CHRONIC LYMPHOCYTIC LEUKEMIA (CLL): THE CLINICALLY RELEVANT DRUG R406 IMPAIRS T CELL ACTIVATION AND PROLIFERATION.

COLADO A; BORGE M; PODAZA E.; FERNANDEZ GRECCO H.; CABREJO M.; BEZARES RF; GIORDANO M; GAMBERALE R

Mar del Plata

Congreso; LXII Reunión Anual de la Sociedad Argentina de Inmunología; 2014

Despite advances in the treatment of CLL patients, the disease remains incurable with standard therapies and relapse is inevitable. Leukemic B cells survive and proliferate within lymphoid tissues in close contact with stroma, myeloid cells and T lymphocytes. Activated T cells support the accumulation of the leukemic clone by producing soluble and contact dependent factors, such as IL4 and IFN and the expression of CD40L. Several orally bioavailable kinase-inhibitors are currently being tested in clinical trials with promising clinical responses and minimal side effects. This is the case of the SYK inhibitor Fostamatinib (R788) which is converted in vivo into its bioactive form R406 and favors the redistribution of CLL cells from lymphoid tissues to circulation. R406 reduces leukemic cell migration, chemokine secretion and BCR signaling in vitro. The objective of this study was to determine whether R406 is able to impair the activation, proliferation and migratory response of T cells from CLL patients. We first evaluated R406-induced apoptosis on T cells from CLL patients, finding significant levels of apoptosis only at the higher dose used (40 µM, p=0.02). Then we wondered whether clinically relevant doses of R406 (˂5 µM) were able to inhibit T cell activation and proliferation. To this aim, PBMC from CLL patient were cultured with or without R406 in the presence of isotope control or anti-CD3 antibodies. We found that R406 impaired the expression of the activation markers CD25, CD69 and CD40L on T cells, evaluated by flow cytometry at 24hs (p˂0.05) and the T-cell proliferation evaluated by the CFSE dilution assay at 5 days (p˂0.05). We also observed, by using the Transwell system assay, that R406 inhibits T cell migration towards CXCL12 (p=0.01).