EHA国际视野丨Swaminathan Iyer教授:ELA026在初治mHLH患者中的疗效

作者:肿瘤瞭望   日期:2024/11/8 16:43:53  浏览量:1266

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《肿瘤瞭望-血液时讯》特邀Swaminathan Iyer教授分享ELA026在mHLH治疗中的作用机制及其临床意义。

恶性肿瘤相关噬血细胞性淋巴组织细胞增生症(mHLH)是一种极具侵袭性和致命性的疾病,其治疗策略的创新一直是血液领域研究的重点和难点之一。近期,ELA026——一种靶向于信号调节蛋白(SIRP)-a/b1/g的新型单克隆抗体,已在治疗mHLH的临床试验中显示出积极的初步疗效。在2024年6月13日至16日召开的第29届欧洲血液协会年会(EHA 2024)上,美国德克萨斯大学MD安德森癌症中心、研究主要作者Swaminathan Iyer教授及其团队在一项I期研究中发现,ELA026不仅提高了初治mHLH患者的缓解率,还显著改善了其2个月生存率。这一发现为mHLH的治疗提供了新的希望。《肿瘤瞭望-血液时讯》特邀Swaminathan Iyer教授分享ELA026在mHLH治疗中的作用机制及其临床意义。

《肿瘤瞭望-血液时讯》:作为一种靶向信号调节蛋白(SIRP)-a/b1/g的新型单克隆抗体,ELA026在治疗继发性噬血细胞性淋巴组织细胞增生症(sHLH)中显示出较高的缓解率并显著改善了生存率。您能否阐述一下这种新方法如何改变我们的治疗策略?

Swaminathan Iyer教授:由Abhishek Maiti博士在EHA会议上向大家展示我们团队的研究成果。作为这项I期研究的主要作者,我非常荣幸能将这些重要发现分享给大家。本研究是一项正在进行中的开放标签、单臂、1b期全球性研究(NCT05416307),主要探讨了ELA026——一种靶向信号调节蛋白(SIRP)-a/b1/g的新型单克隆抗体,在治疗继发性噬血细胞性淋巴组织细胞增生症(sHLH)中的应用。我们的研究特别关注了恶性肿瘤相关HLH(mHLH)患者群体。
 
我们分析了三个队列的数据。前2个队列主要致力于确定剂量和治疗方案,而队列3纳入了初治复发/难治性mHLH患者。HLH是一种极具侵袭性和致命性的疾病,2个月时的死亡率约为50%[1]。这种高死亡率主要归因于与恶性肿瘤相关的并发症。这些并发症常常阻碍了对恶性肿瘤本身及其引发的细胞因子风暴的必要治疗。
 
ELA026耗尽巨噬细胞或肿瘤细胞中的SIRP蛋白,从而抑制细胞因子风暴和疾病进展。在纳入初治mHLH患者的队列3中,2个月生存率约为100%。包括T细胞淋巴瘤在内的许多患者,在接受治疗后均能顺利出院,恢复家庭生活。这标志着一项重大的医学进展,我们期待后续能够开展ELA026与化疗联合治疗方案的研究,以提升治疗效果。
 
Oncology Frontier-Hematology Frontier:Our first question for you is:As a novel class of monoclonal antibody targeting signal regulatory protein(SIRP)-a/b1/g,ELA026 has shown a high response rate and improved survival in the treatment of secondary hemophagocytic lymphohistiocytosis(sHLH).Could you elaborate on how this novel approach could potentially change our treatment strategies?
 
Dr.Swaminathan Iyer:Dr.Abhishek Maite presented our findings,and as the senior author of this phase 1 study,I’m pleased to discuss the results.This international study investigates ELA026,a novel monoclonal antibody that targets signal regulatory protein(SIRP)-a/b1/g,in the treatment of secondary hemophagocytic lymphohistiocytosis(sHLH).Our data presentation specifically focused on the subset of patients with malignancy-associated HLH.We examined data from three cohorts.The first two cohorts were primarily aimed at dose-finding and establishing the treatment protocol,while the third cohort involved treatment-naïve and early refractory patients.HLH is a highly aggressive and life-threatening condition,with a two-month mortality rate of approximately 50%.This high mortality rate is primarily attributed to complications related to the underlying malignancy.These complications often prevent necessary treatment for both the malignancy and the cytokine storm it causes.ELA026 works by depleting SIRP proteins in macrophages and sometimes in tumor cells,thereby reducing the cytokine storm and controlling the disease progression.In the third cohort,which included treatment-naïve patients,the response rate was approximately 100%by two months.Many patients,including those with T-cell lymphoma,were able to be discharged and return home.This represents a significant breakthrough,and we are hopeful that further data will demonstrate how ELA026 can be integrated with chemotherapy.
 
《肿瘤瞭望-血液时讯》:在评估ELA026的疗效时,诸如铁蛋白、sCD25和C反应蛋白等生物标志物的应答与临床应答密切相关。监测这些生物标志物如何帮助我们更好地理解sHLH的病理机制,并指导个性化治疗策略的发展?

Swaminathan Iyer教授:生物标志物在评估疾病应答和细胞因子风暴方面发挥着关键作用。我们使用铁蛋白和可溶性白细胞介素-2受体(sIL-2R,sCD25)作为sHLH诊断和应答的评估标准。优化HLH炎症指数(OHI)是一种能够准确识别铁蛋白和sCD25水平的特殊指标。此外,C反应蛋白(CRP)也是治疗应答的生物标志物之一。
 
初始应答(标志物)为sCD25,后期应答(标志物)为铁蛋白。铁蛋白和sCD25水平的降低是应答标准之一,与《新英格兰医学杂志》(NEJM)上发表的一项依马利尤单抗(人类抗干扰素γ抗体)联合地塞米松治疗儿童原发性HLH的疗效和安全性的研究中所引用的数据[2]相一致。我们应用了该研究中的改良后的完全缓解(CR)标准,即要求铁蛋白水平减少90%。
 
Oncology Frontier-Hematology Frontier:When evaluating the efficacies of ELA026,biomarker responses such as ferritin,sCD25,and C-reactive protein are closely related to the clinical response.How does the monitoring of these biomarkers help us better understand the pathology of sHLH and guide the development of personalized treatment strategies?
 
Dr.Swaminathan Iyer:Biomarkers play a pivotal role in assessing the response of the disease and the cytokine storm.In the context of sHLH,we utilize ferritin and sIL-2R(soluble IL-2 receptor,also known as sCD25)as part of the diagnostic and response assessment criteria.The Optimized Hematological Inflammatory Index(OHI)is a specific measure that incorporates both ferritin and sCD25.Additionally,C-reactive protein serves as a biomarker indicative of the response to therapy.The initial response you receive is the sIL-2R,and ferritin is recognized as a later response.A reduction in ferritin and sIL-2R is one of the response criteria,as referenced in a study published in the New England Journal of Medicine on emapalumab.We applied the modified CR(complete remission)criteria from that study,which requires a 90 percent reduction in ferritin levels.

《肿瘤瞭望-血液时讯》:鉴于感染的高风险,该研究采取了哪些措施来降低这些风险,以及这些措施在临床实践中的可行性和有效性如何?

Swaminathan Iyer教授:低血细胞计数,包括白细胞、贫血或血小板减少,是患者面临的重大挑战,因其可能引发严重的并发症,如出血或感染。对于复发或难治性HLH患者来说,尤其需要注意并发症的管理,他们通常接受了大量化疗和类固醇治疗,从而增加了真菌感染的风险。
 
在初治患者队列中并未观察到太多诸如感染在内的风险。这可以归因于两个因素:患者接受的化疗程度以及预防性使用抗真菌、抗细菌和抗病毒药物。尽管血细胞计数可能在很长一段时间内保持低下,即使在生物标志物应答后恢复时间也可能延迟,但继续进行抗感染治疗至关重要。这种方法对于预防患者因感染而死亡至关重要,以期改善他们的整体预后和生活质量。
 
Oncology Frontier-Hematology Frontier:Given the high risk of infection,what measures were taken in the study to mitigate these risks,and how feasible and effective are these measures in clinical practice?
 
Dr.Swaminathan Iyer:Low blood cell counts,including white blood cells,anemia,or thrombocytopenia,are significant challenges because they can lead to severe complications such as bleeding or infections.This is particularly problematic in patients with relapsed or refractory HLH,who have often been heavily treated with chemotherapy and steroids,thereby increasing their susceptibility to fungal infections.In the treatment-naïve cohort of our study,we observed fewer infections.This can be attributed to two factors:the extent of chemotherapy the patients receive and the prophylactic use of antifungal,antibacterial,and antiviral medications.Although blood cell counts may remain low for an extended period and recovery might be delayed even after achieving a biomarker response,it is crucial to continue anti-infective therapies.This approach is essential to prevent patients from succumbing to infections,thereby improving their overall outcomes and quality of life.
 
参考文献
 
1.J Clin Oncol.2023 Apr 1;41(10):1888-1897.doi:10.1200/JCO.22.00437.
 
2.LocatelliF,et al.Emapalumab in Children with Primary HemophagocyticLymphohistiocytosis.N Engl J Med 2020;382:1811-1822
 
3.2024 EHA abstract LB3442:ELA026 TARGETING OF SIRP(+)IMMUNE CELLS RESULTS IN A HIGH RESPONSE RATE AND IMPROVED 2-MONTH SURVIVAL OF TREATMENT-NAIVE MALIGNANCY-ASSOCIATED HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS IN A PHASE 1 STUDY

 

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