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

项目摘要 自发性犬骨肉瘤是一种定义明确的人类骨肉瘤的大型动物模型，表现出类似的 临床表现和分子异常。事实上，CANINE OS在历史上一直被用来帮助开发 新的肢体备用技术，评估各种非特异性免疫疗法，如L-MTP-PE，以及 评估靶向治疗预防转移性疾病的疗效。尽管尽了最大努力， 过去30年来，在预防和治疗转移性疾病方面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，主要是扩散到肺部。许多临床试验都有 在患有宏观转移的人和狗身上进行了微观和宏观的研究 然而，所有这些都没有显示出改善的结果。这一点在以下方面尤为明显 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退化 黑色素瘤和肺癌等癌症。以免疫疗法为基础的一个特别艰巨的挑战 OS的治疗与肿瘤微环境(TME)诱导抗肿瘤的通透性有关 免疫反应。我们的数据表明，相对较低的突变负荷加上整体上的抑制 OS的免疫反应可能是观察到的对当前治疗方法缺乏反应的原因之一。我们 提出在OS中靶向免疫抑制因子TME是产生有效和持久的抗-TME的关键 肿瘤免疫。要做到这一点，可能需要同时调制 TME包括Tregs、MDSCs、M2巨噬细胞和过表达的抑制性检查点分子。在支持中 其中，我们生成了一系列数据，展示了多种疗法的免疫活性，包括 有良好安全记录的再用途药物(氯沙坦、奥克拉西尼)，小分子抑制剂 犬PK/PD(toceranib、RV1001、reparisin、JHU-292)和针对检查点分子的抗体(抗- PD1)。然而，对抗转移性OS最有效的确切组合还没有 这是这项提案的一个主要目标。因此，我们假设自适应飞行员试验设计 可用于快速筛选TME靶向免疫治疗药物组合 宏观化疗耐药的转移性OS和这一信息可以改进以评估 在随后的佐剂试验中，最有效的方法对抗微观转移的活性。这 将通过测试四种TME修饰免疫疗法组合来实现抗肿瘤和免疫 肉眼可见OS转移的狗的调节活性，询问相关的生物标志物 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 在患有显微转移性OS的狗身上联合应用。此建议书生成的数据将创建一个 通过消除被认为不活跃的方法对OS患者进行未来免疫治疗研究的蓝图 并产生一套临床生物标志物来指导治疗。

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.