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 Romidepsin was withdrawn from its PTCL indication following a negative randomized phase 4 study (romidepsin-CHOP [cyclophosphamide, doxorubicin hydrochloride (hydroxydaunorubicin),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.