Biological rationale for a combined therapy with syk inhibitors and anti-CD20 mAbs in Chronic Lymphocytic Leukemia: overcoming ABT-199 resistance induced by autologous activated T cells

ELÍAS, ESTEBAN ENRIQUE; VERGARA-RUBIO, MARICEF; RISNIK, DENISE; BEZARES, RAIMUNDO FERNANDO; VICENTE, ÁNGELES; GIORDANO, MIRTA; COLADO, ANA; PODAZA, ENRIQUE; GRECCO, HORACIO FERNANDEZ; SANCHEZ-AVALOS, JULIO CÉSAR; BORGE, MERCEDES; ALMEJÚN, MARÍA BELÉN; CORDINI, GREGORIO; CABREJO, MARÍA; CUSTIDIANO, MARÍA DEL ROSARIO; GARATE, GONZALO MARTÍN; GAMBERALE, ROMINA

Santiago de Chile

Workshop; Cell Biology Summer Course 2018; 2018

Institut Curie de Paris

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 ABT199, 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 ABT199 resistance using combined therapies with antiCD20 MoAbs and/or BCR-associated kinase inhibitors (BCR-KI). To this aim peripheral blood mononuclear cells from CLL patients were cultured with antiCD3 (aCD3) to activate autologous T cells with or without ABT199 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 antiCD20, Rituximab (Rx) by flow cytometry. We confirmed that autologous T cell activation induced ABT199 resistance on CLL cells (n=18, p