Nanoromidepsin, a polymer nanoparticle of the HDAC inhibitor, improves safety and efficacy in models of T-cell lymphoma
Abstract
Abstract Histone deacetylase inhibitors (HDACis) are valued treatment options for patients with T-cell malignancies. Romidepsin is a selective class I HDACi initially approved for patients with relapsed or refractory cutaneous and peripheral T-cell lymphomas (PTCLs). Romidepsin was withdrawn from its PTCL indication following a negative randomized phase 4 study (romidepsin-CHOP [cyclophosphamide, doxorubicin hydrochloride (hydroxydaunorubicin), vincristine sulfate (Oncovin), and prednisone]) that showed no benefit over CHOP alone, further diminishing options for patients. Herein, we describe the development of, to our knowledge, a first-in-class polymer nanoparticle (PNP) of romidepsin using an innovative amphiphilic diblock copolymer–based nanochemistry platform. Nanoromidepsin exhibited superior pharmacologic properties with improved tolerability and safety in murine models of T-cell lymphoma (TCL). The PNP also exhibited superior antitumor efficacy in multiple models, including in vitro TCL cell lines, ex vivo samples from patients with large granular lymphocyte (LGL) leukemia, and murine TCL xenografts. Nanoromidepsin demonstrated greater accumulation in tumors and a statistically significant improvement in overall survival compared with romidepsin in murine xenograft models. These findings justify the clinical development of nanoromidepsin in patients with T-cell malignancies.
Article Details
Authors (17)
Ipsita Pal
University of Virginia Comprehensive Cancer Center Charlottesville Virginia USA
Anuradha Illendula
1University of Virginia Comprehensive Cancer Center, University of Virginia, Charlottesville, VA
Andrea Joyner
1University of Virginia Comprehensive Cancer Center, University of Virginia, Charlottesville, VA
John Sanil Manavalan
1University of Virginia Comprehensive Cancer Center, University of Virginia, Charlottesville, VA
Tess M. Deddens
1University of Virginia Comprehensive Cancer Center, University of Virginia, Charlottesville, VA
Ariana Sabzevari
Department of Microbiology, Immunology, and Cancer Biology Charlottesville Virginia USA
Deepthi P. Damera
1University of Virginia Comprehensive Cancer Center, University of Virginia, Charlottesville, VA
Samir Zuberi
1University of Virginia Comprehensive Cancer Center, University of Virginia, Charlottesville, VA
Enrica Marchi
1University of Virginia Comprehensive Cancer Center, University of Virginia, Charlottesville, VA
Todd E. Fox
2Division of Hematology and Oncology, University of Virginia, Charlottesville, VA
Marya E. Dunlap-Brown
5Molecular Immunologic and Translational Sciences Core, University of Virginia, Charlottesville, VA
Kallesh D. Jayappa
Department of Medicine Division of Hematology/Oncology University of Virginia School of Medicine Charlottesville Virginia USA
Jihane Khalife
1University of Virginia Comprehensive Cancer Center, University of Virginia, Charlottesville, VA
Jeffrey W. Craig
Department of Pathology University of Virginia Medical Center Charlottesville Virginia USA
Thomas P. Loughran
University of Virginia Comprehensive Cancer Center Charlottesville Virginia USA
David J. Feith
University of Virginia Comprehensive Cancer Center Charlottesville Virginia USA
Owen A. O’Connor
Department of Microbiology, Immunology, and Cancer Biology Charlottesville Virginia USA