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

项目摘要/摘要 这项提议将研究一种新的小分子策略，作为一种激活坏死性下垂的方法，克服 免疫抑制肿瘤微环境(TME)与重燃免疫检查点阻断(ICB) 人体实体瘤的反应性。我们最近对流感病毒(IAV)的研究勾勒出了一条新的途径 核性坏死性下垂。当宿主传感器蛋白ZBP1启动IAV感染期间的核坏死性下垂 检测病毒Z-RNA(左手dsRNA)并从细胞核触发RIPK3依赖的坏死性下垂，释放 核“危险信号”(潮湿和警报)，并驱动强烈的炎症反应。但什么是 在严重流感中有害的可能有利于癌症免疫治疗，因为引发炎症 TME中的核坏死性下垂是使冷肿瘤变热的一种有吸引力的方法。我们发现了一种化合物 (CBL0137)，激活ZBP1，并有效逆转ICB在黑色素瘤小鼠模型中的无反应。 CBL0137通过诱导细胞中Z-DNA的形成来激活ZBP1，绕过了主动病毒复制的需要。 在这里，我们建议在患者中进行一项小型可行性试验来测试CBL0137 nivolumab/ipilimumab的组合 对于局部晚期和转移性黑色素瘤，ICB在这种肿瘤类型中表现出了巨大的希望，但在哪里 反应迟钝仍然是一个严重的问题。我们假设，通过 CBL0137联合免疫治疗不仅会激活抗黑色素瘤的免疫反应 ICB，但也将克服CAF和MDSCs在黑色素瘤TME中产生的耐药性。我们建议 检验这一假说有两个目的： 目的1.进行概念验证性临床试验，以考察CBL0137 ICB(Nivolumab)的可行性 和ipilimumab)治疗黑色素瘤。这一目标将确定静脉注射CBL0137是否安全 联合CBL0137 nivolumab/ipilimumab在一线免疫治疗的环境下耐受 局部晚期和转移性黑色素瘤。 目的2.阐明新佐剂CBL0137 ICB对黑色素瘤患者的生物学效应。我们会 系统分析治疗中的活检：(1)评估Z-DNA的形成和坏死性下垂的激活。 黑色素瘤TME；和(2)表征治疗诱导的恶性和反应性细胞类型的变化 用原位空间转录和免疫荧光技术检测黑色素瘤TME中的CAF和MDSCs 方法，每种方法都与尖端信息学相结合。这些研究将提供前所未有的机制 CBL0137在ICB治疗中对肿瘤间质的影响 临床和转化性肿瘤学(Olszanski，Astsaturov)以及坏死性下垂和免疫方面的专家团队 (Balachandran)将领导拟议的研究。这一概念将建立CBL0137与ICB的协同效应，并将 打开了一系列全新的机会，使用这种能激活坏死性下垂的‘病毒模拟物’作为一种手段 让免疫寒冷的肿瘤变热。

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.