Oncotarget

Research Papers:

A novel ex vivo high-throughput assay reveals antiproliferative effects of idelalisib and ibrutinib in chronic lymphocytic leukemia

Daniel Primo, Lydia Scarfò, Aliki Xochelli, Mattias Mattsson, Pamela Ranghetti, Ana Belén Espinosa, Alicia Robles, Julian Gorrochategui, Joaquín Martínez-López, Javier de la Serna, Marcos González, Alberto Chaparro Gil, Eduardo Anguita, Sandra Iraheta, Veerendra Munugalavadla, Christophe Quéva, Stacey Tannheimer, Richard Rosenquist, Kostas Stamatopoulos, Joan Ballesteros _ and Paolo Ghia

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Oncotarget. 2018; 9:26019-26031. https://doi.org/10.18632/oncotarget.25419

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Abstract

Daniel Primo1, Lydia Scarfò2, Aliki Xochelli3, Mattias Mattsson4, Pamela Ranghetti2, Ana Belén Espinosa1, Alicia Robles1, Julian Gorrochategui1, Joaquín Martínez-López5, Javier de la Serna5, Marcos González6, Alberto Chaparro Gil7,11, Eduardo Anguita7,11, Sandra Iraheta8, Veerendra Munugalavadla9, Christophe Quéva9, Stacey Tannheimer9, Richard Rosenquist4,10, Kostas Stamatopoulos3,4, Joan Ballesteros1 and Paolo Ghia2

1Vivia Biotech, Tres Cantos, Madrid, Spain

2Strategic Research Program on CLL and B Cell Neoplasia Unit, Università Vita-Salute San Raffaele and IRCCS Istituto Scientifico San Raffaele, Milan, Italy

3Institute of Applied Biosciences, Center for Research and Technology Hellas, Thessaloniki, Greece

4Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden

5Department of Hematology, Hospital Universitario 12 de Octubre, Madrid, Spain

6Hematology Service, IBSAL-Hospital Universitario, Centro de Investigación del Cáncer (CIC)- IBMCC, Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Universidad de Salamanca, Salamanca, Spain

7Department of Hematology, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), Madrid, Spain

8Department of Hematology and Hemotherapy, Hospital Universitario de Canarias, La Laguna, Spain

9Gilead Sciences, Foster City, CA, USA

10Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

11Department of Medicine, Universidad Complutense de Madrid (UCM), Madrid, Spain

Correspondence to:

Joan Ballesteros, email: jballesteros@viviabiotech.com

Keywords: chronic lymphocytic leukemia; Ibrutinib; idelalisib; antiproliferative; ex vivo

Received: August 13, 2017     Accepted: April 28, 2018     Published: May 25, 2018

ABSTRACT

PI3Kδ (idelalisib) and BTK (ibrutinib) inhibitors have demonstrated significant clinical activity in chronic lymphocytic leukemia (CLL) interfering with the cross-talk between CLL cells and the lymph node microenviroment, yet their mechanism of action remains to be fully elucidated. Here, we developed an ex vivo model with the aim of reproducing the effects of the microenvironment that would help shed light on the in vivo mechanism of action of idelalisib and ibrutinib and predict their clinical efficacy in individual patients. First we explored the effects of various cell-extrinsic elements on CLL apoptosis and proliferation and found that the combination of CpG+IL2+HS5 stromal cell line + human serum +CLL plasma and erythrocyte fractions represented the best co-culture conditions to test the effects of the novel inhibitors. Then, using this assay, we investigated the impact of idelalisib and ibrutinib on both survival and proliferation in 30 CLL patients. While both drugs had a limited direct pro-apoptotic activity, a potent inhibition of proliferation was achieved at clinically achievable concentrations. Notably, up to 10% of CLL cells still proliferated even at the highest concentrations, likely mirroring the known difficulty to achieve complete responses in vivo. Altogether, this novel assay represents an appropriate ex vivo drug testing system to potentially predict the clinical response to novel inhibitors in particular by quantifying the antiproliferative effect.


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