While immune checkpoint inhibitor (CPI) therapies have revolutionized the treatment of metastatic melanoma and other malignancies, many patients fail to respond, necessitating to explore combination therapies to improve response rates. Histone deacetylases (HDACs) are epigenetic modifying proteins that remove acetyl groups from histones and non-histone proteins. HDAC inhibitors (HDACi) have shown success in the treatment of several hematologic malignancies. Beyond direct tumor cytotoxicity, HDACi have also demonstrated immunomodulatory effects. We previously published data showing the anti-tumor efficacy of the class I/IV HDACi mocetinostat in pre-clinical murine models through upregulation of tumor antigen presentation machinery and downregulation of Tregs. As a result of these and other data, a phase Iβ clinical trial (NCT03565406) was initiated to evaluate combination of mocetinostat with nivolumab and ipilimumab for the treatment of unresectable stage III/IV metastatic melanoma. A total of 10 patients were treated. Objective responses by RECIST 1.1 criteria were seen in 7/10 patients; 2 patients had complete responses, 5 had partial responses and 3 had progressive disease. To further understand the impact of mocetinostat on immune function, we evaluated serum and peripheral blood (PBMC) samples from patients prior to and on-treatment, in addition to in vitro treatment of treatment-naive patient PBMC samples with mocetinostat. Both in vitro treated and in vivo paired patient samples demonstrated a decrease in M2-like monocytes (CD80-CD86-CD163+CD206+) and an increase in M1-like monocytes (CD80+CD86+CD163-CD206-). We also observed a decrease in myeloid derived suppressor cells (MDSC, CD14+CD11b+HLA-DRlow) and expression of NOS2, an enzyme involved in MDSC mediated T-cell suppression, in this subset in both treated patients in vivo and in vitro. CD4+ and CD8+ T-cells showed increased levels of the proliferation marker Ki67 on-treatment relative to baseline in vivo in treated patients. Analysis of patient serum levels showed an increase in Granzyme A, Granzyme B, IFNγ and TNF. Similar upregulation of inflammatory and cytolytic proteins were seen in vitro. Assessment of histone 3 acetylation levels showed robust increases in all patients assessed on-treatment except 1 patient (progressive disease). Combining the results of in vitro assays with patient sample analyses, these data suggest that mocetinostat decreases immunosuppressive immune cell phenotypes while augmenting anti-tumor phenotypes, demonstrating potential of combination therapy with CPI.

Citation Format: David M. Woods, Andressa S. Laino, Melinda Vassallo, Jeffrey Weber. The Class I/IV HDAC Inhibitor Mocetinostat Augments Anti-Tumor Immune Responses in Melanoma Patients [abstract]. In: Abstracts: AACR Special Virtual Conference on Epigenetics and Metabolism; October 15-16, 2020; 2020 Oct 15-16. Philadelphia (PA): AACR; Cancer Res 2020;80(23 Suppl):Abstract nr PO-007.