Abstract
Histone deacetylase (HDAC) inhibitors are a widely recognized and valued treatment option for patients with relapsed or refractory peripheral T cell lymphomas (PTCL). Romidepsin is a relatively selective Class I HDAC inhibitor originally approved for patients with relapsed or refractory (R/R) cutaneous T cell lymphoma (CTCL) and subsequently R/R PTCL. Unfortunately, the FDA approval of romidepsin for R/R PTCL was withdrawn due to a negative Phase 4 post-marketing requirement (PMR), diminishing further the treatment options for patients with PTCL. Herein we describe the development of a first-in-class polymer nanoparticle of romidepsin (Nanoromidepsin) using an innovative amphiphilic di-block copolymer-based nanochemistry platform. Nanoromidepsin exhibited superior pharmacologic disposition, with improved tolerability and safety in murine models of T-cell lymphoma. Nanoromidepsin also exhibited superior anti-tumor efficacy in multiple models including in vitro T cell lymphoma (TCL) cell lines, ex vivo LGL leukemia primary patient samples, and murine TCL xenografts. Nanoromidepsin demonstrated greater accumulation in tumors and a statistically significant improvement in overall survival (OS) compared to romidepsin in murine xenograft models. These findings collectively justify the clinical development of Nanoromidepsin in patients with T-cell malignancies.
Competing Interest Statement
OAO has received Scientific Advisory Board membership from Myeloid Therapeutics, Dren Bio and Kymera Therapeutics and research support for clinical trial from BMS. DJF has received research funding, honoraria, and/or stock options from AstraZeneca, Dren Bio, Recludix Pharma, and Kymera Therapeutics. TPL has received Scientific Advisory Board membership, consultancy fees, honoraria, and/or stock options from Keystone Nano, Flagship Labs 86, Dren Bio, Recludix Pharma, Kymera Therapeutics, and Prime Genomics. JWC has received Honoria from BeiGene and consultancy fees and expert testimony from Bayer. EM reports research funding from Merck, Celgene/Bristol Myers Squibb, Astex Pharmaceuticals, and Myeloid Therapeutics and serves in the data safety monitoring committee with Everest Clinical Research. Other authors declare no competing interests. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.
