Wednesday, October 04, 2006

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.

1. Hamblin TJ, Verrier Jones J, Peacock DB. The immune response to x 174 in man: iv primary and secondary antibody production in patients with chronic lymphatic leukaemia. Clinical and Experimental Immunology 1975; 21:101 108.
2. Sinisalo M, Aittoniemi J, Oivanen P, Olander R-M, Vilpo J. Response to vaccination against different types of antigens in patients with chronic lymphocytic leukaemia. Brit J Haematol 2001; 114:107-110.
3. Oscier D, Fegan C, Hillmen P et al. Guidelines on the management of chronic lymphocytic leukaemia. Brit J Haematol 2004; 125:294-317.
4. Jurlander J, de Nully Brown P, Skov PS et al. Improved vaccination response during ranitidine treatment, and increased plasma histamine concentrations, in patients with B cell chronic lymphocytic leukemia. Leukemia 1995; 9:1902-1909.
5. van der Velden AMT, Mulder AHL, Hartkamp A, Diepersloot RJA, van Velzen-Blad H, Biesma DH. Influenza virus vaccination and booster in B cell chronic lymphocytic leukaemia patients. Eur J Int Med 2001; 12:420-424.
6. Ljungman P, Nahi H, Linde A. Vaccination of patients with haematological malignancies with one or two doses of influenza vaccine: a randomized study. Brit J Haematol 2005; 130:96-98.
7. Orsini E, Guarina A, Chiaretti S, Mauro FR, Foa R. The circulating dendritic cell compartment in patients with chronic lymphocytic leukemia is severely defective and unable to stimulate an effective T-cell response. Cancer Res 2003; 63:4497-4506.
8. Orsini E, Pasquale A, Maggio R et al. Phenotypic and functional chatacterization of monocyte-derived dendritic cells in chronic lymphocytic leukaemia patients: influence of neoplastic CD19 cells in vivo and in vitro. Brit J Haematol 2004; 125:720-728.
9. Messmer D, Telusma G, Wasil T et al. Dendritic cells from chronic lymphocytic leukemia patients are normal regardless of Ig V gene mutation status. J Mol Med 2004; 10:7-12.
10. Stanley MA. Imiquimod and the imidazoquiniolones: mechanism of action and therapeutic potential. Clin Exp Dermatol 2002; 27:571-577.
11. Rechsteiner G, Warger T, Osterloh P, Schild H, Radsak MP. Cutting edge: priming of CTL by transcutaneous peptide immunization with Imiquamod. J Immunol 2005; 174:2476-2480.
12. Warger T, Osterloh P, Rechsteiner G et al. Synergistic activation of dendritic cells by combined Toll-like receptor ligation induces superior CTL responses in vivo. Blood. 2006; 108:544-550.

1 comment:

Anonymous said...

Sounds like a great idea for a clinical trial for CLL patients. As you describe it, it certainly sounds logical.

It, of course, would be a huge advance to help correct the ever-present impaired immune system for CLL patients.

As far as I understand it, even in a person with a persistant complete remission, the immune system never recovers in spite of an of CLL cells anywhere.

Either CLL is proceeded by an unknown defect in the immune system, it occurs virtually simultaneously with the development of the clonal population, or the CLL itself drives the immune system to malfunction.

I'm glad Dr. Hamblin included references; I plan on reading about dendritic cells and CLL.