Fludarabine modulates composition and function of the T cell pool in patients with chronic lymphocytic leukaemia.

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Blank Fludarabine modulates composition and function of the T cell pool in

patients with chronic lymphocytic leukaemia.

FJ Gassner, L Weiss, R Geisberger, JP Hofbauer, A Egle, TN Hartmann, R Greil,

and I Tinhofer

Cancer Immunol Immunother, September 21, 2010; .

Laboratory for Immunological and Molecular Cancer Research (LIMCR), 3rd Medical

Department with Haematology, Medical Oncology, Haemostaseology, Rheumatology and

Infectiology, Paracelsus Medical University Salzburg, Muellner Hauptstrasse 48,

5020, Salzburg, Austria.

The combination of cytotoxic treatment with strategies for immune activation

represents an attractive strategy for tumour therapy. Following reduction of

high tumour burden by effective cytotoxic agents, two major immune-stimulating

approaches are being pursued. First, innate immunity can be activated by

monoclonal antibodies triggering antibody-dependent cellular cytotoxicity.

Second, tumour-specific T cell responses can be generated by immunization of

patients with peptides derived from tumour antigens and infused in soluble form

or loaded onto dendritic cells. The choice of cytotoxic agents for such

combinatory regimens is crucial since most substances such as fludarabine are

considered immunosuppressive while others such as cyclophosphamide can have

immunostimulatory activity. We tested in this study whether fludarabine and/or

cyclophosphamide, which represent a very effective treatment regimen for chronic

lymphocytic leukaemia, would interfere with a therapeutic strategy of T cell

activation. Analysis of peripheral blood samples from patients prior and during

fludarabine/cyclophosphamide therapy revealed rapid and sustained reduction of

tumour cells but also of CD4(+) and CD8(+) T cells. This correlated with a

significant cytotoxic activity of fludarabine/ cyclophosphamide on T cells in

vitro. Unexpectedly, T cells surviving fludarabine/cyclophosphamide treatment in

vitro had a more mature phenotype, while fludarabine-treated T cells were

significantly more responsive to mitogenic stimulation than their untreated

counterparts and showed a shift towards T(H)1 cytokine secretion. In

conclusion, fludarabine/cyclophosphamide therapy though inducing significant and

relevant T cell depletion seems to generate a micromilieu suitable for

subsequent T cell activation.

PMID: 20857100