Fludarabine modulates composition and function of the T cell pool in patients with chronic lymphocytic leukaemia.
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.
Gassner
Franz Josef
FJ
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.
Weiss
Lukas
L
Geisberger
Roland
R
Hofbauer
Josefina Piñón
JP
Egle
Alexander
A
Hartmann
Tanja Nicole
TN
Greil
Richard
R
Tinhofer
Inge
I
D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D003520:Cyclophosphamide / Q000494:pharmacology; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D019653:Myeloablative Agonists / Q000494:pharmacology; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000494:pharmacology
D015703:Antigens, CD; D019653:Myeloablative Agonists; D003520:Cyclophosphamide; D014740:Vidarabine; C024352:fludarabine