Clinical revival of romidepsin with nanoparticles Free

In this issue of Blood, Pal et al¹ report the development of nanoromidepsin, a polymer nanoparticle formulation of romidepsin, which demonstrated improved efficacy, reduced toxicity, and enhanced tumor targeting in preclinical models. These findings reaffirm the clinical potential of romidepsin for treating patients with refractory T-cell lymphomas.

Peripheral T-cell lymphomas (PTCLs) represent a rare, biologically heterogeneous, and clinically challenging subset of non-Hodgkin lymphomas. Despite recent advances in molecular characterization, the clinical outcomes for most PTCL subtypes remain poor with standard chemotherapy. The 5-year overall survival rates are consistently <30% for most patients, except for those with anaplastic lymphoma kinase–positive anaplastic large cell lymphoma (ALCL).² These unsatisfactory results highlight the need for more effective and biologically rational therapeutic strategies for PTCLs.

Recent genetic studies have shown that PTCLs, particularly those of T follicular helper (TFH) cell origin, are highly enriched in mutations in epigenetic regulator genes, such as TET2, DNMT3A, IDH2, and EZH2.³ These mutations play critical roles in DNA methylation, histone modification, and chromatin structure, thus ultimately affecting gene expression and cellular identity. The heightened sensitivity of PTCLs to histone deacetylase (HDAC) inhibitors, hypomethylating agents, and enhancer of zeste homolog (EZH)1/2 dual inhibitors in preclinical models has led to the development of several epigenetically-targeted therapies, such as romidepsin,^4,5 belinostat,⁶ azacitidine,⁷ and valemetostat.⁸ This has established PTCLs as typical and representative epigenetic malignancies.

Romidepsin is a potent and selective class I HDAC inhibitor that has emerged as an important therapeutic option for relapsed or refractory PTCLs and primary cutaneous T-cell lymphoma (CTCLs). Its promising efficacy was validated through phase 2 trials, which demonstrated meaningful objective response rates (25%-38%) and durable remission in a subset of patients. Based on these results, romidepsin received accelerated approval by the US Food and Drug Administration for treating CTCLs in 2009 and was later approved (in 2011) for the treatment of PTCLs as well. Notably, a clinical benefit was also observed in patients with stable disease,⁹ highlighting its potential value beyond traditional response criteria. However, despite its proven efficacy, the broader clinical development of romidepsin has stalled over recent years. A confirmatory phase 3 trial that compared romidepsin-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) vs standard CHOP in patients with previously untreated PTCLs did not demonstrate a significant benefit in terms of progression-free or overall survival in the romidepsin-CHOP arm,¹⁰ leading to the withdrawal of its PTCL indication in the United States. In the exploratory post hoc analysis of that study, however, romidepsin-CHOP therapy was suggested to provide a survival advantage over standard CHOP alone, particularly in patients with TFH phenotypes, thus reaffirming the importance of developing treatment strategies based on molecular subtypes when addressing PTCL. However, these findings were insufficient to preserve the drug’s regulatory standing.

In the article under discussion, the authors present a novel strategy for revitalizing the clinical potential of romidepsin using nanotechnology. Specifically, they engineered a first-in-class polymer nanoparticle (PNP) formulation, dubbed nanoromidepsin, using an amphiphilic diblock copolymer-based platform. Their study reported significantly enhanced pharmacokinetics, tumor targeting, tolerability, and antitumor activity in both in vitro and in vivo models of T-cell malignancies, including large granular lymphocyte leukemia and TCL xenografts.

The hypothesis tested by the authors of that study was whether encapsulating romidepsin in a rationally designed nanocarrier could overcome the pharmacologic limitations of small-molecule HDAC inhibitors, namely, poor tumor penetration, rapid systemic clearance, and dose-limiting toxicities that often reduce its efficacy.

The results they obtained were persuasive. When compared with unformulated romidepsin, nanoromidepsin demonstrated superior tumor uptake, reduced toxicity and, most importantly, enhanced survival, in murine xenograft-based disease models. Their in vitro assays also showed increased cytotoxicity toward TCL cell lines. This was accompanied by improved pharmacokinetic profiles in murine models, characterized by longer circulation times and greater tumor retention. Collectively, these findings suggest that the PNP platform successfully addressed the major limitations of romidepsin, thereby facilitating sustained and more effective epigenetic modulation of malignant T cells.

Although HDAC inhibition is not a new concept in the treatment of PTCL, these results are undoubtedly novel and provide an important new direction for hemato-oncology research. The clinical stagnation of romidepsin has shifted the field’s interest toward other epigenetic targets and immune-based therapies. By re-engineering rather than replacing the HDAC inhibitor, the authors presented a practical and innovative solution that leveraged nanotechnology to renew interest in a once promising therapeutic approach.

Naturally, certain key limitations merit discussion as well. The data presented by the authors are exclusively preclinical, and the transition from murine models to human patients is highly uncertain. Although conceptually appealing, nanoparticle-based delivery systems can behave unpredictably in human systems in which immune clearance, off-target accumulation, and manufacturing complexity can pose significant translational challenges. However, the long-term safety profiles of polymer-based carriers remain to be clarified. Another critical question is the applicability of this approach across different PTCL subtypes. The heterogeneity of PTCL in molecular, phenotypic, and clinical aspects means that even a therapy with broad-spectrum activity, such as nanoromidepsin, may not confer uniform benefits. Whether similar improvements in efficacy and tolerability will be observed in genetically diverse subtypes, such as PTCL not otherwise specified, TFH lymphoma, or ALCL, remains an open and important question.

Despite these limitations, the broader implications of Pal et al’s study cannot be overlooked. Similar to how antibody-drug conjugates revolutionized treatment strategies for many types of cancers through targeted payload delivery, PNPs may similarly facilitate precise and potent therapeutic approaches for difficult-to-treat malignancies. In this sense, nanoromidepsin may serve as proof of concept not only for romidepsin but also for a new generation of epigenetic therapeutics optimized for delivery and retention.

Pal et al have provided a compelling rationale for revisiting romidepsin, not through the discovery of new molecular targets but through a new formulation paradigm. The promising preclinical performance of nanoromidepsin underscores the importance of drug delivery systems in oncology and may signal a resurgence of HDAC inhibitor use to treat T-cell malignancies. Whether this approach can be translated into clinical success will depend on the outcomes of future early-phase trials. However, the groundwork laid by this study is both scientifically sound and clinically hopeful.

Conflict-of-interest disclosure: W.M. declares no competing financial interests.