Rasku Mary Ann, Clem Amy L, Telang Sucheta, Taft Beverly, Gettings Kelly, Gragg Hana, Cramer Daniel, Lear Sheron C, McMasters Kelly M, Miller Donald M, Chesney Jason
Molecular Targets Program, James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, USA.
J Transl Med. 2008 Mar 11;6:12. doi: 10.1186/1479-5876-6-12.
Cognate immunity against neoplastic cells depends on a balance between effector T cells and regulatory T (Treg) cells. Treg cells prevent immune attack against normal and neoplastic cells by directly suppressing the activation of effector CD4+ and CD8+ T cells. We postulated that a recombinant interleukin 2/diphtheria toxin conjugate (DAB/IL2; Denileukin Diftitox; Ontak) may serve as a useful strategy to deplete Treg cells and break tolerance against neoplastic tumors in humans.
We administered DAB/IL2 (12 microg/kg; four daily doses; 21 day cycles) to 16 patients with metastatic melanoma and measured the effects on the peripheral blood concentration of several T cell subsets and on tumor burden.
We found that DAB/IL2 caused a transient depletion of Treg cells as well as total CD4+ and CD8+ T cells (< 21 days). T cell repopulation coincided with the de novo appearance of melanoma antigen-specific CD8+ T cells in several patients as determined by flow cytometry using tetrameric MART-1, tyrosinase and gp100 peptide/MHC conjugates. Sixteen patients received at least one cycle of DAB/IL2 and five of these patients experienced regressions of melanoma metastases as measured by CT and/or PET imaging. One patient experienced a near complete response with the regression of several hepatic and pulmonary metastases coupled to the de novo appearance of MART-1-specific CD8+ T cells. A single metastatic tumor remained in this patient and, after surgical resection, immunohistochemical analysis revealed MART1+ melanoma cells surrounded by CD8+ T cells.
Taken together, these data indicate that transient depletion of T cells in cancer patients may disrupt the homeostatic control of cognate immunity and allow for the expansion of effector T cells with specificity against neoplastic cells. Several T cell depleting agents are clinically available and this study provides strong rationale for an examination of their efficacy in cancer patients.
NCT00299689 (ClinicalTrials.gov Identifier).
针对肿瘤细胞的同源免疫取决于效应T细胞和调节性T（Treg）细胞之间的平衡。Treg细胞通过直接抑制效应CD4+和CD8+ T细胞的激活来防止对正常细胞和肿瘤细胞的免疫攻击。我们推测重组白细胞介素2/白喉毒素偶联物（DAB/IL2；地尼白介素-布舍瑞林；Ontak）可能是一种有用的策略，可用于消耗Treg细胞并打破人类对肿瘤的耐受性。
我们对16例转移性黑色素瘤患者给予DAB/IL2（12微克/千克；每日4剂；21天为一个周期），并测量其对几种T细胞亚群外周血浓度和肿瘤负荷的影响。
我们发现DAB/IL2导致Treg细胞以及总CD4+和CD8+ T细胞短暂耗竭（<21天）。T细胞再填充与通过使用四聚体MART-1、酪氨酸酶和gp100肽/MHC偶联物的流式细胞术测定的几名患者中黑色素瘤抗原特异性CD8+ T细胞的重新出现同时发生。16例患者接受了至少一个周期的DAB/IL2，其中5例患者的黑色素瘤转移灶通过CT和/或PET成像测量出现消退。1例患者出现近乎完全缓解，几个肝转移灶和肺转移灶消退，同时出现MART-1特异性CD8+ T细胞。该患者仍有单个转移瘤，手术切除后，免疫组织化学分析显示MART1+黑色素瘤细胞被CD8+ T细胞包围。
综上所述，这些数据表明癌症患者T细胞的短暂耗竭可能会破坏同源免疫的稳态控制，并允许对肿瘤细胞具有特异性的效应T细胞扩增。临床上有几种T细胞耗竭剂可用，本研究为检验它们在癌症患者中的疗效提供了有力的理论依据。
NCT00299689（ClinicalTrials.gov标识符）。
Zotero 插件
