(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: 9789214
• 负责人: Jennifer A. Wargo
• 金额: $ 43.99万
• 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/9789214
• 关键词: Address; Antibiotics; Antibodies; Bacteria; Behavior; Biological Markers; Biopsy; Blood; C57BL/6 Mouse; CTLA4 gene; Clinical; Clinical Trials; Collaborations; Data; Disease; Effectiveness; Fatty Acids; Flow Cytometry; Genome; Gnotobiotic; Goals; Health; Immune; Immune response; Immunity; Immunotherapy; Incidence; Inflammation; 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; SLEB2 gene; 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-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; melanoma; metabolomics; microbiome; microbiome analysis; mouse model; novel; peripheral blood; pre-clinical; predicting response; predictive marker; resistance mechanism; responders and non-responders; response; response biomarker; 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 多年来，新型黑色素瘤疗法取得了巨大进展，特别是在 2011 年 FDA 批准 ipilimumab（抗 CTLA-4 抗体）强调了免疫疗法 2014 年和 2015 年，派姆单抗和纳武单抗（抗 PD-1 抗体）用于治疗黑色素瘤。此外，当 CTLA-4和PD-1阻断联合，缓解率显着提高，导致FDA 该方案（ipilimumab + nivolumab）于 2015 年获得批准 - 然而，毒性确实很高。尽管有这些 尽管取得了进展，但仍有相当一部分患者对这些药物没有达到临床反应。 因此，非常需要识别可以预测免疫反应或抵抗的生物标志物。 检查点封锁——无论是单一疗法还是组合疗法——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 了解对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 对一组接受免疫检查点阻断的患者进行分子分析，最近证明 早期治疗肿瘤活检中的免疫浸润可以高度预测疗效。然而它依然存在 尚不清楚什么有助于加强应对措施，因此迫切需要确定可行的战略 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组在塑造健康和免疫反应中的作用。 疾病，以及临床前证据表明肠道内存在的细菌可能会调节不同的反应 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进行研究。这代表 巨大的知识差距和获得的见解可能会导致制定治疗策略，以增强对 黑色素瘤中的免疫检查点阻断。 我们已经开始解决接受免疫治疗的黑色素瘤患者的临床样本中的这一知识差距。 检查点封锁，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 表明对治疗有反应的人和无反应的人存在差异特征，并且具有洞察力 通过免疫分析和代谢组学研究研究机制。我们还在小鼠体内生成了数据 黑色素瘤模型，证明具有相同基因组但不同的 C57BL/6 小鼠中肿瘤生长的差异 肠道微生物组。我们现在将通过这项提案以这些研究为基础，探索微生物组的作用 塑造抗肿瘤免疫反应和对黑色素瘤免疫检查点阻断的临床反应。