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

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.

Aurora A Inhibition Eliminates Myeloid Cell–Mediated Immunosuppression and Enhances the Efficacy of Anti–PD-L1 Therapy in Breast Cancer

“…Ã , P < 0.05; ÃÃ , P < 0.01; ÃÃÃ , P < 0.001. ns, nonsignificant. therapy showed synergistic effect in peripheral T-cell lymphoma (43). Given that Aurora A inhibition enhanced T-lymphocyte responses, we wondered whether promoting the activity of T cells via disruption of the immune-checkpoint signaling of PD-1/ PD-L1 might further enhance the efficacy of alisertib.…”

Novel Aurora Kinase Inhibitor-Based Combination Therapies for PTCL

“…Cytokine signaling through the MAPK pathway also induces PD-L1 expression leading to profound immune suppression in PTCL. Targeting mitosis with alisertib and immune suppression with an anti-PD-L1 antibody leads to a highly synergistic combination in a syngeneic mouse model of PTCL [52]. Targeting mitosis with alisertib plus vincristine is synergistic causing mitotic catastrophe.…”

“…Targeting mitosis with alisertib plus vincristine is synergistic causing mitotic catastrophe. This combination is synthetic lethal when combined with anti-PD-L1 plus PI3K inhibition [52]. Further, Aurora A kinase inhibition combined with histone deacetylase inhibitors is also synergistic implicating epigenetic modulation.…”

“…Immunohistochemistry (IHC) analysis of tumor samples from patients treated with alisertib for r/r PTCL (SWOG 1108) showed a high Ki-67 and programmed death ligand (PD-L1): PD-1 staining ratio of 8.9-fold [52]. Increased levels of PD-L1 are associated with immune suppression.…”

“…Bio X Cell, NH) in mice with r/r PTCL xenografts (CRL-2396 cells) [52]. Since the pan-PI3K inhibitor (PF-04691502) inhibits expression of the PD-L1 along with vincristine, these were also added to the former drug combination, and the results were compared between the two groups.…”