Janik John E, Morris John C, O'Mahony Deirdre, Pittaluga Stefania, Jaffe Elaine S, Redon Christophe E, Bonner William M, Brechbiel Martin W, Paik Chang H, Whatley Millie, Chen Clara, Lee Jae-Ho, Fleisher Thomas A, Brown Maggie, White Jeffrey D, Stewart Donn M, Fioravanti Suzanne, Lee Cathryn C, Goldman Carolyn K, Bryant Bonita R, Junghans Richard P, Carrasquillo Jorge A, Worthy Tat'Yana, Corcoran Erin, Conlon Kevin C, Waldmann Thomas A
Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
Proc Natl Acad Sci U S A. 2015 Oct 20;112(42):13045-50. doi: 10.1073/pnas.1516107112. Epub 2015 Oct 5.
Despite significant advances in the treatment of Hodgkin's lymphoma (HL), a significant proportion of patients will not respond or will subsequently relapse. We identified CD25, the IL-2 receptor alpha subunit, as a favorable target for systemic radioimmunotherapy of HL. The scientific basis for the clinical trial was that, although most normal cells with exception of Treg cells do not express CD25, it is expressed by a minority of Reed-Sternberg cells and by most polyclonal T cells rosetting around Reed-Sternberg cells. Forty-six patients with refractory and relapsed HL were evaluated with up to seven i.v. infusions of the radiolabeled anti-CD25 antibody (90)Y-daclizumab. (90)Y provides strong β emissions that kill tumor cells at a distance by a crossfire effect. In 46 evaluable HL patients treated with (90)Y-daclizumab there were 14 complete responses and nine partial responses; 14 patients had stable disease, and nine progressed. Responses were observed both in patients whose Reed-Sternberg cells expressed CD25 and in those whose neoplastic cells were CD25(-) provided that associated rosetting T cells expressed CD25. As assessed using phosphorylated H2AX (γ-H2AX) as a bioindicator of the effects of radiation exposure, predominantly nonmalignant cells in the tumor microenvironment manifested DNA damage, as reflected by increased expression of γ-H2AX. Toxicities were transient bone-marrow suppression and myelodysplastic syndrome in six patients who had not been evaluated with bone-marrow karyotype analyses before therapy. In conclusion, repeated (90)Y-daclizumab infusions directed predominantly toward nonmalignant T cells rosetting around Reed-Sternberg cells provided meaningful therapy for select HL patients.
尽管霍奇金淋巴瘤（HL）的治疗取得了显著进展，但仍有相当一部分患者无反应或随后复发。我们将白细胞介素-2受体α亚基CD25确定为HL全身放射免疫治疗的理想靶点。该临床试验的科学依据是，除调节性T细胞外，大多数正常细胞不表达CD25，但少数里德-施特恩贝格细胞以及围绕里德-施特恩贝格细胞的大多数多克隆T细胞表达CD25。对46例难治性和复发性HL患者进行了评估，静脉注射放射性标记的抗CD25抗体（90）Y-达利珠单抗，最多注射7次。（90）Y能产生强烈的β射线，通过交叉火力效应在一定距离外杀死肿瘤细胞。在接受（90）Y-达利珠单抗治疗的46例可评估HL患者中，有14例完全缓解，9例部分缓解；14例病情稳定，9例病情进展。无论里德-施特恩贝格细胞表达CD25的患者，还是肿瘤细胞CD25阴性但相关玫瑰花结T细胞表达CD25的患者，均观察到了反应。以磷酸化H2AX（γ-H2AX）作为辐射暴露效应的生物指标进行评估，肿瘤微环境中的主要非恶性细胞出现了DNA损伤，表现为γ-H2AX表达增加。毒性反应为短暂的骨髓抑制和6例在治疗前未进行骨髓核型分析患者的骨髓增生异常综合征。总之，主要针对围绕里德-施特恩贝格细胞的非恶性T细胞进行重复静脉注射（90）Y-达利珠单抗，为部分HL患者提供了有效的治疗。
