Phase 1 Study of Resiquimod Gel Therapy for Cutaneous T-Cell Lymphoma

描述(由申请人提供)： 皮肤T细胞淋巴瘤(CTCL)是一种罕见的皮肤传输型CD4T细胞的恶性肿瘤。皮肤和血液广泛受累的晚期疾病患者预后较差，细胞免疫功能明显缺陷。这些缺陷的基础是外周血树突状细胞(DC)数量的显著下降以及这些细胞产生细胞因子的能力的显著不足，包括对抗肿瘤免疫至关重要的白细胞介素12(I-12)和干扰素α(干扰素α)。由于宿主免疫功能似乎在CTCL的疾病控制反应中发挥了不可或缺的作用，研究人员一直在研究一些激活患者DC的机制，研究人员的初步数据表明，Resiquimod在体外能够诱导晚期CTCL患者外周血细胞产生高水平的免疫刺激细胞因子白细胞介素12(IL-12)和干扰素(干扰素)α，这与自然杀伤(NK)细胞和分化簇(CD)8 T细胞的显著激活以及CD80/CD86在凋亡细胞(APC)上的上调有关。这项拨款建议了一项初步的单中心第1阶段开放标签试验，Requimod凝胶通过皮肤具有很高的生物利用度。CTCL患者将被监测1)临床反应，2)不良反应，以及一系列独特的体内免疫学分析，包括3)体内免疫刺激效应，包括DC、NK和CD8 T细胞激活，以及CD8细胞毒性T细胞和NK细胞在皮肤内的渗透以及他们产生干扰素的能力。

DESCRIPTION (provided by applicant): Cutaneous T-cell lymphoma (CTCL) is a rare malignancy of skin-trafficking CD4+ T-cells. Patients with advanced disease with extensive skin and blood involvement have a poor prognosis and exhibit marked defects in cell mediated immunity. Underlying these defects is an associated profound decline in the numbers of peripheral blood dendritic cells (DCs) along with marked deficiencies in the ability of these cells to produce cytokines, including interleukin-12 (I-12) and interferon alpha (IFN alpha), which are critical for antitumor immunity. Because host immune function appears to play an integral role in mediating disease-controlling responses in CTCL, the investigators have been investigating a number of mechanisms for activating DCs in patients, including the use of resiquimod which has been recognized as powerfully immune stimulatory by virtue of activation of DCs following binding to Toll like receptors (TLR) 7 and 8. Preliminary data of the investigators indicate that resiquimod exhibits the capacity to induce in vitro the production of high levels of the immune stimulatory cytokines interleukin-12 (IL-12) and interferon (IFN) alpha from the peripheral blood cells of advanced CTCL patients which is associated with marked activation of natural killer (NK) cells and cluster of differentiation (CD) 8+ T-cells and upregulation of CD80/CD86 on apoptotic cells (APCs). This grant proposes an initial single center phase 1, open label trial of resiquimod gel which is highly bioavailable through the skin. Patients with CTCL will be monitored for 1) clinical responses, 2) adverse effects, and a unique series of in vivo immunological assays including 3) in vivo immune stimulatory effects including DC, NK and CD8 T-cell activation, and cutaneous intralesional infiltration with CD8+ cytotoxic T-cells and NK cells as well as their ability to produce IFN gamma.