BOSTON--(BUSINESS WIRE)--Acetylon Pharmaceuticals, Inc., the leader in the development of selective histone deacetylase (HDAC) inhibitors for enhanced therapeutic outcomes, today announced the publication of two abstracts describing preclinical studies that demonstrate the potential for HDAC6 inhibition with ricolinostat (ACY-1215) to augment immunotherapy approaches for the treatment of melanoma. In studies conducted in collaboration with the laboratories of Eduardo Sotomayor, M.D. at the George Washington University School of Medicine and Health Sciences, Washington, DC and Jeffrey S. Weber, M.D., Ph.D. at the NYU Langone Medical Center, New York, NY, ricolinostat exhibited immune-dependent anti-tumor activity in a preclinical model of melanoma. Separately, Acetylon’s collaborators showed that ricolinostat augmented ex vivo melanoma immunotherapy in studies with patient-derived T-cells. The abstracts were published in conjunction with the 2016 American Society of Clinical Oncology (ASCO) Annual Meeting in a special edition of the Journal of Clinical Oncology.
Researchers have previously shown that pan-HDAC inhibitors induce apoptosis and, through HDAC6, regulate the immunogenicity of melanoma cells. Studies have also demonstrated that the growth of melanoma cells lacking HDAC6 is significantly delayed as compared to wild-type cells. In a clinical setting, non-selective HDAC inhibition has been associated with significant toxicity and adverse events. Selective HDAC inhibition, on the other hand, is expected to reduce or eliminate these often-severe side effects associated with non-selective HDAC inhibition. Acetylon is developing ricolinostat (ACY-1215), a selective HDAC6 inhibitor, for the treatment of multiple myeloma and lymphoma.
“The anti-tumor activity of ricolinostat observed in a preclinical model of melanoma, in addition to its positive effects on the proliferation and function of melanoma patient-derived T-cells during ex vivo expansion, provide a solid rationale for further development,” said Simon S. Jones, Ph.D., Senior Vice President, Preclinical Development of Acetylon. “Based on these exciting results, clinical trials with ACY-241, a selective HDAC6 inhibitor in tablet form, will be initiated in melanoma and non-small cell lung cancer in combination with the immune checkpoint inhibitors Opdivo® alone or in combination with Yervoy®. We are currently evaluating the safety and antitumor activity of ACY-241 in multiple myeloma and ricolinostat in lymphoma, and these new preclinical data in melanoma highlight the broad versatility and immunomodulatory capability of selective HDAC6 inhibitors across multiple oncology indications.”
Details of the abstracts are as follows:
Category: Melanoma/Skin Cancers
Abstract Number: e21075
Citation: J Clin Oncol 34, 2016 (suppl; abstr e21075)
Title: In vitro and in vivo anti-melanoma activity of ricolinostat, a selective HDAC6 inhibitor with immunomodulatory properties.
In a preclinical model of melanoma, treatment with the selective HDAC6 inhibitor, ricolinostat, resulted in dose- and immune-dependent inhibition of tumor growth, with no toxicities observed at the doses studied. This anti-tumor effect was enhanced when ricolinostat was administered in combination with either anti-CTLA-4 or anti-PD-1 treatment. Additionally, treatment of T-cells with ricolinostat resulted in a significant increase in central memory T-cells with strong anti-melanoma activity in vivo as compared to control-treated T-cells, suggesting that HDAC6 is a novel target for melanoma immunotherapy.
Category: Developmental Therapeutics – Immunotherapy
Abstract Number: e14521
Citation: J Clin Oncol 34, 2016 (suppl; abstr e14521)
Title: Selective histone deacetylase inhibition augments melanoma immunotherapy.
The effects of ACY-1215 on immune cell biology were explored, specifically on ex vivo T-cells from melanoma patients. Results of the study demonstrated that treatment of melanoma patient-derived T-cells with ACY-1215 resulted in increased expression of activation and costimulatory markers and an enhanced central memory phenotype of CD4 and CD8 T-cells during expansion. Additionally, when tumor infiltrating lymphocytes (TILs) isolated from surgical biopsies were treated with ACY-1215, they exhibited higher levels of IFNɣ/CD107a expressing CD8 T-cells, enhanced cytotoxicity, and increased expression of genes associated with an inflammatory response and T-cell memory. These data indicated that ACY-1215 augments T-cell proliferation and function during ex vivo expansion, which may have implications for the ex vivo treatment of melanoma patient T-cells prior to adoptive transfer.
About HDAC6 Inhibition
Ricolinostat (ACY-1215) and ACY-241 selectively inhibit the intracellular enzyme HDAC6, which leads to an accumulation of excess protein and in addition may disrupt critical proliferative signals in malignant cells. Disruption of these molecular processes in cancer cells triggers programmed cell death, called "apoptosis," with little or no effect on normal cells. Currently available HDAC drugs also affect the expression of numerous other genes in normal cells as well as cancer cells, which can result in side effects such as gastrointestinal dysfunction, lowered blood platelet levels and risk of hemorrhage and profound fatigue as well as potential for significant cardiac toxicity. Selective inhibition of HDAC6 is expected to reduce or eliminate these often-severe side effects associated with non-selective HDAC inhibition and may enable the development of optimized treatment regimens, including maximally effective combination drug therapies.
Acetylon Pharmaceuticals, Inc., based in Boston, Massachusetts, is a leader in the development of novel small molecule drugs targeting epigenetic mechanisms for the enhancement of therapeutic outcomes in cancer and other critical human diseases. The Company’s epigenetic drug discovery platform has yielded a proprietary portfolio of optimized Class I and Class II histone deacetylase (HDAC) selective compounds for oral administration. Alteration of HDAC regulation through selective HDAC inhibition is thought to be applicable to a broad range of diseases including cancer, sickle cell disease and beta-thalassemia, and autoimmune and neurodegenerative diseases. Acetylon’s lead drug candidates, ricolinostat (ACY-1215) and ACY-241, are selective HDAC6 inhibitors currently in Phase 2 clinical development for the treatment of multiple myeloma. In 2013, the Company announced a strategic collaboration agreement with Celgene Corporation, which includes an exclusive option for the future acquisition of Acetylon by Celgene. Acetylon’s scientific founders are affiliated with Harvard University, the Dana-Farber Cancer Institute, the Massachusetts General Hospital, and Harvard Medical School. www.acetylon.com