Topical resiquimod can induce disease regression and enhance T-cell effector functions in cutaneous T-cell lymphoma
Topical resiquimod can induce disease regression and enhance T-cell effector functions in cutaneous T-cell lymphoma
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DOI：
10.1182/blood-2015-02-630335
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发表时间：
2015-09-17
期刊：
影响因子：
20.3
通讯作者：
Clark, Rachael A.
中科院分区：
文献类型：
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作者：
Rook, Alain H.;Gelfand, Joel C.;Clark, Rachael A.
早期皮肤T细胞淋巴瘤(CTCL)是一种皮肤局限性淋巴瘤，除干细胞移植外无法治愈。12例IA-IIA期CTCL患者接受了0.03%和0.06%Toll样受体7/8激动剂Resiquimod凝胶外用的1期试验。在75%的患者中，治疗后的皮损明显改善，30%的患者的皮损全部清除。Resiquimod还能使未经治疗的皮损消退。通过改进的严重程度加权评估工具分析，92%的患者的体表面积改善了50%以上，2名患者的疾病完全消失。5例促滤泡性疾病患者中有4例也有明显改善。副作用很小，而且主要局限于皮肤。T细胞受体测序和流式细胞术研究表明，90%的患者克隆性恶性T细胞减少，30%的患者恶性T细胞完全消除。高应答率与良性T细胞克隆在治疗后皮肤中的招募和扩张、皮肤T细胞效应器功能的增强以及自然杀伤细胞功能增强的趋势有关。在恶性T细胞完全或接近消除的患者中，残留的临床炎症与良性T细胞产生的细胞因子有关。50%的患者循环树突状细胞激活增加，这与治疗的全身反应一致。综上所述，局部利奎莫德在早期CTCL中是安全有效的，也是据我们所知的第一种局部治疗方法，可以导致一些患者未治疗的皮损清除和完全缓解。这项试验在www.Clinicaltrials.gov上注册为#NCT813320。
Early-stage cutaneous T-cell lymphoma (CTCL) is a skin-limited lymphoma with no cure aside from stem cell transplantation. Twelve patients with stage IA-IIA CTCL were treated in a phase 1 trial of 0.03% and 0.06% topical resiquimod gel, a Toll-like receptor 7/8 agonist. Treated lesions significantly improved in 75% of patients and 30% had clearing of all treated lesions. Resiquimod also induced regression of untreated lesions. Ninety-two percent of patients had more than a 50% improvement in body surface area involvement by the modified Severity-Weighted Assessment Tool analysis and 2 patients experienced complete clearing of disease. Four of 5 patients with folliculotropic disease also improved significantly. Adverse effects were minor and largely skin limited. T-cell receptor sequencing and flow cytometry studies of T cells from treated lesions demonstrated decreased clonal malignant T cells in 90% of patients and complete eradication of malignant T cells in 30%. High responses were associated with recruitment and expansion of benign T-cell clones in treated skin, increased skin T-cell effector functions, and a trend toward increased natural killer cell functions. In patients with complete or near eradication of malignant T cells, residual clinical inflammation was associated with cytokine production by benign T cells. Fifty percent of patients had increased activation of circulating dendritic cells, consistent with a systemic response to therapy. In summary, topical resiquimod is safe and effective in early-stage CTCL and the first topical therapy to our knowledge that can induce clearance of untreated lesions and complete remissions in some patients. This trial was registered at www.clinicaltrials.gov as #NCT813320.