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凝胶是一种局部应用的免疫调节剂和TLR7/8激动剂。它刺激树突状细胞（DC） 健康和发炎的皮肤都可以有效增强免疫反应。在一个小阶段试验中， 经过严格预处理的难治性，皮肤有限的皮肤T细胞淋巴瘤（CTCL），局部resiquimod 逆转免疫逃避，改善的免疫检测和诱导效应抗癌反应均可局部 并系统地。 90％的患者在治疗病变中的恶性T细胞克隆减少，有83％的患者患有 治疗和远处，未处理的皮肤病变的回归，表明这种局部疗法增强了 系统性免疫反应。该药物增强局部和全身免疫反应的能力 这表明局部重复莫基族可能是皮肤感染和癌症的新方法。我们 提出对时间敏感的提议，首先是针对新鲜活检标本和血液样本的人类辅助研究 行业赞助的，多中心，第二阶段，双盲，安慰剂对照的Resiquimod凝胶试验 IA，IB和IIA CTCL的治疗。我们假设局部resiquimod增强了先天性和 自适应免疫反应，我们提出了三个目的，旨在研究局部resiquimod对i） 先天免疫系统，ii）自适应免疫系统，以及iii）发现的机制 未经治疗的病变回归。我们将使用单细胞RNA测序（SCRNA-SEQ），基于纳米弦的基因 表达分析，多重免疫染色和TCR测序，以研究皮肤活检之前和之后 Resiquimod疗法，我们将按照飞行时间（Cytof），TCR测序和功能性使用细胞仪 治疗前后研究血液样本的测定。我们将评估特定的假设 resiquimod诱导巨噬细胞极化从M2转移到M1，激活NK细胞，增强 将T细胞募集到皮肤中，逆转肿瘤微环境内T细胞的耗尽和/或 生成新的肿瘤特异性T细胞。我们将确定未处理病变的回归是否与 可检测的I型干扰素或Th1细胞因子的可检测水平，循环直流或NK细胞的激活或行进 肿瘤特异性的T细胞通过血液到未处理的病变。这些研究很敏感，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。我们的研究将阐明 这种有希望的新药物的作用机制，并确定它如何逆转免疫逃避和 增强CTCL中的免疫检测。这些研究可能支持使用Resiquimod在治疗中 其他皮肤癌和感染。