A multicenter phase Ib trial of the histone deacetylase inhibitor entinostat in combination with pembrolizumab in patients with myelodysplastic syndromes/neoplasms or acute myeloid leukemia refractory to hypomethylating agents

Bewersdorf, Jan Philipp; Shallis, Rory M.; Sharon, Elad; Park, Silvia; Ramaswamy, Rahul; Roe, Caroline E.; Irish, Jonathan M.; Caldwell, Anne; Wei, Wei; Yacoub, Abdulraheem; Madanat, Yazan F.; Zeidner, Joshua F.; Altman, Jessica K.; Odenike, Olatoyosi; Yerrabothala, Swaroopa; Kovacsovics, Tibor; Podoltsev, Nikolai A.; Halene, Stephanie; Little, Richard F.; Piekarz, Richard; Gore, Steven D.; Kim, Tae Kon; Zeidan, Amer M.

doi:10.1007/s00277-023-05552-4

Cited by 6 publications

(1 citation statement)

References 41 publications

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“…They were manifested in the inhibition of Tregs and MDSCs and an increase in the immune response. Unfortunately, this combination of drugs did not help to improve the results of treatment of patients with myelodysplastic syndrome and acute myeloid leukemia (Bewersdorf et al, 2024).…”

Section: Combining Immune Checkpoint Inhibitors With Epigenetic Modif...mentioning

confidence: 99%

Biological mechanisms of resistance to immune checkpoint inhibitors and overcoming this resistance: Challenges in medical oncology

Moskalenko

2024

Regul. Mech. Biosyst.

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Immune checkpoint inhibitors have opened up new possibilities in clinical oncology. Monoclonal antibodies have shown their high clinical efficiency. They block CTLA-4, PD-1, and PD-L1 receptors and activate the immune response. Many patients have stable and even complete responses. However, some patients have primary or acquired resistance. Therefore, the treatment results in this category of patients are not predictable. Mechanisms of resistance to immune checkpoint inhibitors have not been definitively studied. Many theories try to explain the mechanisms of this phenomenon. Our study aimed to structure and combine the data into groups depending on the etiological factor that reduces the immune response. In addition, based on understanding the mechanisms of resistance and the results of recent clinical studies, we aimed to identify the main ways to overcome it. Therefore, mechanisms that lead to resistance may be associated with tumor properties, tumor microenvironment, or patient characteristics. Tumor properties that reduce the immune response include a) low tumor mutation burden and loss of tumor neoantigens, b) changes in the processing or presentation of neoantigens, and c) changes in signaling pathways of tumor development and epigenetic modifications in genes. The tumor microenvironment is represented by stromal and immune cells, extracellular matrix, cytokines, and blood vessels. Each structure can enhance or reduce the immune response and contribute to the acquired resistance to immune checkpoint inhibitors. The effectiveness of the treatment depends not only on the cells in the tumor microenvironment but also on the metabolic background. In addition, the basic characteristics of the patient ( gender, gut microbiota, HLA-I genotype) can modify the immune response. Based on knowledge about the mechanisms of resistance to immune checkpoint inhibitors, several therapeutic strategies aimed at activating antitumor activity have been evaluated. All of them are based on combining immune checkpoint inhibitors with other drugs. One of the most common options is a combination of PD-1/PD-L1 and CTLA-4 inhibitors. Alternative immune checkpoints are TIM-3, LAG-3, TIGIT and VISTA. Combining immunotherapy with chemotherapy, targeted therapy, neoangiogenesis inhibitors, epigenetic modifiers, PARP or TGF-β inhibitors enhances antitumor response by preventing depletion of effector T cells, enhancing T cell infiltration in the tumor, changes on the tumor microenvironment, and decreasing the accumulation of immunosuppressive cells. This review explores the biological mechanisms of resistance and potential ways of solving this problem.

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Section: Combining Immune Checkpoint Inhibitors With Epigenetic Modif...mentioning

confidence: 99%

Biological mechanisms of resistance to immune checkpoint inhibitors and overcoming this resistance: Challenges in medical oncology

Moskalenko

2024

Regul. Mech. Biosyst.

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Epigenetics-targeted drugs: current paradigms and future challenges

Dai,

Qiao,

Fang

et al. 2024

Sig Transduct Target Ther

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Epigenetics governs a chromatin state regulatory system through five key mechanisms: DNA modification, histone modification, RNA modification, chromatin remodeling, and non-coding RNA regulation. These mechanisms and their associated enzymes convey genetic information independently of DNA base sequences, playing essential roles in organismal development and homeostasis. Conversely, disruptions in epigenetic landscapes critically influence the pathogenesis of various human diseases. This understanding has laid a robust theoretical groundwork for developing drugs that target epigenetics-modifying enzymes in pathological conditions. Over the past two decades, a growing array of small molecule drugs targeting epigenetic enzymes such as DNA methyltransferase, histone deacetylase, isocitrate dehydrogenase, and enhancer of zeste homolog 2, have been thoroughly investigated and implemented as therapeutic options, particularly in oncology. Additionally, numerous epigenetics-targeted drugs are undergoing clinical trials, offering promising prospects for clinical benefits. This review delineates the roles of epigenetics in physiological and pathological contexts and underscores pioneering studies on the discovery and clinical implementation of epigenetics-targeted drugs. These include inhibitors, agonists, degraders, and multitarget agents, aiming to identify practical challenges and promising avenues for future research. Ultimately, this review aims to deepen the understanding of epigenetics-oriented therapeutic strategies and their further application in clinical settings.

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