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/文摘

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.