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Journal For Immunotherapy of Cancer Sep 2021Tumor-associated macrophages (TAMs) play a key immunosuppressive role that limits the ability of the immune system to fight cancer and hinder the antitumoral efficacy of...
BACKGROUND
Tumor-associated macrophages (TAMs) play a key immunosuppressive role that limits the ability of the immune system to fight cancer and hinder the antitumoral efficacy of most treatments currently applied in the clinic. Previous studies have evaluated the antitumoral immune response triggered by (TLR) agonists, such as poly(I:C), imiquimod (R837) or resiquimod (R848) as monotherapies; however, their combination for the treatment of cancer has not been explored. This study investigates the antitumoral efficacy and the macrophage reprogramming triggered by poly(I:C) combined with R848 or with R837, versus single treatments.
METHODS
TLR agonist treatments were evaluated in vitro for toxicity and immunostimulatory activity by Alamar Blue, ELISA and flow cytometry using primary human and murine M-CSF-differentiated macrophages. Cytotoxic activity of TLR-treated macrophages toward cancer cells was evaluated with an in vitro functional assay by flow cytometry. For in vivo experiments, the CMT167 lung cancer model and the MN/MCA1 fibrosarcoma model metastasizing to lungs were used; tumor-infiltrating leukocytes were evaluated by flow cytometry, RT-qPCR, multispectral immunophenotyping, quantitative proteomic experiments, and protein-protein interaction analysis.
RESULTS
Results demonstrated the higher efficacy of poly(I:C) combined with R848 versus single treatments or combined with R837 to polarize macrophages toward M1-like antitumor effectors in vitro. In vivo, the intratumoral synergistic combination of poly(I:C)+R848 significantly prevented tumor growth and metastasis in lung cancer and fibrosarcoma immunocompetent murine models. Regressing tumors showed increased infiltration of macrophages with a higher M1:M2 ratio, recruitment of CD4 and CD8 T cells, accompanied by a reduction of immunosuppressive CD206 TAMs and FOXP3/CD4 T cells. The depletion of both CD4 and CD8 T cells resulted in complete loss of treatment efficacy. Treated mice acquired systemic antitumoral response and resistance to tumor rechallenge mediated by boosted macrophage cytotoxic activity and T-cell proliferation. Proteomic experiments validate the superior activation of innate immunity by poly(I:C)+R848 combination versus single treatments or poly(I:C)+R837, and protein-protein-interaction network analysis reveal the key activation of the STAT1 pathway.
DISCUSSION
These findings demonstrate the antitumor immune responses mediated by macrophage activation on local administration of poly(I:C)+R848 combination and support the intratumoral application of this therapy to patients with solid tumors in the clinic.
Topics: Animals; Antiviral Agents; Cell Line, Tumor; Combined Modality Therapy; Drug Synergism; Humans; Imidazoles; Immunotherapy; Mice; Neoplasms; Poly I-C; Tumor-Associated Macrophages
PubMed: 34531246
DOI: 10.1136/jitc-2021-002408 -
Pharmaceutics Sep 2022Melanoma is the most lethal form of skin cancer and surgery remains the preferred and most effective treatment. Nevertheless, there are cases where surgery is not a... (Review)
Review
Melanoma is the most lethal form of skin cancer and surgery remains the preferred and most effective treatment. Nevertheless, there are cases where surgery is not a viable method and alternative treatments are therefore adopted. One such treatment that has been tested is topical 5% imiquimod (IMQ) cream, which, although showing promise as a treatment for melanoma, has been found to have undesirable off-target effects. Resiquimod (RSQ) is an immunomodulatory molecule that can activate immune responses by binding to Toll-like receptors (TLR) 7 and 8 and may be more effective than IMQ in the context of melanoma treatment. RSQ can cross the stratum corneum (SC) easily without requiring pretreatment of the skin. In a gel formulation, RSQ has been studied as a monotherapy and adjuvant for melanoma treatment in pre-clinical studies and as an adjuvant in clinical settings. Although side effects of RSQ in gel formulation were also reported, they were never severe enough for the treatment to be suspended. In this review, we discuss the potential use of RSQ as an adjuvant for melanoma treatment.
PubMed: 36297510
DOI: 10.3390/pharmaceutics14102076 -
Nature Communications Sep 2023The durable response rate to immune checkpoint blockade such as anti-programmed cell death-1 (PD-1) antibody remains relatively low in hepatocellular carcinoma (HCC),...
The durable response rate to immune checkpoint blockade such as anti-programmed cell death-1 (PD-1) antibody remains relatively low in hepatocellular carcinoma (HCC), mainly depending on an immunosuppressive microenvironment with limited number of CD8 T cells, especially stem-like CD8 T cells, in tumor tissues. Here we develop engineered microparticles (MPs) derived from alpha-fetoprotein (AFP)-overexpressing macrophages to load resiquimod (R848@M2pep-MPs) for enhanced anti-PD-1 therapy in HCC. R848@M2pep-MPs target and reprogram immunosuppressive M2-like tumor-associated macrophages (TAMs) into M1-like phenotype. Meanwhile, R848@M2pep-MPs-reprogrammed TAMs act as antigen-presenting cells, not only presenting AFP antigen to activate CD8 T cell-mediated antitumor immunity, but also providing an intra-tumoral niche to maintain and differentiate stem-like CD8 T cells. Combination immunotherapy with anti-PD-1 antibody generates strong antitumor immune memory and induces abundant stem-like CD8 T cell proliferation and differentiation to terminally exhausted CD8 T cells for long-term immune surveillance in orthotopic and autochthonous HCC preclinical models in male mice. We also show that the R848-loaded engineered MPs derived from macrophages overexpressing a model antigen ovalbumin (OVA) can improve anti-PD-1 therapy in melanoma B16-OVA tumor-bearing mice. Our work presents a facile and generic strategy for personalized cancer immunotherapy to boost anti-PD-1 therapy.
Topics: Male; Animals; Mice; Tumor-Associated Macrophages; alpha-Fetoproteins; Carcinoma, Hepatocellular; CD8-Positive T-Lymphocytes; Liver Neoplasms; Immunosuppressive Agents; Antigens, Neoplasm; Tumor Microenvironment
PubMed: 37704614
DOI: 10.1038/s41467-023-41438-9 -
Expert Opinion on Investigational Drugs Jan 2013Resiquimod is an immune response modifier which stimulates cells through a toll-like receptors (TLR) 7 and 8 dependent pathway resulting in activation of immune... (Review)
Review
INTRODUCTION
Resiquimod is an immune response modifier which stimulates cells through a toll-like receptors (TLR) 7 and 8 dependent pathway resulting in activation of immune responses that are effective against viral and tumor lesions.
AREAS COVERED
Studies on genital herpes, hepatitis C and actinic keratosis (AK) as well as papers of molecular activities of resiquimod were identified by a PubMed search. Although effective against genital HSV-2 in animal models, development of topical resiquimod for the treatment of recurrent genital herpes in humans was stopped due to inconsistent results in clinical trials. Reduction of HCV viral load was achieved by oral application but was associated with unacceptable side effects. Topical treatment of AK was well tolerated and effective with clearance rates higher compared to imiquimod. The molecular mode of action underlying the clinical efficacy primarily depends on cytokine induction in TLR7/8 expressing dendritic cells in the skin.
EXPERT OPINION
Topical resiquimod was shown to be a safe and effective treatment option for AK and appears to have potential as a treatment modality for patients with extended skin areas affected with AK (field cancerization). Resiquimod may also have potential for the therapy or prevention of epithelial viral infections.
Topics: Administration, Topical; Animals; Antineoplastic Agents; Antiviral Agents; Humans; Imidazoles; Skin Diseases; Treatment Outcome; Virus Diseases
PubMed: 23205468
DOI: 10.1517/13543784.2013.749236 -
Current Opinion in Investigational... Feb 20033M Pharmaceuticals is developing a topical formulation of resiquimod as an immunomodulator for the potential treatment of herpes simplex virus (HSV) infections. As of... (Review)
Review
3M Pharmaceuticals is developing a topical formulation of resiquimod as an immunomodulator for the potential treatment of herpes simplex virus (HSV) infections. As of September 2001, resiquimod was to be commercialized worldwide in association with Eli Lilly. Phase III trials for the treatment of HSV infection were initiated in November 2000 and were ongoing in September 2001. In October 2001, US and European filings were scheduled for 2004, and by February 2002, Lilly was anticipating launch in either 2004 or 2005. The compound has also been investigated for the potential treatment of various other diseases, including other viral infections and eczema and as a vaccine adjuvant.
Topics: Administration, Topical; Antiviral Agents; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Contraindications; Eczema; Herpes Simplex; Humans; Imidazoles; Papillomavirus Infections; Structure-Activity Relationship
PubMed: 12669385
DOI: No ID Found -
Expert Opinion on Emerging Drugs Dec 2021Resiquimod is a Toll-like receptor (TLR)-7 and TLR-8 agonist that, like imiquimod, belongs to the class of imidazoquinolines, small organic molecules with potent...
Resiquimod is a Toll-like receptor (TLR)-7 and TLR-8 agonist that, like imiquimod, belongs to the class of imidazoquinolines, small organic molecules with potent antiviral and anticancer activity. Resiquimod activates myeloid and plasmacytoid dendritic cells while also promoting release of cytokines as interleukin-6, tumor necrosis factor-α and interferon-γ more effectively than imiquimod. Given these immunologic effects, resiquimod is emerging as a new topical pharmacotherapy for actinic keratosis (AK). In the pivotal trial by Stockfleth et al. complete clinical clearance in all the resiquimod-treated arms was more significant than placebo varying from 56% to 74%. Partial clinical clearance, or disappearance of >75% of AKs, was also significantly higher in the resiquimod arms varying from 75% to 87%. Overall, resiquimod is a new molecule that remains a promising therapy for AK, although additional studies are needed to further evaluate its efficacy.
Topics: Adjuvants, Immunologic; Humans; Imidazoles; Imiquimod; Keratosis, Actinic
PubMed: 34749552
DOI: 10.1080/14728214.2021.2004694 -
Expert Review of Vaccines Oct 2007Synthetic immune response modifiers, such as resiquimod, are Toll-like receptor 7 and 8 agonists that act as vaccine adjuvants, enhancing antigen-specific antibody... (Review)
Review
Synthetic immune response modifiers, such as resiquimod, are Toll-like receptor 7 and 8 agonists that act as vaccine adjuvants, enhancing antigen-specific antibody production and skewing immunity towards a Th1 response. These compounds stimulate dendritic cells to secrete cytokines, upregulate costimulatory molecule expression and enhance antigen presentation to T cells. The compounds have demonstrated vaccine adjuvant properties in a number of animal models. The adjuvant effects can be enhanced by measures that allow the drug to stay localized with the vaccine without quickly entering the systemic circulation. Clinical studies demonstrate that topical application of resiquimod and analogs is safe and effective at activating the local immune response. For injection, resiquimod or a similar compound may need to be formulated to allow for local immune activation without induction of systemic cytokines.
Topics: Adjuvants, Immunologic; Animals; Humans; Imidazoles; Immunologic Factors; Vaccines
PubMed: 17931162
DOI: 10.1586/14760584.6.5.835 -
Antiviral Research Nov 2004Genital herpes is one of the most common sexually transmitted diseases worldwide. Currently, there are three FDA-approved nucleoside analogs and other therapies such as... (Review)
Review
Genital herpes is one of the most common sexually transmitted diseases worldwide. Currently, there are three FDA-approved nucleoside analogs and other therapies such as foscarnet and cidofovir used to treat genital herpes. Resiquimod, the latest immune response modifier (IRM), has shown in vivo evidence of efficacy against herpes simplex virus (HSV) type 2. The first clinical trial involving resiquimod demonstrated that it reduced the recurrence rate of genital herpes, but phase III trials were suspended due to lack of efficacy. Resiquimod shows promise for other viral infections and as a vaccine adjuvant.
Topics: Adjuvants, Immunologic; Adult; Animals; Guinea Pigs; Herpes Genitalis; Herpesvirus 2, Human; Humans; Imidazoles; Th1 Cells; Viral Vaccines
PubMed: 15498602
DOI: 10.1016/j.antiviral.2004.07.002 -
The Journal of Antimicrobial... Dec 2001Augmenting the host's natural immune response to viruses by the administration of exogenous cytokines such as interferon-alpha (IFN-alpha) is a strategy increasingly... (Review)
Review
Augmenting the host's natural immune response to viruses by the administration of exogenous cytokines such as interferon-alpha (IFN-alpha) is a strategy increasingly employed in antiviral therapeutics. Enhancing the release of endogenous cytokines is, however, an alternative approach. The imidazoquinolinamines imiquimod and resiquimod have demonstrated potency as inducers of IFN-alpha and other cytokines both in vitro and in vivo. Cytokine gene activation is mediated via the signal transducer and activator of transcription 1 (STAT-1) and involves the transcription factors NFkappaB and alpha4F1. Antiviral activity has been demonstrated against a variety of viruses, and clinical efficacy has been demonstrated against genital warts, herpes genitalis and molluscum contagiosum. Imiquimod is administered as a 5% cream (Aldara) and has been licensed for the treatment of anogenital warts in immunocompetent patients. Complete clearance of warts has been observed in up to half of treated patients with only local side effects reported. Resiquimod can be administered topically but also exists as an oral formulation. The range of potential infections for which these agents may have clinical utility includes chronic hepatitis C virus infection and Kaposi's sarcoma. In addition, the imidazoquinolinamines may find roles in the therapy of cancers and as vaccine adjuvants.
Topics: Adjuvants, Immunologic; Aminoquinolines; Animals; Humans; Imidazoles; Imiquimod; Immunologic Factors
PubMed: 11733457
DOI: 10.1093/jac/48.6.751 -
The British Journal of Dermatology Feb 2019
Topics: Double-Blind Method; Humans; Imidazoles; Keratosis, Actinic
PubMed: 30714105
DOI: 10.1111/bjd.17436