(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健康问题，其发病率正在迅速上升。在过去的几年中， 近年来，新型黑色素瘤疗法取得了巨大进展-特别是关于 免疫疗法，如FDA在2011年批准ipilimumab（抗CTLA-4抗体）所强调的， pembrolizumab和nivolumab（抗PD-1抗体）在2014年和2015年用于黑色素瘤。此外，当 CTLA-4和PD-1阻断联合使用，缓解率显著增加，导致FDA 该方案（ipilimumab + nivolumab）在2015年获得批准-然而，毒性公认很高。尽管有这些 尽管药物治疗取得了进展，但仍有相当比例的患者对这些药物没有达到临床反应。 因此，非常需要鉴定可以预测免疫应答或抵抗的生物标志物， 检查点阻断-无论是单一疗法还是联合疗法-并确定可行的策略， 增强这些有效疗法的有效性。我们集团一直积极致力于更好地 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， 以及免疫检查点阻断患者队列中的分子谱分析，最近证明， 在早期治疗肿瘤活检中的免疫浸润高度预测反应。然而，它仍然 不清楚哪些因素有助于加强应对，迫切需要确定可采取行动的战略， 改善所有患者对治疗的反应。 越来越多的人认识到肠道微生物组在塑造健康和免疫反应中的作用， 疾病和临床前证据表明，肠道内存在的细菌可以调节对 黑色素瘤中的免疫检查点阻断，尽管这一概念尚未在患者中研究。这代表 一个重大的知识差距，获得的见解可能导致治疗策略，以加强对 黑色素瘤免疫检查点阻断。 我们已经开始在来自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， 检查点阻断，并且还在小鼠黑色素瘤模型中研究这一点。我们有初步证据 这表明治疗应答者与治疗无应答者之间存在差异特征， 通过免疫分析和代谢组学研究来研究其机制。我们还在小鼠中产生了数据， 黑色素瘤模型，证明具有相同基因组但不同的C57 BL/6小鼠中的差异肿瘤生长 肠道微生物我们现在将通过这项提案在这些研究的基础上探索微生物组的作用 在形成抗肿瘤免疫应答和对黑色素瘤中免疫检查点阻断的临床应答中。

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.