Regression of lymphomatous skin deposits in a chronic lymphocytic leukemia patient treated with the Toll-like receptor-7/8 agonist, imiquimod

Abstract

The identification of clinically relevant, active immunomodulatory agents is important for developing immunotherapeutic approaches to chronic lymphocytic leukemia (CLL) and other B-cell lymphomas that are not curable with conventional chemotherapy. In this investigation, the imidazoquinoline Toll-like receptor (TLR)-7/8 agonist, imiquimod, was found to mediate the clearance of a lymphomatous skin lesion in a CLL patient. Imidazoquinolines also activated TLR-7/8 signaling pathways, resulting in increased expression of costimulatory molecules on circulating tumor cells. These observations extend the therapeutic spectrum of imiquimod to cutaneous B-cell lymphomas and suggest the use of TLR-7/8 agonists in CLL immunotherapy.

Toll-like receptor agonists in the treatment of chronic lymphocytic leukemia

“…Similar observations regarding the effect of CpG oligonucleotides on costimulatory molecule expression have been made by Jahrsdorfer et al [38][39][40] Qualitatively similar findings have been made with imidazoquinolines, which are agonists of TLR-7. 32,35,41 Consistent with signaling through TLR-7, the imidazoquinoline, S28690, activated the NF-kB, JNK and p38 pathways, which were blocked by the IRAK1 inhibitor, AG126, and the endosomal inhibitors, chloroquine and bafilomycin. 32 S28690 invariably increased the expression of the costimulatory molecules that were reported to be increased by CpG oligonucleotides, and also stimulated TNF-a and IL-6 production.…”

“…Accordingly, topical imiquimod (another imidazoquinoline licensed for the treatment of genital warts and certain skin cancers 16 ) was used to treat a patient with skin involvement by CLL cells and found to clear cutaneous leukemia cells over a period of several weeks. 35 Minimal systemic activity was noted, but the strong local activity suggested that intravenous administration of imidazoquinolines might be useful for treating CLL. Accordingly, a phase I dose-escalation trial of the TLR-7-specific imidazoquinoline, 852A, 70 is ongoing at the Toronto-Sunnybrook Regional Cancer Center, based on the results of a previous phase-I study in solid tumor patients, which suggested a maximum tolerated dose of 1.2 mg/m 2 .…”

“…31 In addition, TLR expression is subject to control by cytokines, such as type 1 IFNs. 34 Published data indicate that CLL cells do not normally express TLR8 mRNA, 35 or TLR-3 and TLR-4 proteins (as measured by responses to dsRNA or LPS, respectively 32 ). However, gene array and proteomic studies are needed to document fully the expression of TLRs, other than TLR-7 and TLR-9 (along with additional components of TLR-signaling pathways) by CLL cells.…”

Obstacles to effective Toll-like receptor agonist therapy for hematologic malignancies

“…Exciting results have been seen with a TLR-7/8 agonist (AL-DARA) in cutaneous lymphomas (Spaner et al, 2005;Coors et al, 2006). However, recent phase I/II trials of CpG oligonucleotides in lymphoma patients provided no evidence of clinical responses despite increased NK activation (Link et al, 2006).…”

“…Hyperbaric oxygen may be able to increase intratumoral oxygen tension (Al Waili et al, 2005). The importance of improving tumor oxygenation is possibly shown by the discrepancy between the responses of cutaneous and systemic lymphomas to TLR-agonist therapy (Spaner et al, 2005;Link et al, 2006). While topical administration may yield higher local agonist levels, the greater susceptibility of cutaneous lesions may also be due to proximity to the atmosphere, resulting in higher partial oxygen pressures and greater oxidative phosphorylation in the tumor cells.…”