Clinical and immune correlate results from a phase 1b study of the histone deacetylase inhibitor mocetinostat with ipilimumab and nivolumab in unresectable stage III/IV melanoma

Abstract

Checkpoint immunotherapies (CPIs) have improved outcomes for metastatic melanoma patients, with objective response rates to combination ipilimumab and nivolumab of ~58%. Preclinical data suggest that histone deacetylase (HDAC) inhibition enhances antitumor immune activity and may augment CPI. In a phase Ib open-label pilot trial (NCT03565406), patients with therapy-naive metastatic melanoma were treated with the class I/IV HDAC inhibitor mocetinostat orally three times a week in combination with nivolumab and ipilimumab every 3 weeks for 12 weeks followed by 12-week maintenance cycles of nivolumab every 2 weeks and mocetinostat at the same dose and schedule as induction. The endpoints of the trial were safety, definition of a recommended phase 2 dose, preliminary assessment of response, and correlative marker determination. Patient PBMC and serum samples collected at baseline and on-treatment were assessed by flow cytometry and Luminex assays for immune correlates. Ten patients were treated: nine with 70-mg and one with 50-mg mocetinostat. In the 70-mg cohort, eight patients had objective responses. The patient in the 50-mg cohort had an early progression of disease. All patients had grade 2 or higher toxicities, and six had grades 3 and 4 toxicities. Patient PBMC showed significant decreases in myeloid-derived suppressor cells and trends towards reduced anti-inflammatory monocyte phenotypes. Patient serum showed significant upregulation of granzyme A and TNF and trends towards increased granzyme B and IFNγ. Collectively, combining CPI and mocetinostat had favorable response rates but with high levels of toxicity. Assessment of immune correlates supports a shift away from immunosuppressive phenotypes towards enhanced immune responses.

The novel combination of mocetinostat and capecitabine has a greater anti-tumoral effect on induced breast cancer in BALB/c mice

“…Capecitabine is particularly effective for metastatic breast cancer in single use, but it is also effective for other types of cancer in combination [23]. Mocetinostat is HDACi and has a very long inhibitory effect on cancer cells despite accumulating in very small amounts in tissues [24]. The use of capecitabine and mocetinostat alone and in combination with other drugs has been demonstrated in many solid cancers such as breast cancer [25][26][27][28].…”

Nivolumab and Ipilimumab Acting as Tormentors of Advanced Tumors by Unleashing Immune Cells and Associated Collateral Damage

“…However, this suppression can lead to various adverse effects on the skin. In 2018, tyrosine kinase inhibitors replaced the previous first-line therapy for metastatic renal cell carcinoma [20,21].…”

“…As a coinhibitory receptor, CTLA-4 plays a crucial role in immunological homeostasis by carefully controlling T cell activity to avert autoimmunity [17][18][19][20][21][22][23][24][25]. Its dysregulation highlights its vital role in immune modulation, whether through hypofunction resulting in autoimmunity or excessive expression linked to immunosuppression in malignancy.…”

Silicon switch: Carbon–silicon Bioisosteric replacement as a strategy to modulate the selectivity, physicochemical, and drug‐like properties in anticancer pharmacophores

“…As such, histone deacetylase inhibitors were proven to be able to reverse the activation of tumor suppressor genes, resulting in the inhibition of the viability and malignant proliferation of tumor cells (Hai et al, 2021; Meyer‐Almes, 2019; Sanaei & Kavoosi, 2019). Furthermore, the efficacy of histone deacetylase inhibitors has been demonstrated in a number of clinical studies (Mottamal et al, 2015; Prince et al, 2009; Singh et al, 2018; Slingerland et al, 2014; Weber et al, 2022). Madsen et al, designed and synthesized a silanediol analog ( 39 ) of the histone deacetylase inhibitor vorinostat ( 40 ) (Figure 8), which unfortunately displayed only a marginal activity compared with the parent compounds, but could serve as a lead for further structure–activity relationship studies (Madsen et al, 2014).…”