In the pathological condition of psoriasis, systemic IL-17A elevation can trigger microglia activation, provoke pro-inflammation mediators to release, evoke neuroinflammation, subsequently inhibit hippocampal neurogenesis, and result in depression. IL-17A, as an important pathogenic factor in psoriasis, contributes to its critical role in mediating systemic inflammation and depression comorbidity.

P2, N=27, Active, not recruiting, Ascendis Pharma A/S | Recruiting --> Active, not recruiting | N=92 --> 27

P2, N=54, Completed, Chengdu Suncadia Medicine Co., Ltd. | Active, not recruiting --> Completed | Trial primary completion date: Jul 2024 --> Nov 2024

CT26 mouse model was established to assess the synergistic effect of silencing HIF-1α combined with oxaliplatin (OXA) and imiquimod (IMQ) on tumor growth. Compared with those in the control group, the expression levels of the anti-inflammatory cytokines IL-10 and IL-4 significantly decreased (P < 0.05). In conclusion, our findings suggest that inhibiting HIF-1α could serve as a rational strategy to enhance the antitumor response in the TME.

Decoy10 and a closely related product, Decoy20, produced single agent anti-tumor activity or combination-mediated durable regression of established subcutaneous, metastatic or orthotopic colorectal, hepatocellular (HCC), pancreatic, and non-Hodgkin's lymphoma (NHL) tumors in mice, with induction of both innate and adaptive immunological memory (syngeneic and human tumor xenograft models). Decoy bacteria combination-mediated regressions were observed with a low-dose, oral non-steroidal anti-inflammatory drug (NSAID), anti-PD-1 checkpoint therapy, low-dose cyclophosphamide (LDC), and/or a targeted antibody (rituximab). Efficient tumor eradication was associated with plasma expression of 15-23 cytokines and chemokines, broad induction of cytokine, chemokine, innate and adaptive immune pathway genes in tumors, cold to hot tumor inflammation signature transition, and required NK, CD4+ and CD8+ T cells, collectively demonstrating a role for both innate and adaptive immune activation in the anti-tumor immune response.

The study concluded the immunotherapeutic activity of ATSLA in experimental psoriatic skin lesions. This will enrich the psoriasis immunotherapeutic list with novel candidates of parasitic origin.

Imiquimod (IMQ)-induced psoriasis-like mice were used to verify the therapeutic effects of SCP...Besides, SCP could also inhibit the phosphorylation of PI3K, Akt, and mTOR, and the good docking activity of SCP with the three pathway proteins further proved SCP can treat psoriasis via PI3K/Akt/mTOR signaling pathway. In conclusion, SCP may be a potential drug for treating psoriasis and is worth further research.

P2/3, N=740, Not yet recruiting, Eikon Therapeutics

The SNAs@CCMR consisted of antisense oligonucleotides grafted gold nanoparticles (SNAs) as core and TLR7 agonist imiquimod (R837) functionalized cancer cell membrane (CCM) as shell, in which the acid-labile Schiff base bond was used to connect the R837 and CCM...These chain processes not only damaged the primary tumor, but also produced plenty of tumor-associated antigens, which matured the surrounding dendritic cells (DCs) and activated anti-tumor T cells along with the released R837, resulting in the enhanced immunotherapy with suppressive immune escape. Both in vivo and in vitro experiments demonstrated that our nanoparticles were able to inhibit primary tumor and its metastasis via multi-regulation of carcinogenic microRNAs and RNAs dependent photothermal-immune activations, which provided a promising strategy to reprogram the immunosuppressive microenvironment in tumor tissue for better malignant tumor therapy.

Inhibiting GBP5 can mitigate the renal injury caused by psoriasis through NF-κB/STAT3 axix.

In summary, Gyp reduced excessive cell growth and inflammation in psoriasis by suppressing nuclear factor kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT3) through activation of Nrf2.

P2, N=85, Recruiting, Baylor College of Medicine

P1, N=15, Active, not recruiting, Medical University of South Carolina | Trial completion date: Sep 2024 --> Dec 2024

P=N/A, N=6, Terminated, University of California, Davis | N=110 --> 6 | Active, not recruiting --> Terminated; PI failed to submit the study for continuing review to IRB, failed to respond.

P1, N=146, Completed, Jiangsu HengRui Medicine Co., Ltd. | Not yet recruiting --> Completed | N=104 --> 146

Nrf2 and GPX4 might be the two major targets of SHK in psoriatic skin lesion. Our study highly lighted the basic biological mechanism of SHK on ferroptosis regulation.

This work suggests that the highly lipophilic prodrug approach can efficiently deliver IMQ to intestinal lymphatics. In addition, this study demonstrates the feasibility of an amide prodrug approach for intestinal lymphatic targeting.

Oral propranolol is a mainstay of treatment for IH and is well-tolerated, though propranolol-refractory IH and other drug-related adverse events are documented and can limit its usage. From this preliminary analysis, we discerned that hemangioma tissues can be grown in tissue culture and used for drug treatment studies. We also conclude acute and chronic modulation of cell cycle, angiogenesis factors, and immunostimulatory conditions may be associated with imiquimod mechanisms of action in hemangioma involution.

P1/2, N=188, Active, not recruiting, Ascendis Pharma Oncology Division A/S | Recruiting --> Active, not recruiting

BML-111 modulates the p38/MAPK signaling pathway and Th1/Th2/Th17 cytokine response, and alleviates psoriasis-like dermatitis in mice.

A mouse model for psoriasis combined with SDs was established by smearing 62.5 mg of 5% imiquimod (IMQ) cream for seven consecutive days, along with a daily injection of p-chlorophenyl alanine (PCPA) solution at a dosage of 300 mg/kg at days 6-7...XYAS may treat psoriasis complicated by SDs through two main mechanisms: (1) Improving melatonin-RORα axis in the skin can lead to an increase in mnSOD and a reduction in Cyt-C levels, which provide protection against oxidative stress, mitochondrial damage, and psoriatic inflammation. (2) Reducing IL-6, IL-17A, and TNF-α production to suppress IL-23/Th17 pro-inflammatory signaling axis and epidermal hyperplasia in psoriasis.

Local therapies can be considered in superficial and low-risk nodular BCCs, with imiquimod frequently used for its antitumor and immunoregulatory properties...Interferons and Interleukin-2 were evaluated in a small number of studies with different results. Systemic immunotherapies with programmed death-ligand 1 (PD-L1) inhibitors showed inconsistent results in patients with advanced BCCs, being effective in some patients that progressed on or were intolerant to hedgehog pathway inhibitors (HHI).

In the imiquimod (IMQ) -induced mouse inflammatory model, the therapeutic effect of GFRS on the pathogenesis of psoriasis-like dermatitis was studied...GFRS restored IMQ-induced spleen size and reduced the secretion and expression of TNF-α, IL-6, Interferon-γ (IFN-γ) and IL-17 A in serum. In summary, our results demonstrate that GFRS alleviates IMQ-induced dermatitis symptoms, effectively reduces the secretion of inflammatory factors, and inhibits IL-17 A expression.

An 87-year-old female presented with a recurrent vulvar lesion refractory to topical imiquimod and treated with multiple wide local excisions (WLE)...AAEMPD, a rare variant of EMPD, shares similar prognosis and behavior with the classic Paget disease. Recognition and accurate diagnosis of this subtype is crucial for optimal patient management, given distinct treatment strategies compared with other entities in the differential diagnosis.

P1/2, N=473, Recruiting, Ascendis Pharma Oncology Division A/S | Trial completion date: Aug 2027 --> Aug 2029 | Trial primary completion date: May 2026 --> Aug 2027

A psoriasis-like skin inflammation mouse model was induced by imiquimod (IMQ) and treated with BBR and a p38 activator anisomycin...BBR repressed NLRP3 inflammasome activation and pyroptosis by inhibiting the p38 MAPK/NF-κB pathway. Collectively, BBR suppressed keratinocyte NLRP3/GSDMD pathway pyroptosis by suppressing the p38 MAPK/NF-κB pathway, thereby affecting psoriasis skin inflammation.

We found elevated levels of mitochondrial DNA in patients with psoriasis, along with high expression of AIM2 in both the human psoriatic epidermis and a mouse model of psoriasis induced by topical imiquimod (IMQ) application. Finally, the genetic absence of inflammasome components downstream AIM2, ASC, and caspase-1 alleviated IMQ-induced skin inflammation. Collectively, our data show that AIM2 is involved in developing psoriasis through its canonical activation.

Adding a STAT-3 inhibitor yielded similar effects to IMQ, altering cell proliferation, migration and apoptosis. Overall, IMQ appears to inhibit U87 cell proliferation and migration, inducing programmed cell death through STAT-3 modulation.

Our results suggest that elevated SKP2 can empower keratinocytes proliferation and psoriasis-like epidermis hyperplasia via downregulation of P27 Kip1. Therefore, targeting SKP2-P27 Kip1 axis might be a promising therapeutic strategy for the treatment of psoriasis in future.

P1, N=7, Active, not recruiting, Mayo Clinic | Trial completion date: Dec 2024 --> Dec 2025

Mcl-1 overexpression ameliorates IMQ-induced ROS generation and mitochondrial fragmentation, thereby increasing mitochondrial stability and ultimately attenuating IMQ-induced cell death. Investigating the roles of Mcl-1 in mitochondria is a potential strategy for cancer therapy development.

In addition, an immune adjuvant of imiquimod (R837) is incorporated...Specifically, QUE inhibits the activation state of hepatic stellate cells and reduces highly expressed programmed death receptor ligand 1 (PD-L1) on tumor cells, meanwhile R837 exposes calreticulin on tumor cell surface as an "eat me" signal and leads to a large number of DCs maturing for enhanced antigen presentation. Consequently, the cooperative immune regulation results in a remodeled TME with high infiltration of cytotoxic T lymphocytes for enhanced HCC immunotherapy, which demonstrates an effective immunotherapy paradigm for dense ECM characterized solid tumors with high PD-L1 expression.

We showed that TLR7 activation by imiquimod in peripheral blood monocyte-derived CD11c+ DCs triggered mROS production, leading to enhanced IL-12 secretion and subsequent NK cell activation, as evidenced by increased IFN-γ production and tumor cell cytotoxicity. Notably, mROS neutralization abrogates NK cell-mediated tumor cell lysis, and TLR7-mediated DC activation of NK cells occurs independently of MyD88, suggesting involvement of the noncanonical NF-κB pathway. Our findings provide a rationale for targeting the TLR7/mROS/IL-12 axis to enhance the efficacy of DC-based cancer immunotherapy.

CarboCell can be injected through standard thin-needle technologies and has inherent imaging contrast which secure accurate intratumoral positioning. In particular, here we report the therapeutic performance for a dual-drug CarboCell providing sustained release of a Toll-like receptor 7/8 agonist and a transforming growth factor-β inhibitor in preclinical tumor models in female mice.

Representative agonists from this series were successfully able to induce the production of various proinflammatory cytokines and chemokines from human peripheral blood mononuclear cells. Anti-HER2-25 and anti-HER2-26 ADCs made from this class of payloads demonstrated mechanism-based activation of TLR7/8 in a THP1/N87 coculture system.

Assisted by imiquimod, substantial CTL infiltration occurs, accompanied by pro-inflammatory factor release (TNF-α, IL-6), transforming M2 macrophages into the M1 phenotype. Ultimately, the proposed strategy combines PD-L1/PD-1 blockade, imiquimod and mild thermal treatment to synergistically enhance tumor immunogenicity, remodel the TME, and restrain hepatic carcinoma, making strides in ICB synergistic immune-thermal therapy.

P1/2, N=40, Recruiting, Shanghai Zhimeng Biopharma, Inc. | Not yet recruiting --> Recruiting | Trial completion date: Mar 2024 --> Dec 2025 | Trial primary completion date: Mar 2024 --> Dec 2024

P2, N=90, Recruiting, Chia Tai Tianqing Pharmaceutical Group Co., Ltd.

P1/2, N=175, Active, not recruiting, Bolt Biotherapeutics, Inc. | N=390 --> 175 | Trial completion date: Oct 2026 --> Jan 2026

P2, N=11, Active, not recruiting, Bolt Biotherapeutics, Inc. | N=66 --> 11

Taken together, these data demonstrate that RT combined with a nanoformulated immunostimulant diminished the immunosuppressive TME resulting in tumor regression. These findings set the stage for clinical studies of this approach.

phenformin ameliorates the psoriasis-like inflammatory response by inhibiting c-Myc expression in keratinocytes, suggesting its potential as a topical drug for the treatment of psoriasis.