Co-targeting aurora kinase with PD-L1 and PI3K abrogates immune checkpoint mediated proliferation in peripheral T-cell lymphoma: a novel therapeutic strategy

// Shariful Islam 1, * , Eric Vick 2, * , Bryan Huber 2 , Carla Morales 2 , Catherine Spier 3 , Laurence Cooke 4 , Eric Weterings 5 and Daruka Mahadevan 4 1 Cancer Biology GIDP, University of Arizona Cancer Center, Tucson, AZ 85724, USA 2 West Cancer Center and University of Tennessee Health Sciences Center, Memphis, TN 38163, USA 3 Department of Hematopathology, University of Arizona, Tucson, AZ 85724, USA 4 Department of Medicine, The University of Arizona Cancer Center, Tucson, AZ 85724, USA 5 Department of Radiation Oncology, University of Arizona, Tucson, AZ 85724, USA * These authors have contributed equally to this work Correspondence to: Daruka Mahadevan, email: dmahadevan@uacc.arizona.edu Keywords: T-cell lymphoma; immune checkpoint; aurora kinases; anti-PD-L1; PI3K isoforms Received: June 27, 2017 Accepted: October 13, 2017 Published: November 01, 2017 ABSTRACT Peripheral T-cell non-Hodgkin lymphoma (PTCL) are heterogeneous, rare, and aggressive diseases mostly incurable with current cell cycle therapies. Aurora kinases (AKs) are key regulators of mitosis that drive PTCL proliferation. Alisertib (AK inhibitor) has a response rate ~30% in relapsed and refractory PTCL (SWOG1108). Since PTCL are derived from CD4 + /CD8 + cells, we hypothesized that Program Death Ligand-1 (PD-L1) expression is essential for uncontrolled proliferation. Combination of alisertib with PI3Kα (MLN1117) or pan-PI3K inhibition (PF-04691502) or vincristine (VCR) was highly synergistic in PTCL cells. Expression of PD-L1 relative to PD-1 is high in PTCL biopsies (~9-fold higher) and cell lines. Combination of alisertib with pan-PI3K inhibition or VCR significantly reduced PD-L1, NF-κB expression and inhibited phosphorylation of AKT, ERK1/2 and AK with enhanced apoptosis. In a SCID PTCL xenograft mouse model, alisertib displayed high synergism with MLN1117. In a syngeneic PTCL mouse xenograft model alisertib demonstrated tumor growth inhibition (TGI) ~30%, whilst anti-PD-L1 therapy alone was ineffective. Alisertib + anti-PD-L1 resulted in TGI >90% indicative of a synthetic lethal interaction. PF-04691502 + alisertib + anti-PD-L1 + VCR resulted in TGI 100%. Overall, mice tolerated the treatments well. Co-targeting AK, PI3K and PD-L1 is a rational and novel therapeutic strategy for PTCL.