The Imiquimod Trial

Respiratory infections are one of the commonest causes of death in patients with chronic lymphocytic leukemia (CLL). Immunodeficiency is one of the most important features of the disease. Severe hypogammaglobulinemia is a common complication, and even patients with early disease have an impaired ability to produce an antibody response to a novel antigen [1]. Even with a recall antigen like tetanus toxoid antibody responses were only seen in stage A patients in 4/14 patients and not at all in more advanced stage patients [2].

Although patients with CLL are advised to receive annual vaccination against influenza [3], the production of a protective antibody response is extremely uncertain. There have been three recent studies of attempts to increase responses by giving a second booster vaccination shortly after the initial dose. In the first [4] the response rate went from 14% to 35%; in the second [5] from 0% to 5%; and in the third [6] which included patients with other haematological malignancies, the response rose from 18% to 22%. In real life it is likely that the most beneficial effect of influenza vaccination for CLL patients is herd immunity, with spouses, relatives and friends being vaccinated

The cause of the immunodeficiency in CLL is not known. Although it is worse in more advanced patients, it precedes treatment and it precedes the development of hypogammaglobulinemia. It occurs very early in the disease, long before the lymphoid system is overwhelmed by infiltration with CLL cells.

One possibility is a defect in antigen presentation. The most important antigen presenting cells are dendritic cells. In CLL the circulating dendritic cell is severely defective and unable to stimulate an effective T cell response [7]. This defect seems to be due to the presence of the CLL cells, possible operating via one of the many cytokines (including IL-6, IL-10, VEGF and M-CSF) that CLL cells produce [8]. Nevertheless, when stimulated by an appropriate cytokine milieu it is possible stimulate and activate dendritic cells derived from the peripheral blood of CLL patients [9].

A new group of immune stimulants, the imidazoquinolones [10], act by binding to Toll receptor 7 on the surface of macrophages, inducing the secretion of the pro-inflammatory cytokines IFN-gamma, TNF-alpha, and IL-12. This local cytokine milieu favours the development of activated dendritic cells. One of the imidazoquinolones, Imiquimod, is licensed for the treatment of genital and perianal warts and for basal cell carcinoma, and is available as a cream to apply to the skin. The drug has also being investigated as an adjuvant in cancer vaccine studies where preliminary experiments demonstrate its capacity for activating dendritic cells and markedly enhancing the production of cytotoxic T lymphocytes [11, 12].

We propose to investigate the possibility that the application of Imiquimod to the site of a subcutaneous vaccination might enhance the immune response to influenza vaccine in patients with chronic lymphocytic leukaemia. In order, to see an effect of Imiquimod it will be necessary to give the vaccine subcutaneously rather than intramuscularly. Influenza vaccines are licensed for this mode of administration and although it is normally reserved for patients with bleeding disorders, it is equally efficacious. However, to control for the different route of administration and for the fact that CLL patients mostly belong to an older generation and might give a poorer response to vaccination because of this, we propose to offer subcutaneous influenza vaccination to patients’ spouses, measuring responses in a similar way. This would, in any case, be part of routine management to take advantage of herd immunity.

References
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