Topical Imiquimod has Therapeutic and Immunomodulatory Effects Against Intracranial Tumors

Abstract

Topical imiquimod cream (trade name, Aldara) is a toll-like receptor (TLR) 7 agonist that is approved for the treatment of cutaneous tumors. Aldara is also employed as a vaccine adjuvant in clinical trials in patients with glioma and other tumors. The main mechanism of action ascribed to Aldara has been the local activation of TLR7+ cells near the application site. Here we report the unexpected finding that Aldara has therapeutic and immunomodulatory activity as a single agent in mice bearing intracranial tumors. Repeated administration of Aldara onto the skin significantly increased the survival of mice bearing intracranial GL261 glioma and EMT6 breast carcinoma. Aldara treatment was associated with a reduction in the number CD4+Foxp3+ regulatory T cells (Treg) in the blood and brain tumor site. Mice treated with Aldara exhibited a generalized lymphopenia in the blood amidst an increase in brain tumor infiltrating CD4+ and CD8+ T cells and dendritic cells. Brain infiltrating CD8+ T cells were tumor-reactive as demonstrated by degranulation and interferon gamma secretion in a GL261-dependent manner. Additionally, soluble imiquimod directly inhibited the proliferation of GL261 cells in a TLR7-independent manner. This is the first report demonstrating that topical application of imiquimod can enhance T cell responses to intracranial tumors as a single agent. The results must be interpreted with caution considering anatomical and biological differences between mice and humans. Nevertheless, Aldara that is being used as a vaccine adjuvant in clinical trials may have direct anti-tumor effects that are independent of exogenous antigen. Further studies in humans are warranted.

Improved Treatment Efficacy of Antiangiogenic Therapy when Combined with Picornavirus Vaccination in the GL261 Glioma Model

“…Both CD8+ and CD4+ T-cell responses have been shown to drive VEGF upregulation in the CNS under neuroinflammatory conditions, which could contribute to angiogenesis and tumor progression [35,36]. Alternatively, tumor antigen-specific cytotoxic CD8+ T cells and T helper 1/17 CD4+ T cells have been shown to contribute to antitumor immunity, hindering tumor outgrowth [34,[37][38][39]. Clinical trials are currently underway combining antiangiogenic and immune-based therapies, including a phase II trial by the Alliance for Clinical Trials in Oncology (clinicaltrials.gov identifier NCT01814813) comparing the efficacy of bevacizumab with and without a heat shock protein-peptide complex (HSPPC-96) vaccine.…”

Bacterial Immunotherapy-Antitumoral Potential of the Streptococcal Toxin Streptolysin S-

“…Another potent inducer of tumor-directed cellular immune responses is the TLR7 agonist imiquimod. In recent years, several studies proved enhancement of antigen-specific T cell activation followed by tumor eradication (Rechtsteiner et al, 2005;Prins et al, 2006;Xiong & Ohlfest, 2011). Very recently, we provided evidence for tumor growth control by avitalized grampositive bacteria.…”

Intracerebral Administration of Heat-InactivatedStaphylococcusEpidermidisEnhances Oncolysis and Prolongs Survival in a 9L Orthotopic Gliosarcoma Model

“…The common mechanism of action of such immunostimulatory adjuvants (ISA) like inactivated whole bacteria such as S. epidermidis [19] or Bacillus Calmette-Guérin [20], bacterial cell-wall peptides [21,22,23], or synthetic molecules like imiquimod [24,25] is the activation of Toll-like receptors, and the subsequent attraction and stimulation of antigen-presenting cells resulting in selective lysis of glioma cells.…”