(PQ10) Enhancing responses to immune checkpoint blockade in melanoma via modulation of the microbiome

摘要 黑色素瘤是一个主要的世界性健康问题，其发病率正在迅速上升。在过去的几年中 多年来，在新的黑色素瘤疗法方面取得了巨大的进展，特别是在 2011年FDA批准ipilimumab(抗CTLA-4抗体)作为免疫治疗的重点，以及 2014年和2015年用于黑色素瘤的pembrolizumab和nivolumab(抗PD-1抗体)。此外，当 CTLA-4和PD-1阻滞剂联合使用，应答率显著增加，导致FDA 该方案(ipilimumab+nivolumab)于2015年获得批准--然而，公认的毒性很高。尽管如此 尽管取得了很大进展，但仍有相当大比例的患者对这些药物没有达到临床疗效。 因此，迫切需要确定可以预测免疫应答或抵抗的生物标志物。 检查站封锁--无论是作为单一疗法还是联合疗法--并确定将 增强这些有效疗法的有效性。我们的团队一直在积极努力，以更好地 了解免疫检查点阻断疗法的反应。在这些研究中，我们进行了深度免疫 在一组接受免疫检查点阻断的患者中进行了分子特征分析，最近证明 早期治疗肿瘤活检中的免疫浸润物对疗效有很高的预测性。然而，它仍然存在 不清楚是什么有助于加强应对，迫切需要确定可行的战略，以 改善所有患者对治疗的反应。 人们越来越认识到肠道微生物群在塑造健康和健康的免疫反应中的作用 疾病，以及临床前证据表明肠道内存在的细菌可能调节对 黑色素瘤的免疫检查点阻断，尽管这一概念尚未在患者中进行研究。这代表了 显著的知识差距和获得的洞察力可能导致治疗策略，以增强对 黑色素瘤的免疫检查点阻断。 我们已经开始在接受免疫治疗的黑色素瘤患者的临床样本中解决这一知识缺口。 检查点封锁，并正在对小鼠黑色素瘤模型进行研究。我们有初步证据 这表明对治疗有反应的人和无反应的人存在不同的签名，并具有洞察力 通过免疫图谱和代谢组学研究来研究机制。我们还在一只小鼠身上产生了数据 黑色素瘤模型，在基因组相同但不同的C57BL/6小鼠中显示出不同的肿瘤生长 肠道微生物群。我们现在将在这些研究的基础上，通过这项提议来探索微生物组的作用 在黑色素瘤中形成抗肿瘤免疫反应和免疫检查点阻断的临床反应。

ABSTRACT Melanoma is a major world health problem with an incidence rate that is rising rapidly. Within the past several years, there has been tremendous progress in novel melanoma therapies – particularly with regard to immunotherapy as highlighted by the FDA approval of ipilimumab (anti-CTLA-4 antibody) in 2011 and pembrolizumab and nivolumab (anti-PD-1 antibodies) for melanoma in 2014 and 2015. Furthermore, when CTLA-4 and PD-1 blockade are combined, response rates are significantly increased, leading to the FDA approval of this regimen (ipilimumab + nivolumab) in 2015 – however, toxicity is admittedly high. Despite these advances, there are still a significant proportion of patients who do not achieve clinical response to these agents. Therefore, there is tremendous need to identify biomarkers that may predict response or resistance to immune checkpoint blockade – either as monotherapy or in combination – and to identify actionable strategies that will enhance the effectiveness of these potent therapies. Our group has been actively engaged in efforts to better understand responses to immune checkpoint blockade therapies. In these studies, we performed deep immune and molecular profiling in a cohort of patients on immune checkpoint blockade, and recently demonstrated that an immune infiltrate in early on-treatment tumor biopsies is highly predictive of response. However it remains unclear what contributes to enhanced responses, and there is a critical need to identify actionable strategies to improve responses to therapy in all patients. There is a growing appreciation of the role of the gut microbiome in shaping immune responses in health and disease, and pre-clinical evidence that bacteria present within the gut may modulate differential responses to immune checkpoint blockade in melanoma, though this concept has not been studied in patients. This represents a significant knowledge gap, and insights gained could lead to therapeutic strategies to enhance responses to immune checkpoint blockade in melanoma. We have begun to address this knowledge gap in clinical samples from melanoma patients treated with immune checkpoint blockade, and are also studying this in a murine melanoma model. We have preliminary evidence suggesting that differential signatures exist in responders versus non-responders to therapy, and have insight into mechanisms via immune profiling and metabolomic studies. We have also generated data in a murine melanoma model, demonstrating differential tumor growth in C57BL/6 mice with identical genomes but differing gut microbiomes. We will now build on these studies through this proposal to explore the role of the microbiome in shaping anti-tumor immune responses and clinical responses to immune checkpoint blockade in melanoma.