Preclinical Pharmacologic Evaluation of Pralatrexate and Romidepsin Confirms Potent Synergy of the Combination in a Murine Model of Human T-cell Lymphoma

Purpose:T-cell lymphomas (TCLs) are aggressive diseases, which carry a poor prognosis. The emergence of new drugs for TCL has created a need to survey these agents in a rapid and reproducible fashion, in order to prioritize combinations which should be prioritized for clinical study. Mouse models of TCL that can be used for screening novel agents and their combinations are lacking. Developments in non-invasive imaging modalities like surface bioluminescence (SBL) and 3-dimensional-ultrasound are challenging conventional approaches in xenograft modeling relying on caliper measurements. The recent approval of pralatrexate and romidepsin creates an obvious combination that could produce meaningful activity in TCL, which has yet to be studied in combination. Experimental Design:High-throughput screening (cHTS) and multi-modality imaging approach of SBL and 3D-US in a xenograft NOG mouse model of TCL were used to explore the in vitro and in vivo activity of pralatrexate and romidepsin in combination. Corresponding mass spectrometry based pharmacokinetic and immunohistochemistry based pharmacodynamic analysis of xenograft tumors were performed to better understand a mechanistic basis for the drug: drug interaction. Results:In vitro, pralatrexate and romidepsin exhibited concentration-dependent synergism in combination against a panel of TCL cell lines. In a NOG murine model of TCL, the combination of pralatrexate and romidepsin exhibited enhanced efficacy compared with either drug alone across a spectrum of tumors using complimentary imaging modalities such as SBL and 3D-US. Conclusions:Collectively, these data strongly suggest that the combination of pralatrexate and romidepsin merit clinical study in patients with TCLs.