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.
Highlights
Peripheral T-cell non-Hodgkin lymphomas (PTCL) belong to a rare (~15% of NHL) and heterogeneous group of lymphoid malignancies, comprised of several subtypes: extra-nodal (NK/T-cell, nasal-type, enteropathytype, hepatosplenic, subcutaneous panniculitis-like) and nodal PTCL (NOS), anaplastic large cell lymphoma (ALCL, ALK-negative) and angioimmunoblastic T-cell lymphoma (AITL) [1, 2].PTCL’s have a poor prognosis due to a very aggressive disease course and they are mostly incurable with current anti-proliferative therapies [3]
Western blotting demonstrated that the PTCL cell lines CRL-2396, TIB-48 and SUP-T1 over-express PD-L1 relative to PD-1 (Figure 1A, 1B)
IHC of pre-alisertib PTCL patient biopsies (n=22) from the SWOG1108 study reveals that PD-L1 is overexpressed relative to PD-1 with a staining ratio of 8.9 fold (p=0.0037) in favor of PD-L1 (Figure 1C) and Ki-67 (Figure 1D) compared to a normal lymph node control is an indication of aggressiveness of this disease
Summary
Peripheral T-cell non-Hodgkin lymphomas (PTCL) belong to a rare (~15% of NHL) and heterogeneous group of lymphoid malignancies, comprised of several subtypes: extra-nodal (NK/T-cell, nasal-type, enteropathytype, hepatosplenic, subcutaneous panniculitis-like) and nodal PTCL (NOS) (not otherwise specified), anaplastic large cell lymphoma (ALCL, ALK-negative) and angioimmunoblastic T-cell lymphoma (AITL) [1, 2].PTCL’s have a poor prognosis due to a very aggressive disease course and they are mostly incurable with current anti-proliferative therapies [3]. Aurora kinases (AKs) are key molecular and cellular drivers of PTCL proliferation [4]. AKs are mitotic serine/threonine kinases and 3 homologous isoforms (A, B/C) have been identified. AK-A localizes to centrosomes and the proximal mitotic spindle during mitosis. This enzyme is critical to bipolar spindle formation and participates in centrosome maturation, separation, as well as mitotic entry. Over-expression of AK-B > A is observed in PTCL cell lines and in human PTCL samples [4, 6]. An AK-A inhibitor, alisertib, reversed the deleterious effects of AKs on genetic instability, proliferation and anti-apoptosis. Protein levels of AK-A and/or B do not appear to predict for an alisertib response, there is a ~30% response rate to alisertib as a single-agent in relapsed and refractory PTCL [6]
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