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

(PQ10) 通过调节微生物组增强黑色素瘤中免疫检查点阻断的反应

• 批准号: 10245169
• 负责人: Jennifer A. Wargo
• 金额: $ 44.82万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-20 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10245169
• 关键词: Address; Antibiotics; Bacteria; Behavior; Biological Markers; Biopsy; Blood; C57BL/6 Mouse; CTLA4 blockade; CTLA4 gene; Clinical; Clinical Trials; Collaborations; Data; Disease; Effectiveness; Fatty Acids; Flow Cytometry; Genome; Gnotobiotic; Goals; Health; Immune; Immune response; Immunity; Immunotherapy; Incidence; Knowledge; Lead; Life; Light; Malignant Neoplasms; Metastatic Melanoma; Methods; Mission; Modeling; Molecular; Molecular Profiling; Mus; Nature; Nivolumab; Organism; PD-1 blockade; Patients; Public Health; Regimen; Research; Resistance; Role; Sampling; Serum; Shapes; Systemic Therapy; Testing; Therapeutic; Toxic effect; Transplant Recipients; Tumor Immunity; Tumor-infiltrating immune cells; United States National Institutes of Health; Whole-Genome Shotgun Sequencing; Work; World Health; anti-CTLA4 antibodies; anti-PD1 antibodies; anti-PD1 therapy; anti-tumor immune response; bacterial genetics; base; burden of illness; cohort; cytokine; disability; fecal transplantation; gastrointestinal; gut microbiome; gut microbiota; immune checkpoint blockade; improved; insight; ipilimumab; melanoma; metabolomics; microbiome; microbiome analysis; mouse model; novel; pembrolizumab; peripheral blood; pre-clinical; predicting response; predictive marker; programmed cell death protein 1; resistance mechanism; responders and non-responders; response; response biomarker; systemic inflammatory response; therapy resistant; treatment response; tumor; tumor growth

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.

抽象的 黑色素瘤是世界健康问题，事件速度正在迅速上升。在过去几个 多年来，新型黑色素瘤疗法取得了巨大进展 - 特别是 FDA在2011年（抗CTLA-4抗体）的FDA批准强调的免疫疗法和 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封锁合并，响应率显着提高，导致FDA 该方案（ipilimumab + nivolumab）在2015年获得了批准 - 但是，毒性肯定很高。尽管如此 进步，仍然有很大一部分未对这些药物实现临床反应的患者。 因此，巨大需要识别可能预测对免疫反应或抗性的生物标志物 检查点封锁 - 无论是单一疗法还是组合 - 并确定可操作的策略 增强这些有效疗法的有效性。我们的小组一直在积极努力改善 了解对免疫切除剂封锁疗法的反应。在这些研究中，我们进行了深度免疫 以及在免疫切除障碍物中的一组患者中的分子分析，最近证明 早期治疗肿瘤活检中的免疫灌注是高度预测反应的。但是它仍然存在 不清楚是什么促进加强反应的原因，并且迫切需要确定可行的策略 改善所有患者对治疗的反应。 人们对肠道微生物组在塑造健康和健康中的免疫调查中的作用越来越欣赏 疾病，以及肠道内存在的细菌可能调节对 黑色素瘤中的免疫检查点阻断，尽管该概念尚未在患者中进行研究。这代表 一个重大的知识差距和获得的见解可能会导致治疗策略，以增强对 黑色素瘤中的免疫检查点阻滞。 我们已经开始解决以免疫治疗的黑色素瘤患者的临床样本中的知识差距 检查点封锁，还在鼠类黑色素瘤模型中研究了这一点。我们有初步证据 暗示反应者与未回应的治疗中存在差异签名，并且有洞察力 通过免疫分析和代谢组学研究进入机制。我们还在鼠中生成了数据 黑色素瘤模型，显示具有相同基因组的C57BL/6小鼠的差异肿瘤生长，但分化 肠道微生物组。现在，我们将通过此建议以这些研究为基础，以探索微生物组的作用 在塑造抗肿瘤免疫调查和对黑色素瘤免疫调查阻断的临床反应时。