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

项目总结/摘要 该提案将研究一种新的小分子策略，作为激活坏死性凋亡，克服细胞凋亡的一种手段。 免疫抑制性肿瘤微环境（TME）和重燃免疫检查点阻断（ICB） 人实体瘤的反应性。我们最近对流感病毒（IAV）的研究概述了一种新的途径， 细胞核坏死当宿主感受器蛋白ZBP 1 检测病毒Z-RNA（左手双链RNA）并从细胞核触发RIPK 3依赖性坏死性凋亡，释放 核“危险信号”（DAMP和警报），并驱动强有力的炎症反应。但什么是 在严重的流感中有害，可能有利于癌症免疫治疗，因为触发炎症， TME中的核坏死是使冷肿瘤变热的有吸引力的方式。我们发现一种化合物 （CBL0137），其激活ZBP1并有效逆转小鼠黑素瘤模型中的ICB无反应性。 CBL0137通过诱导细胞中的Z-DNA形成来激活ZBP1，从而绕过对活跃病毒复制的需要。 在此，我们建议在患者中进行小型可行性试验，以测试CBL0137+纳武单抗/伊匹单抗的组合。 局部晚期和转移性黑色素瘤，一种ICB显示出巨大前景的肿瘤类型，但其中 反应迟钝仍然是一个重大问题。我们假设， CBL0137与免疫疗法的组合将不仅激活抗黑素瘤免疫应答， ICB，但也将克服由CAF和MDSC在黑色素瘤TME中赋予的抗性。我们提出 两个目的来检验这个假设： 目标1.进行概念验证临床试验，以检查CBL0137 + ICB（纳武单抗）的可行性 和伊匹单抗）。该目标将确定CBL 0137静脉给药是否安全 在一线免疫治疗的背景下，通过将CBL0137+纳武单抗/伊匹单抗组合， 局部晚期转移性黑色素瘤 目标2.阐明新辅助CBL0137 + ICB在黑色素瘤患者中的生物学效应。我们将 系统地分析治疗中活检：（1）评估Z-DNA形成和坏死性凋亡激活， 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 (e.g., CAFs和MDSC）在黑色素瘤TME中的作用，使用原位空间转录组学和免疫荧光 方法，每一个加上尖端的信息学。这些研究将提供前所未有的机制 深入了解CBL0137在ICB治疗期间对肿瘤基质的作用。 临床和转化肿瘤学（Olszanski，Astsaturov）以及坏死性凋亡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的协同作用，并将 打开了一个全新的机会，使用这种坏死性凋亡激活的“病毒模拟物”作为一种手段， 使免疫学上冷的肿瘤变热。

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.