Domatinostat favors the immunotherapy response by modulating the tumor immune microenvironment (TIME)

Abstract

Background: The efficacy of PD-(L)1 blockade depends on the composition of the tumor immune microenvironment (TIME) and is generally higher in tumors with pre-existing cytotoxic T cells (CTL) than in those with low CTL numbers. Nonetheless, a significant proportion of patients with pre-existing immunity fail to respond, indicating a therapeutic potential for combining PD-(L)1 blockade with additional immunomodulatory agents in both CTL-high and-low immune phenotypes. Here, we evaluated domatinostat (4SC-202), a class I-selective histone deacetylase (HDAC) inhibitor, for its effect on the TIME and its antitumoral efficacy using syngeneic mouse models with CTL-high or CTL-low tumors. Methods: Domatinostat was evaluated in PD-1 blockade-insensitive CTL-low (CT26) and CTL-high (C38) syngeneic models alone and in combination with different immune-inhibitory and-stimulatory approaches. Effects on the immunophenotype were assessed via flow cytometry and RNA-seq analyses. The changes in RNA-seq-based immune signatures determined in a murine setting were investigated in patient samples from the first-dose cohort of the SENSITIZE trial (NCT03278665) evaluating domatinostat combined with pembrolizumab in advanced-stage melanoma patients refractory/nonresponding to PD-1 blockade. Results: Domatinostat increased the expression of antigen-presenting machinery (APM) genes and MHC class I and II molecules, along with CTL infiltration, in tumors of both immune phenotypes. In combination with PD-(L)1 blockade, domatinostat augmented antitumor effects substantially above the effects of single-agent therapies, displaying greater benefit in tumors with pre-existing CTLs. In this setting, the combination of domatinostat with agonistic anti-4-1BB or both PD-1 and LAG3 blockade further increased the antitumor efficacy. In CTL-low tumors, domatinostat enhanced the expression of genes known to reinforce immune responses against tumors. Specifically, domatinostat increased the expression of Ifng and genes associated with responses to pembrolizumab and nivolumab. Clinically, these findings were confirmed in patients with advanced melanoma treated with domatinostat for 14 days, who demonstrated elevated expression of APM and MHC genes, the IFNG gene, and the IFN-γ and pembrolizumab response signatures in individual tumor samples. Conclusion: In summary, these data suggest a promising potential of domatinostat in combination with immunotherapy to improve the outcome of refractory cancer patients.

The HDAC Inhibitor Domatinostat Promotes Cell-Cycle Arrest, Induces Apoptosis, and Increases Immunogenicity of Merkel Cell Carcinoma Cells

“…This observation explains previous reports, that Domatinostat enhances the infiltration of cytotoxic T cells into tumors of syngeneic mouse models resulting in synergistic effects when combined with immune checkpoint blocking antibodies(Hamm et al, 2018). Moreover,Bretz et al (2019), recently investigated the changes in immune gene expression signatures by RNA-seq of patient samples obtained in the SENSITIZE trial (NCT03278665). This trial evaluates the efficacy of domatinostat combined with pembrolizumab in advanced-stage melanoma patients refractory/non-responding to prior PD-1 blockade.…”

“…syngeneic colorectal models, it induces infiltration of cytotoxic T cells into the tumor microenvironment and synergizes with immune checkpoint inhibitors treatment(Bretz et al, 2019). However, the relevance of the different working mechanisms of domatinostat and other HDACi are not fully understood.…”

The Fate of Th17 Cells is Shaped by Epigenetic Modifications and Remodeled by the Tumor Microenvironment

“…The use of the class I-selective HDAC inhibitor Domatinostat to enhance the expression of PD-1 on immune cells or PD-L1 on tumor cells and then to potentiate the efficiency of immunotherapies has been investigated by Bretz et al and has shown promising results in mice with an increase of lymphocyte infiltration and tumor regression. This study further supports the development of epigenetic therapy in combination with existing cancer immunotherapy [92]. Another study showed that the inhibition of LSD1 (histone lysine-specific demethylase) associated with an anti-PD-1 antibody suppressed tumor growth and lung metastases in breast cancer.…”

In silico analyses of the tumor microenvironment highlight tumoral inflammation, a Th2 cytokine shift and a mesenchymal stem cell-like phenotype in advanced in basal cell carcinomas

“…Omland et al successfully used 18 BCC samples to characterize important markers for cancer-associated fibroblasts and extra-cellular matrix remodeling, which were further validated experimentally (Omland et al 2017b). A recent melanoma study compared the tumor environment by Gene Set Expression Analysis in six melanoma pre-treatment and six posttreatment samples (Bretz et al 2019), which is similar in number to our vismodegib-sensitive BCC group. Second, given the in-silico nature, this study lacks histopathological validation by immunohistochemistry.…”