Cindi Study: A Phase II Clinical Trial to Combine CD24Fc with Ipilimumab and Nivolumab to Decrease Immune Related Adverse Events (irAE)

摘要 Ipiimumab和Nivolumab的联合应用已成为最有效的癌症免疫疗法， 导致70%的转移性黑色素瘤患者实现了三年以上的生存。然而，更大的 超过50%的患者出现3-4级免疫相关不良事件(IRAE)。在新佐剂环境中， 3-4级可达73%-90%。通过增加免疫系统的活性，结合 Ipilimumab和nivolumab可增强宿主对炎症信号的反应。尽管任何器官系统 可以受到影响，irAEs最常见的累及胃肠道、内分泌腺、皮肤和肝脏。较少 通常，中枢神经系统和心血管、肺、肌肉骨骼和血液系统 都牵涉其中。IRAE已被认为是癌症免疫治疗的一大瓶颈：irAEs不仅 是对患者生存和福祉的主要威胁，但也限制了剂量和时间表，从而减少 癌症免疫治疗的疗效。因此，迫切需要新的方法来打击伊拉克。不是 前瞻性试验明确了有效管理特定irAEs和临床实践的策略。 仍然是可变的。在这里，我们提出，预防心脏事件是最好的管理方法。 当肿瘤细胞被宿主免疫杀死时，危险相关的分子模式(DAMP)被释放 系统。越来越多的数据表明，对潮湿的先天反应可能会导致免疫调节 对宿主组织的破坏。自从CD24-Siglec G/10相互作用被证明抑制了对 我们假设，CD24Fc促进Siglec 10的激活可能会减少IRAE 接受Ipiimumab和Nivolumab联合治疗的患者。为了支持这一假设，我们 已经建立了一个完全模拟人类IRAE的小鼠模型。我们已经进一步证明了 CD24Fc有效降低重症IRAE，同时增强Ipiimumab+抗鼠的免疫治疗效果 PD-1。 基于这些令人兴奋的数据，我们提出了一项名为CINDI的II期临床试验(结合CD24Fc到 Ipilimumab和Nivolumab可降低IRAE)。由于我们已经获得了概念验证数据， 对于CD24Fc的基本概念和在人类疾病中的生物学活性，我们提出了一个快速通道阶段 I/II SBIR拨款用于临床检验我们的新假说。第一阶段SBIR将实现提交IND的目标 并建立辛迪审判所需的基础设施。第二阶段SBIR将使用固定剂量的 探讨CD24Fc与ipilimumab和nivolumab联合应用降低血流量的安全性和有效性。 这种组合的毒性不会影响癌症的免疫治疗效果。 我们提出的研究代表了预防IRAE的新范式，因此有可能极大地 提高联合免疫治疗的水平。

Summary Combination of Ipilimumab and Nivolumab has emerged as the most effective cancer immunotherapy, resulting in 70% of metastatic melanoma patients to achieve survival beyond three years. However, greater than 50% of the patients developed grades 3-4 immune related adverse events (irAE). In neo-adjuvant setting, the grades 3-4 irAE can reach 73-90%. By increasing the activity of the immune system, combination of Ipilimumab and Nivolumab enhances the host response to inflammatory signals. Although any organ system can be affected, irAEs most commonly involve the gastrointestinal tract, endocrine glands, skin, and liver. Less often, the central nervous system and cardiovascular, pulmonary, musculoskeletal, and hematologic systems are involved. It has been recognized that IrAE is a major bottleneck in cancer immunotherapy: irAEs not only are major threats to patient survival and wellbeing, but also limit the dosing amount and schedule thus reduce the efficacy of cancer immunotherapy. Therefore, novel approach is urgently needed to combat irAE. No prospective trials have defined strategies for effectively managing specific irAEs and the clinical practice remains variable. Here we propose that prevention of irAEs is the best management approach. Danger-associated molecular patterns (DAMPs) are released when tumor cells killed by the host immune system. Accumulating data suggested that innate responses to DAMPs may lead to immune-mediated destruction to host tissues. Since CD24-Siglec G/10 interaction has been shown to dampen response to DAMPs, we hypothesize that fostering activation of Siglec 10 by CD24Fc may reduce irAE among patients receiving Ipilimumab and Nivolumab combination therapy. In support of this hypothesis, we have established a mouse model that fully recapitulate human irAE. We have further demonstrated that CD24Fc effectively reduce severe irAE while enhancing immunotherapeutic effect of Ipilimumab+anti-mouse PD-1. Based on these exciting data, we proposed a phase II clinical trial called CINDI (Combine CD24Fc to Ipilimumab and Nivolumab to Decrease irAE). Since we have obtained proof-of-concept data both for the fundamental concept and for biological activity of CD24Fc in human diseases, we proposed a fast track phase I/II SBIR grant to clinically test our novel hypothesis. Phase I SBIR will achieve the goal to submit IND application and to establish infrastructure required for the CINDI trial. Phase II SBIR will use a fixed dose of CD24Fc to explore the safety and efficacy of combining CD24Fc with ipilimumab and nivolumab to reduce the toxicity of this combination without affecting cancer immunotherapy effects. Our proposed studies represent a new paradigm for prophylaxis of irAE and thus has the potential to greatly improve the horizon of combination immunotherapy.