Reversing immune evasion and enhancing immune detection with topical resiquimod

使用外用瑞西莫德逆转免疫逃避并增强免疫检测

• 批准号: 10241428
• 负责人: Rachael Ann Clark
• 金额: $ 43.81万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-07 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10241428
• 关键词: Adaptive Immune System; Aftercare; Agonist; Ancillary Study; Biological Assay; Biopsy; Biopsy Specimen; Blood; Blood Circulation; Blood specimen; CCL18 gene; CD8-Positive T-Lymphocytes; Cells; Clinical Trials; Clone Cells; Cutaneous T-cell lymphoma; Cytokine Activation; Cytometry; Dendritic Cells; Detection; Distant; Enrollment; Gel; Gene Expression; Gene Expression Profiling; Goals; Immune; Immune Evasion; Immune response; Immunity; Immunologics; Immunomodulators; Impairment; Industry; Infection; Infectious Skin Diseases; Innate Immune System; Interferon Type I; Lesion; Malignant - descriptor; Malignant Neoplasms; Measures; Mediating; Natural Killer Cells; Patients; Pharmaceutical Preparations; Phase; Population; Production; Refractory; Regulatory T-Lymphocyte; Sampling; Skin; Skin Cancer; T cell receptor repertoire sequencing; T-Cell Activation; T-Lymphocyte; TLR7 gene; TLR8 gene; Testing; Th2 Cells; Time; Topical application; Travel; adaptive immune response; anti-cancer; base; chemokine; cytokine; double-blind placebo controlled trial; effector T cell; exhaustion; first-in-human; improved; in vitro Assay; macrophage; migration; nano-string; phase I trial; phase II trial; recruit; resiquimod; response; single-cell RNA sequencing; skin lesion; tumor; tumor microenvironment

Project Summary/Abstract Resiquimod gel is a topically applied immunomodulator and TLR7/8 agonist. It stimulates dendritic cells (DC) in both healthy and inflamed skin and can potently enhance immune responses. In a small phase I trial of in 12 heavily pretreated patients with refractory, skin limited cutaneous T cell lymphoma (CTCL), topical resiquimod reversed immune evasion, improved immunodetection and induced effector anticancer responses both locally and systemically. 90% of patients had reduction in the malignant T cell clone in treated lesions and 83% had regression of both treated and distant, untreated skin lesions, demonstrating that this topical therapy enhances systemic immune responses. The ability of this drug to enhance both local and systemic immune responses suggests that topical resiquimod could be a promising new treatment for both skin infections and cancer. We propose time sensitive, first in human ancillary studies of fresh biopsy specimens and blood samples from an industry sponsored, multicenter, phase II, double blind, placebo-controlled trial of resiquimod gel in the treatment of stage IA, IB and IIA CTCL. We hypothesize that topical resiquimod enhances both innate and adaptive immune responses and we propose three Aims to study the effects of topical resiquimod on i) the innate immune system, ii) the adaptive immune system, and iii) to discover the mechanisms by which untreated lesions regress. We will use single cell RNA sequencing (scRNA-seq), NanoString based gene expression profiling, multiplex immunostaining and TCR sequencing to study skin biopsies before and after resiquimod therapy and we will use cytometry by time of flight (CyTOF), TCR sequencing and functional assays to study blood samples before and after treatment. We will evaluate specific hypotheses that resiquimod induces a shift in macrophage polarization from M2 to M1, activates NK cells, enhances recruitment of T cells into skin, reverses exhaustion of T cells within the tumor microenvironment and/or generates new tumor-specific T cells. We will determine if regression of untreated lesions is associated with detectable levels of type I interferons or Th1 cytokines, activation of circulating DC or NK cells, or travel of tumor-specific T cells through the bloodstream to untreated lesions. These studies are time sensitive because they require the use of fresh biopsy specimens from an ongoing clinical trial. Our studies will clarify the mechanisms of action of this promising new medication and determine how it reverses immune evasion and enhances immunodetection in CTCL. These studies may support the use of resiquimod in the treatment of other skin cancers and infections.

项目摘要/摘要 Resiquimod Gel是一种外用免疫调节剂和TLR7/8激动剂。它刺激树突状细胞(DC)在 健康和发炎的皮肤，并能有效地增强免疫反应。在12个月内进行的I期小试验中 严重预处理的难治性皮肤局限性T细胞淋巴瘤(CTCL)患者，局部用药 逆转免疫逃避、改进免疫检测和诱导局部效应性抗癌反应 而且是系统性的。90%的患者在治疗的皮损中恶性T细胞克隆减少，83%的患者 已治疗和远处未治疗的皮肤损害的消退，表明这种局部治疗增强了 全身免疫反应。这种药物增强局部和全身免疫反应的能力 这表明，局部应用瑞奎莫德可能是治疗皮肤感染和癌症的一种有前途的新疗法。我们 建议时间敏感，首次在人类辅助研究中对新鲜的活组织检查样本和来自 工业赞助、多中心、II期、双盲、安慰剂对照试验 IA、IB和IIA期CTCL的治疗。我们假设局部用药能同时增强先天和后天 获得性免疫反应，我们提出了三个目的来研究局部残留对i)的影响 先天免疫系统，ii)适应性免疫系统，以及iii)发现 未经治疗的皮损会消退。我们将使用单细胞RNA测序(scRNA-seq)，基于纳米串的基因 表达谱、多重免疫染色和TCR测序研究皮肤活检前后的变化 Requimod治疗，我们将使用飞行时间(CyTOF)、TCR测序和功能 检测治疗前后的血样。我们将评估特定的假设，即 利斯奎莫特诱导巨噬细胞极化从M2向M1转变，激活NK细胞，增强 T细胞重新进入皮肤，逆转肿瘤微环境和/或肿瘤内T细胞的耗尽 产生新的肿瘤特异性T细胞。我们将确定未经治疗的皮损的消退是否与 I型干扰素或Th1细胞因子的可检测水平，循环DC或NK细胞的激活，或 肿瘤特异性T细胞通过血流到达未经治疗的病变部位。这些研究具有时间敏感性，因为 他们需要使用正在进行的临床试验中的新鲜活检标本。我们的研究将澄清 这种有希望的新药的作用机制，并确定它如何逆转免疫逃避和 增强CTCL的免疫检测。这些研究可能支持将瑞奎莫德用于治疗卵巢癌。 其他皮肤癌和感染。