molecular Abnormality; Mutation; Neoplasm Metastasis; Outcome; Pattern; Performance; Pharmaceutical Preparations; Pilot Projects; Prevention; Prodrugs; Protocols documentation; Randomized Clinical Trials; Rapid screening; Records; Recurrence; Regulatory T-Lymphocyte; Safety; Sampling; Series; Signal Transduction; T-Lymphocyte; Techniques; Testing; Therapeutic; Tumor Immunity; Tumor Tissue; adaptive immune response; anti-PD-1; anti-tumor immune response; antibody inhibitor; base; chemotherapy; clinical biomarkers; drug repurposing; effectiveness testing; exhaust; human model; immune activation; immune checkpoint blockade; immunotherapy trials; improved; improved outcome; inhibitor/antagonist; limb amputation; macrophage; melanoma; monocyte; neoplasm immunotherapy; neoplastic cell; neutrophil; novel; osteosarcoma; overexpression; permissiveness; pharmacokinetics and pharmacodynamics; pilot trial; pre-clinical; prevent; prospective; recruit; response; small molecule; small molecule inhibitor; targeted treatment; therapy resistant; treatment response; trial design; tumor; tumor DNA; tumor growth; tumor microenvironment

Project Abstract Spontaneous canine osteosarcoma (OS) is a well-defined large animal model of human OS, exhibiting similar clinical presentation and molecular aberrations. Indeed, canine OS has historically been used to help develop novel limb spare techniques, evaluate a variety of non-specific immunotherapeutics such as L-MTP-PE, and assess the efficacy of targeted therapeutics to prevent the outgrowth of metastatic disease. Despite best efforts, progress in the prevention and treatment of metastatic disease has essentially stalled for the past 3 decades; 30% of people and 90% of dogs still die of tumor spread, primarily to the lungs. Numerous clinical trials have been undertaken in people with macroscopic metastases and in dogs with both microscopic and macroscopic disease, yet all have failed to demonstrate improved outcomes. This is particularly evident with respect to immune checkpoint inhibitors that do not induce the dramatic disease regressions typically observed in other cancers such as melanoma and lung cancer. One particularly daunting challenge for immunotherapy-based therapeutics in OS relates to the permissiveness of the tumor microenvironment (TME) for inducing anti-tumor immune responses. Our data suggests that a relatively low mutational load combined with a dampened overall immune response in OS may contribute to the observed lack of response to current treatment approaches. We propose that targeting the immune suppressive TME in OS is essential to generating potent and durable anti- tumor immunity. To accomplish this, it may be necessary to simultaneously modulate several elements in the TME, including Tregs, MDSCs, M2 macrophages and overexpressed inhibitory checkpoint molecules. In support of this, we have generated a body of data demonstrating immunological activity of multiple therapeutics, including repurposed drugs with good safety records (losartan, oclacitinib), small molecule inhibitors with established PK/PD in dogs (toceranib, RV1001, reparixin, JHU-292) and antibodies specific for checkpoint molecules (anti- PD1). However, the exact combinations that are most effective against metastatic OS have not yet been identified, and this is a major goal of this proposal. As such, we hypothesize that an adaptive pilot trial design can be used to rapidly screen TME-targeting immunotherapy drug combinations in dogs with macroscopic chemotherapy-resistant metastatic OS and that this information can be refined to assess activity of the most active approach against microscopic metastases in a subsequent adjuvant trial. This will be accomplished by testing four TME modifying immunotherapy combinations for anti-tumor and immune modulatory activity in dogs with macroscopic OS metastases, interrogating relevant biomarkers associated with responses to therapy, then using this information to conduct an adjuvant immunotherapy trial with the most active combination in dogs with microscopic metastatic OS. The data generated from this proposal will create a blueprint for future immunotherapy studies in people with OS by eliminating approaches deemed inactive and generating a set of clinical biomarkers to guide treatment.

项目摘要 自发性犬骨肉瘤 (OS) 是一种明确的人类 OS 大型动物模型，表现出与人类 OS 相似的特征 临床表现和分子畸变。事实上，canine OS 历史上曾被用来帮助开发 新颖的肢体备用技术，评估各种非特异性免疫疗法，例如 L-MTP-PE，以及 评估靶向治疗预防转移性疾病生长的功效。尽管尽了最大努力， 过去三十年来，预防和治疗转移性疾病的进展基本上停滞不前； 30% 的人和 90% 的狗仍然死于肿瘤扩散（主要扩散到肺部）。大量临床试验已 在患有宏观转移的人和患有微观和宏观转移的狗中进行 疾病，但所有这些都未能显示出改善的结果。这在以下方面尤其明显 免疫检查点抑制剂不会引起通常在其他疾病中观察到的戏剧性疾病消退 癌症，如黑色素瘤和肺癌。基于免疫疗法的一项特别艰巨的挑战 OS 中的治疗与肿瘤微环境 (TME) 诱导抗肿瘤的许可性有关 免疫反应。我们的数据表明，相对较低的突变负荷与总体减弱相结合 OS 中的免疫反应可能导致观察到对当前治疗方法缺乏反应。我们 提出针对 OS 中的免疫抑制性 TME 对于产生有效且持久的抗- 肿瘤免疫。为了实现这一点，可能需要同时调制多个元素 TME，包括 Tregs、MDSC、M2 巨噬细胞和过表达的抑制性检查点分子。支持中 其中，我们生成了一系列数据，证明多种疗法的免疫活性，包括 具有良好安全记录的重新利用药物（氯沙坦、奥拉替尼）、已建立的小分子抑制剂 狗体内的 PK/PD（toceranib、RV1001、reparixin、JHU-292）和检查点分子特异性抗体（抗 PD1）。然而，对于转移性 OS 最有效的确切组合尚未确定。 已确定，这是本提案的主要目标。因此，我们假设适应性试点试验设计 可用于快速筛选患有 TME 的狗的免疫治疗药物组合 宏观化疗耐药的转移性 OS，并且可以细化此信息以评估 在随后的辅助试验中，最积极的方法对抗微观转移的活性。这 将通过测试四种 TME 修饰免疫治疗组合来完成抗肿瘤和免疫治疗 具有宏观 OS 转移的狗的调节活性，询问与 对治疗的反应，然后利用这些信息对最活跃的患者进行辅助免疫治疗试验 具有显微转移性 OS 的狗的组合。该提案生成的数据将创建一个 通过消除被认为无效的方法，为 OS 患者制定未来免疫治疗研究的蓝图 并生成一组临床生物标志物来指导治疗。