PRECLINICAL DEVELOPMENT OF A ROMIDEPSIN NANOPARTICLE DEMONSTRATES SUPERIOR TOLERABILITY AND EFFICACY IN MODELS OF HUMAN T-CELL LYMPHOMA AND LARGE GRANULAR LYMPHOCYTE LEUKEMIA

Pal, I.; Illendula, A.; Joyner, A.; Manavalan, J. S.; Deddens, T. M.; Sabzevari, A.; Damera, D. P.; Zuberi, S.; Marchi, E.; Fox, T. E.; Dunlap-Brown, M. E.; Jayappa, K. D.; Craig, J. W.; Loughran, T. P.; Feith, D. J.; O'Connor, O. A.

doi:10.1101/2024.07.18.603379

bioRxiv · 10.1101/2024.07.18.603379

PRECLINICAL DEVELOPMENT OF A ROMIDEPSIN NANOPARTICLE DEMONSTRATES SUPERIOR TOLERABILITY AND EFFICACY IN MODELS OF HUMAN T-CELL LYMPHOMA AND LARGE GRANULAR LYMPHOCYTE LEUKEMIA

Pal, I.·Illendula, A.·Joyner, A.·Manavalan, J. S.·Deddens, T. M.·Sabzevari, A.·Damera, D. P.·Zuberi, S.·Marchi, E.·Fox, T. E.·Dunlap-Brown, M. E.·Jayappa, K. D.·Craig, J. W.·Loughran, T. P.·Feith, D. J.·O'Connor, O. A.

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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 Unfortunately, the FDA approval of romidepsin for R/R PTCL was withdrawn due to a negative Phase 4 post-marketing requirement (PMR), diminishing further the treatment options for patients with PTCL.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.

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Pal, I., Illendula, A., Joyner, A., Manavalan, J. S., Deddens, T. M., Sabzevari, A., Damera, D. P., Zuberi, S., Marchi, E., Fox, T. E., Dunlap-Brown, M. E., Jayappa, K. D., Craig, J. W., Loughran, T. P., Feith, D. J., O'Connor, O. A.. 2024-07-19. PRECLINICAL DEVELOPMENT OF A ROMIDEPSIN NANOPARTICLE DEMONSTRATES SUPERIOR TOLERABILITY AND EFFICACY IN MODELS OF HUMAN T-CELL LYMPHOMA AND LARGE GRANULAR LYMPHOCYTE LEUKEMIA. https://doi.org/10.1101/2024.07.18.603379

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