A Phase I Proof-of-Concept Study of CBL0137 Combined with Ipilimumab and Nivolumab Therapy in Locally Advanced or Metastatic Melanoma

CBL0137 联合 Ipilimumab 和 Nivolumab 治疗局部晚期或转移性黑色素瘤的 I 期概念验证研究

• 批准号: 10722873
• 负责人: Igor Astsaturov
• 金额: $ 26.37万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10722873
• 关键词: Automobile Driving; Binding; Biological; Biopsy; Blood specimen; Bypass; Cell Nucleus; Cells; Clinical; Clinical Oncology; Clinical Trials; Combination immunotherapy; Coupled; Data; Double-Stranded RNA; Fibroblasts; Human; Immune response; Immunity; Immunofluorescence Immunologic; Immunologic Adjuvants; Immunologics; Immunosuppression; Immunotherapy; In Situ; Inflammatory; Inflammatory Response; Influenza; Informatics; Innate Immune Response; Interferon Type I; Left; Malignant - descriptor; Malignant Neoplasms; Metastatic Melanoma; Metastatic/Recurrent; Mind; Myeloid-derived suppressor cells; Natural Killer Cells; Neoadjuvant Therapy; Nivolumab; Nuclear; Nuclear Protein; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Pre-Clinical Model; Proteins; RIPK3 gene; RNA; RNA Binding; Refractory; Resistance; Safety; Signal Transduction; Solid Neoplasm; T cell infiltration; Testing; Tissue Sample; Tumor Antigens; Validation; Viral; Virus; Virus Diseases; Virus Replication; Work; Z-Form DNA; anti-cancer; anti-tumor immune response; cancer clinical trial; cancer immunotherapy; cell type; experience; feasibility trial; immune checkpoint blockade; immunogenic; immunogenicity; influenza infection; influenzavirus; insight; intravenous administration; ipilimumab; melanoma; mimetics; mouse model; novel; response; sensor; small molecule; synergism; transcriptomics; translational oncology; tumor; tumor microenvironment; tumor-immune system interactions; viral detection

PROJECT SUMMARY/ABSTRACT This proposal will investigate a novel small-molecule strategy as a means to activate necroptosis, overcome the immunosuppressive tumor microenvironment (TME) and rekindle immune checkpoint blockade (ICB) responsiveness of human solid tumors. Our recent work with influenza virus (IAV) has outlined a new pathway of nuclear necroptosis. Nuclear necroptosis during IAV infections is initiated when the host sensor protein ZBP1 detects viral Z-RNA (left-handed dsRNA) and triggers RIPK3-dependent necroptosis from the nucleus, releasing nuclear “danger signals” (DAMPs and alarmins), and driving a potent inflammatory response. But what is deleterious in severe influenza may be beneficial for cancer immunotherapy, because triggering inflammatory nuclear necroptosis in the TME is an attractive way to make a cold tumor hot. We have discovered a compound (CBL0137) which activates ZBP1 and potently reverses ICB unresponsiveness in mouse models of melanoma. CBL0137 activates ZBP1 by inducing Z-DNA formation in cells, bypassing need for active virus replication. Here, we propose to test the combination of CBL0137+nivolumab/ipilimumab in a small feasibility trial in patients with locally advanced and metastatic melanoma, a tumor type in which ICB has shown great promise, but where unresponsiveness remains a significant problem. We hypothesize that that induction of necroptosis with CBL0137 in combination with immunotherapy will not only invigorate the anti-melanoma immune response to ICB, but will also overcome the resistance conferred by CAFs and MDSCs in the melanoma TME. We propose two Aims to test this hypothesis: Aim 1. Conduct a proof-of-concept clinical trial to examine the feasibility of CBL0137+ICB (nivolumab and ipilimumab) in melanoma. This Aim will establish whether intravenous administration of CBL0137 is safe and tolerated in the setting of the frontline immunotherapy by combining CBL0137+nivolumab/ipilimumab in locally advanced and metastatic melanoma. Aim 2. Elucidate the biological effects of neoadjuvant CBL0137+ICB in melanoma patients. We will systematically analyze on-treatment biopsies: (1) to evaluate Z-DNA formation and necroptosis activation in the melanoma TME; and (2) to characterize treatment-induced changes in both malignant and reactive cell types (e.g., CAFs and MDSCs) in the melanoma TME, using in situ spatial transcriptomics and immunofluorescence approaches, each coupled with cutting edge informatics. These studies will provide unprecedented mechanistic insight into the effects of CBL0137 on the tumor stroma during ICB therapy. A team of experts in clinical and translational oncology (Olszanski, Astsaturov), and necroptosis and immunity (Balachandran) will lead the proposed studies. This concept will establish CBL0137 synergy with ICB and will open an entirely new range of opportunities for using this necroptosis-activating ‘virus mimetic’ as a means to make immunologically cold tumors hot.

项目摘要/摘要 该建议将研究一种新型的小分子策略，以此作为激活坏死的一种手段，克服了 免疫抑制肿瘤微环境（TME）和重新点燃免疫检查点封锁（ICB） 人类实体瘤的反应性。我们最近与影响力病毒（IAV）的工作概述了一条新途径 核坏死作用。当宿主传感器蛋白ZBP1启动IAV感染期间的核坏死性。 检测病毒Z-RNA（左手DSRNA）和触发ripk3依赖性坏死的核能，释放 核“危险信号”（潮湿和警报），并推动潜在的炎症反应。但是是什么 严重影响有害可能对癌症免疫疗法有益，因为引发炎症 TME中的核坏死性是使冷肿瘤变热的有吸引力的方法。我们发现了一个化合物 （CBL0137）激活ZBP1并有可能在黑色素瘤小鼠模型中反应反应。 CBL0137通过在细胞中诱导的Z-DNA形成激活ZBP1，绕开了对活动病毒复制的需求。 在这里，我们建议在患者的小型可行性试验中测试CBL0137+Nivolumab/ipilimumab的组合 具有局部晚期和转移性黑色素瘤，这是一种肿瘤类型，其中ICB表现出了巨大的希望，但是 无反应仍然是一个重大问题。我们假设诱导坏死作用 CBL0137与免疫疗法结合使用，不仅会激发抗黑色素瘤免疫反应 ICB，但也将克服黑色素瘤TME中CAF和MDSC授予的电阻。我们建议 两个目的是检验这一假设： AIM 1。进行概念验证临床试验，以检查CBL0137+ICB的可行性（Nivolumab 和ipilimumab）在黑色素瘤中。这个目标将确定CBL0137的静脉内给药是否安全 并通过将CBL0137+Nivolumab/ipilimumab组合在一线免疫疗法的情况下耐受 局部晚期和转移性黑色素瘤。 目标2。阐明新辅助CBL0137+ICB对黑色素瘤患者的生物学作用。我们将 系统地分析了治疗活检：（1）评估Z-DNA形成和坏死性激活 黑色素瘤TME； （2）表征治疗引起的恶性和反应性细胞类型的变化 （例如，CAFS和MDSC）在黑色素瘤TME中，使用原位空间转录组学和免疫荧光 接近，每个都与最先进的信息相结合。这些研究将提供前所未有的机理 深入了解CBL0137对ICB治疗期间肿瘤基质的影响。 临床和翻译肿瘤学专家（Olszanski，Astsaturov）以及坏死和免疫学专家团队 （Balachandran）将领导拟议的研究。这个概念将与ICB建立CBL0137协同作用 打开全新的机会，用于使用这种坏死激活的“病毒模仿”作为一种手段 使免疫学冷肿瘤变热。