Topical resiquimod can induce disease regression and enhance T-cell effector functions in cutaneous T-cell lymphoma

Rook, Alain H.; Gelfand, Joel M.; Wysocka, Maria; Troxel, Andrea B.; Benoit, Bernice M.; Surber, Christian; Elenitsas, Rosalie; Buchanan, Marie; Leahy, Deborah S.; Watanabe, Rei; Kirsch, Ilan R.; Kim, Ellen J.; Clark, Rachael A.

doi:10.1182/blood-2015-02-630335

Cited by 190 publications

(142 citation statements)

References 25 publications

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“…Consistent with this conclusion, administration of the Th1 cytokines IL-12 and IFN-γ can induce lesional regression associated with increased numbers of cytotoxic CD8 + T cells in the resolving skin, and treatment with Toll-like receptor (TLR) agonists that stimulate cellular immunity have shown clinical efficacy in CTCL patients [136–144]. For example, a recent clinical phase 1 trial reported that 75 % of the enrolled CTCL patients had significant improvement in skin lesions treated topically with resiquimod gel (TLR-7 and TLR-8 agonist) and 30 % had clearing of all treated lesions.…”

Section: Drugs That Stimulate Cellular Immunity Induce Disease Regresmentioning

confidence: 92%

Malignant inflammation in cutaneous T‐cell lymphoma—a hostile takeover

et al. 2016

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Cutaneous T-cell lymphomas (CTCL) are characterized by the presence of chronically inflamed skin lesions containing malignant T cells. Early disease presents as limited skin patches or plaques and exhibits an indolent behavior. For many patients, the disease never progresses beyond this stage, but in approximately one third of patients, the disease becomes progressive, and the skin lesions start to expand and evolve. Eventually, overt tumors develop and the malignant T cells may disseminate to the blood, lymph nodes, bone marrow, and visceral organs, often with a fatal outcome. The transition from early indolent to progressive and advanced disease is accompanied by a significant shift in the nature of the tumor-associated inflammation. This shift does not appear to be an epiphenomenon but rather a critical step in disease progression. Emerging evidence supports that the malignant T cells take control of the inflammatory environment, suppressing cellular immunity and anti-tumor responses while promoting a chronic inflammatory milieu that fuels their own expansion. Here, we review the inflammatory changes associated with disease progression in CTCL and point to their wider relevance in other cancer contexts. We further define the term “malignant inflammation” as a pro-tumorigenic inflammatory environment orchestrated by the tumor cells and discuss some of the mechanisms driving the development of malignant inflammation in CTCL.

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Section: Drugs That Stimulate Cellular Immunity Induce Disease Regresmentioning

confidence: 92%

Malignant inflammation in cutaneous T‐cell lymphoma—a hostile takeover

et al. 2016

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“…Dying tumor cells release intracellular components such as high-mobility-group box 1, ATP, and DNA, which are recognized, in turn, by receptors such as Toll-like receptor (TLR) 4 (Apetoh et al, 2007), P2X7 receptor (P2X7R) (Ghiringhelli et al, 2009), and stimulator of interferon genes (STING) (Deng et al, 2014) to regulate immune responses against tumors. Accordingly, a number of innate sensor agonists are being brought forward for investigation in cancer patients (Corrales and Gajewski, 2015; Kaczanowska et al, 2013; Rook et al, 2015). …”

Section: Introductionmentioning

confidence: 99%

CD40 Stimulation Obviates Innate Sensors and Drives T Cell Immunity in Cancer

2016

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SUMMARY Cancer immunotherapies are more effective in tumors with robust T cell infiltrates, but mechanisms to convert T cell-devoid tumors with active immunosuppression to those capable of recruiting T cells remain incompletely understood. Here, using genetically engineered mouse models of pancreatic ductal adenocarcinoma (PDA), we demonstrate that a single dose of agonistic CD40 antibody with chemotherapy rendered PDA susceptible to T cell-dependent destruction and potentiated durable remissions. CD40 stimulation caused a clonal expansion of T cells in the tumor, but the addition of chemotherapy optimized myeloid activation and T cell function. Although recent data highlights the requirement for innate sensors in cancer immunity, these canonical pathways – including TLRs, inflammasome, and Type I interferon/STING – played no role in mediating the efficacy of CD40/chemotherapy. Thus, CD40 functions as a non-redundant mechanism to convert the tumor microenvironment immunologically. Our data provide a rationale for a newly initiated clinical trial of CD40/chemotherapy in PDA.

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“…Remarkably, with this topical treatment, not only the treated but also the untreated lesions showed regression. Activation of DCs, enhanced CD8+ T-cell effector function, and a trend towards improved NK cell function were demonstrated but did not correlate with response [62]. Imiquimod is FDA-and EMA-approved for actinic keratosis, superficial basal-cell carcinoma, and condylomata accuminata [23,24].…”

Section: Toll-like Receptor Agonistsmentioning

confidence: 99%

Innovative Treatment Concepts for Cutaneous T-Cell Lymphoma Based on Microenvironment Modulation

et al. 2017

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Cutaneous T-cell lymphomas (CTCL) are a rare and biologically heterogeneous malignant entity comprising mycosis fungoides and Sézary syndrome as the most common subtypes. The current treatment outcome is characterized by high rates of relapse, but survival is usually not significantly shortened in low-stage disease. This is different in tumor-stage disease or aggressive CTCL subtypes where survival is significantly reduced. Recent advances have been made on several levels of tumor biology: Whole genome sequencing has resulted in novel strategies of NF-κB or JAK inhibition, ongoing translational research has revealed new targets like CD30 or CCR4, and, finally, research focusing on impaired immunosurveillance has gained more importance. Based on the growing knowledge about the functional roles of the tumor microenvironment and non-malignant infiltrating cells, current research aims to develop novel CTCL treatment strategies. This review focuses on the mounting evidence for efficiently targeting tumor-infiltrating immune cells and thereby modulating the tumor microenvironment and restoring immunosurveillance.

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Topical resiquimod can induce disease regression and enhance T-cell effector functions in cutaneous T-cell lymphoma

Abstract: Key Points Topical resiquimod is a safe, effective therapy for early-stage CTCL that can clear both treated and untreated skin lesions. Responding patients had T-cell recruitment into skin, enhanced T-cell effector functions, and eradication of the malignant T-cell clones.

Cited by 190 publications

References 25 publications

Malignant inflammation in cutaneous T‐cell lymphoma—a hostile takeover

Malignant inflammation in cutaneous T‐cell lymphoma—a hostile takeover

CD40 Stimulation Obviates Innate Sensors and Drives T Cell Immunity in Cancer

Innovative Treatment Concepts for Cutaneous T-Cell Lymphoma Based on Microenvironment Modulation

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