?Chronic lymphocytic leukemia: anti-CD20 therapeutic antibodies and BCR kinase inhibitors overcome leukemic cell resistance to venetoclax (ABT-199)

ALMEJUN B; BORGE M; COLADO A; PODAZA E.; RISNIK D; FERNÁNDEZ GRECCO H; BEZARES RF; GIORDANO M.; - GAMBERALE R

Congreso; Reunión conjunta de las sociedades de biociencias; 2017

Leukemic B cells from CLL patients survive and proliferate within lymphoid tissues in contact with activated T cells and myeloid cells and receiving signals through the BCR. Effective therapy should target both, leukemic cells from peripheral blood and from the protective microenvironment. We previously reported that ABT-199, a potent BCL2 inhibitor, is highly cytotoxic against unstimulated CLL cells but it is much less effective against CLL cells that received survival signals from activated T cells, suggesting that leukemic cells from the supportive microenvironment might not be properly targeted by the drug. The aim of this study was to overcome the ABT-199 resistance using combined therapies with anti-CD20 MoAbs and/or BCR-associated kinase inhibitors (BCR-KI). To this aim peripheral blood mononuclear cells from CLL patients were cultured with anti-CD3 (aCD3) to activate autologous T cells with or without ABT-199 and the BCR-KI GS-9973. CLL cell survival was evaluated by flow cytometry; the expression of BCL2 family proteins by western blot and phagocytosis of CFSE-labeled CLL cells coated with anti-CD20, Rituximab (Rx) by flow cytometry and confocal microscopy. We confirmed that autologous T cell activation induced ABT199 resistance on CLL cells (n=18, p