权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

Cindi 研究：将 CD24Fc 与 Ipilimumab 和 Nivolumab 相结合以减少免疫相关不良事件 (irAE) 的 II 期临床试验

基本信息

批准号：
10009672
负责人：
Siwen Hu-Lieskovan
金额：
$ 39.67万
依托单位：
ONCOIMMUNE, INC.
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2021-05-31
项目状态：
已结题

项目摘要

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.

总结 Ipilimumab和Nivolumab的组合已经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的生存期超过三年。然而，超过50%的患者发生3-4级免疫相关不良事件（irAE）。在新辅助治疗中， 3-4级irAE可达73- 90%。通过增加免疫系统的活性， Ipilimumab和Nivolumab增强宿主对炎症信号的反应。尽管任何器官系统 irAE最常累及胃肠道、内分泌腺、皮肤和肝脏。少通常，中枢神经系统和心血管、肺、肌肉骨骼和血液系统参与其中已经认识到IrAE是癌症免疫治疗的主要瓶颈：irAE不仅是患者生存和健康的主要威胁，但也限制了给药量和时间表，从而减少了癌症免疫疗法的疗效。因此，迫切需要新的方法来对抗irAE。没有前瞻性试验已经确定了有效管理特定irAE和临床实践的策略，仍然可变。在这里，我们建议预防irAE是最好的管理方法。当肿瘤细胞被宿主免疫系统杀死时，系统越来越多的数据表明，对DAMP的先天反应可能导致免疫介导的破坏宿主组织。由于CD 24-Siglec G/10相互作用已显示抑制对在DAMP中，我们假设通过CD 24 Fc促进Siglec 10的活化可能会减少接受伊匹单抗和纳武单抗组合疗法的患者。为了支持这一假设，我们已经建立了一个完全重现人类irAE的小鼠模型。我们进一步证明， CD 24 Fc有效减少严重的irAE，同时增强伊匹单抗+抗小鼠的免疫效果 PD-1 基于这些令人兴奋的数据，我们提出了一项名为CINDI（联合收割机CD 24 Fc）的II期临床试验， Ipilimumab和Nivolumab降低irAE）。由于我们已经获得了概念验证数据，基本概念和CD 24 Fc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基金用于临床测试我们的新假设。I期SBIR将实现提交IND的目标申请和建立CINDI试验所需的基础设施。II期SBIR将使用固定剂量的 CD 24 Fc，以探索将CD 24 Fc与伊匹单抗和纳武单抗组合以减少CD 24 Fc的安全性和功效。该组合的毒性而不影响癌症免疫治疗效果。我们提出的研究代表了预防irAE的新范式，因此有可能大大提高提高联合免疫治疗的视野。