Background Treatment with immune checkpoint inhibitors (ICIs) targeting CTLA-4 and the PD-1/PD-L1 axis is effective against many cancer types. However, due in part to unresponsiveness or acquired resistance, not all patients experience a durable response to ICIs. HBI-8000 is a novel, orally bioavailable class I selective histone deacetylase inhibitor that directly modifies antitumor activity by inducing apoptosis, cell cycle arrest, and resensitization to apoptotic stimuli in adult T cell lymphoma patients. We hypothesized that HBI-8000 functions as an epigenetic immunomodulator to reprogram the tumor microenvironment from immunologically cold (nonresponsive) to hot (responsive). Method Mice bearing syngeneic tumors (MC38 and CT26 murine colon carcinoma and A20 B-cell lymphoma were treated daily with HBI-8000 (orally), alone or in combination with PD-1, PD-1 L, or CTLA-4 antibodies. MC38 tumors were also analyzed in nanoString gene expression analysis. Results HBI-8000 augmented the activity of ICI antibodies targeting either PD-1, PD-L1 or CTLA-4, and significantly increased tumor regression (p < 0.05) in the above models. Gene expression analysis of the treated MC38 tumors revealed significant changes in mRNA expression of immune checkpoints, with enhanced dendritic cell and antigen-presenting cell functions, and modulation of MHC class I and II molecules. Conclusions These findings suggest that HBI-8000 mediates epigenetic modifications in the tumor microenvironment, leading to improved efficacy of ICIs, and provide strong rationale for combination therapies with ICIs and HBI-8000 in the clinical setting. Precis As an HDACi, HBI-8000 plays an important role in priming the immune system in the tumor microenvironment. The current preclinical data further justifies testing combination of HBI-8000 and ICIs in the clinic.

Adult T‐cell leukemia/lymphoma (ATL) is an aggressive T‐cell malignancy caused by human T‐cell lymphotropic virus 1. Treatment options for acute ATL patients include chemotherapy, stem cell transplantation, and recently the anti‐chemokine (C‐C motif) receptor 4 antibody, although most patients still have a poor prognosis and there is a clear need for additional options. HBI‐8000 is a novel oral histone deacetylase inhibitor with proven efficacy for treatment of T‐cell lymphomas that recently received approval in China. In the present study, we evaluated the effects of HBI‐8000 on ATL‐derived cell lines and primary cells obtained from Japanese ATL patients. In most cases HBI‐8000 induced apoptosis in both primary ATL cells and cell lines. In addition, findings obtained with DNA microarray suggested Bim activation and, interestingly, the contribution of the NLR family, pyrin domain containing 3 (NLRP3) inflammasome pathway in HBI‐8000‐induced ATL cell death. Further investigations using siRNAs confirmed that Bim contributes to HBI‐8000‐induced apoptosis. Our results provide a rationale for a clinical investigation of the efficacy of HBI‐8000 in patients with ATL. Although the role of NLRP3 inflammasome activation in ATL cell death remains to be verified, HBI‐8000 may be part of a novel therapeutic strategy for cancer based on the NLRP3 pathway.

Tucidinostat (formerly known as chidamide) is an orally available, novel benzamide class of histone deacetylase (HDAC) inhibitor that selectively blocks class I and class IIb HDACs. This multicenter phase IIb study aimed to investigate the efficacy and safety of tucidinostat, 40 mg twice per week (BIW), in patients with relapsed/refractory (R/R) peripheral T-cell lymphoma (PTCL). The primary endpoint was overall response rate (ORR) assessed by an independent overall efficacy review committee. Between March 2017 and March 2019, 55 patients were treated, and 46 and 55 were evaluated for efficacy and safety, respectively. Twenty-one of 46 patients achieved objective responses with an ORR of 46% (95% confidence interval [CI]: 30.9, 61.0), including five patients with complete response (CR). Responses were observed across various PTCL subtypes. In angioimmunoblastic T-cell lymphoma, there were 2 CRs and 5 partial responses (PR) among eight patients, achieving an ORR of 88%. The disease control rate (CR + PR + stable disease) was 72% (33/46). The median progression-free survival, duration of response, and overall survival were 5.6 months, 11.5 months, 22.8 months, respectively. The most common adverse events (AEs) (all grades) were thrombocytopenia, neutropenia, leukopenia, anemia, and diarrhea. The grade ≥ 3 AEs emerging in ≥20% of patients included thrombocytopenia (51%), neutropenia (36%), lymphopenia (22%), and leukopenia (20%). Importantly, most of the AEs were manageable by supportive care and dose modification. In conclusion, the favorable efficacy and safety profiles indicate that tucidinostat would be a new therapeutic option in patients with R/R PTCL. (ClinicalTrials.gov identifier: NCT02953652)

This multicenter, prospective phase IIb trial evaluating the efficacy and safety of tucidinostat (HBI‐8000) in patients with relapsed or refractory (R/R) adult T‐cell leukemia/lymphoma (ATLL) was undertaken in Japan. Eligible patients had R/R ATLL and had failed standard of care treatment with chemotherapy and with mogamulizumab. Twenty‐three patients received tucidinostat 40 mg orally twice per week and were included in efficacy and safety analyses. The primary end‐point was objective response rate (ORR) assessed by an independent committee. The ORR was 30.4% (95% confidence interval [CI], 13.2, 52.9]. Median progression‐free survival was 1.7 months (95% CI, 0.8, 7.4), median duration of response was 9.2 months (95% CI, 2.6, not reached), and median overall survival was 7.9 months (95% CI, 2.3, 18.0). All patients experienced adverse events (AEs), which were predominantly hematologic and gastrointestinal. Incidence of grade 3 or higher AEs was 78.3%; most were laboratory abnormalities (decreases in platelets, neutrophils, white blood cells, and hemoglobin). Tucidinostat was well tolerated with AEs that could be mostly managed with supportive care and dose modifications. Tucidinostat is a meaningful treatment option for R/R ATLL patients; further investigation is warranted.

Objective HBI-8000 (tucidinostat) is a novel, oral histone deacetylase inhibitor that selectivity inhibits Class I (histone deacetylase 1, 2, 3) and Class II (histone deacetylase 10) with direct anti-tumor activity through various mechanisms of action, including epigenetic reprogramming and immunomodulation. It has been approved in China for the treatment of relapsed or refractory peripheral T-cell lymphoma. Methods This multicenter, prospective phase I dose-escalation trial evaluating the safety of twice weekly HBI-8000 was conducted in Japan. Eligible patients had non-Hodgkin’s lymphoma and no available standard therapy. The primary endpoint was maximum tolerated dose; secondary endpoints included anti-tumor activity, safety and pharmacokinetics. Results Fourteen patients were enrolled in the study. Twelve patients were assessed for dose-limiting toxicity: six patients in the 30 mg BIW cohort had no dose-limiting toxicitys; two of six patients in the 40 mg BIW cohort had asymptomatic dose-limiting toxicitys. Treatment was well tolerated; adverse events were predominantly mild to moderate hematologic toxicities and were managed with dose modification and supportive care. Thirteen patients were included in the efficacy analysis. Objective response was seen in five of seven patients in the 40 mg BIW cohort; three partial responders had adult T-cell leukemia-lymphoma. In the 30 mg BIW cohort, three of six patients had stable disease after the first cycle. Conclusions Treatment with HBI-8000 30 and 40 mg BIW were well-tolerated and safe, with hematological toxicities as expected from other studies of histone deacetylase inhibitor. The maximum tolerated dose and recommended dosage for phase II studies of HBI-8000 is 40 mg BIW. Preliminary efficacy results are encouraging.