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Epigenetic Inhibitors: Strategies to Enhance Patient Response to Immunotherapy

Major breakthroughs in the treatment of patients with multiple types of cancer have been achieved by drugs targeting the immune checkpoint pathway. However, despite the promise of immune checkpoint inhibitors as single-agent therapies, the majority of patients either do not respond or eventually progress due to innate or acquired resistance.

Therefore, recent research efforts have focused on combining immunotherapy with targeted therapies. There is growing evidence suggesting that targeted therapies can induce immune effects in tumor cells, the host immune system, and the tumor microenvironment.

Epigenetic Agents Could Enhance Immunotherapy Efficacy

Particularly, the efficacy of immunotherapy drugs may be further enhanced through combining with epigenetic agents. Currently, there are two classes of epigenetic drugs in the clinical setting, which act through the inhibition of the enzymatic activities responsible for epigenetic transcriptional silencing:

  • DNA-methyltransferase (DNMT)
  • Histone deacetylase (HDAC)

DNMT Inhibitors Prevent DNA Methylation and Reduce Cell Proliferation

DNMT inhibitors operate by preventing the addition of methyl groups to genes in cancer cells (1). This is effective as DNA methylation results in the silencing of genes that reduce the speed of cell division, resulting in uncontrolled proliferation. Two drugs that inhibit DNA methylation, azacitidine (Vidaza®) and decitabine (Dacogen®), have been approved by the FDA for treatment of blood cancer.

HDAC Inhibitors Selectively Alter Gene Transcription

HDACs act as transcriptional repressors, due to histone deacetylation, and consequently promote chromatin condensation. Acetylation of histones promotes a more relaxed chromatin structure, allowing transcriptional activation. HDAC inhibitors selectively alter gene transcription, in part, by enabling the chromatin structure to become more relaxed and by changes in the structure of proteins in transcription factor complexes (2), allowing transcriptional activation.

HDACi were initially discovered based on drug screens for differentiation inducers in leukemia (3). There are currently four HDAC inhibitors that have been approved by the FDA:

  1. vorinostat (Zolinza®) for the treatment of refractory cutaneous T cell lymphoma (CTCL)

  2. romidepsin (Istodax®) for the treatment of CTCL and peripheral T cell lymphoma (PTCL)

  3. belinostat (Beleodaq®) for the treatment of PTCL.

  4. oral panobinostat (Farydak®), approved by the FDA in early 2015, as a combination therapy with bortezomib and dexamethasone in patients with recurrent multiple myeloma who have received at least two prior treatment regimens, including bortezomib and an immunomodulatory agent, also being currently studied for other types of cancer.

Immune Evasion is Partly Driven by Altered Epigenetic Markers

Immune evasion is a complex phenomenon that entails alterations in cancer cells and the microenvironment, to inhibit recognition of tumor cells by immune infiltrating cells. It is well established that a fundamental mechanism by which tumors evade immune surveillance is by down-modulating antigen processing machinery.

Therefore, expression of tumor antigen is downregulated, which can lead to enhanced tumor incidence and metastasis due to cytotoxic T lymphocytes (CTL) no longer recognizing target antigens on the tumor cells. This complex process is driven by a multitude of factors including altered epigenetic markers on the tumor cells that control gene expression.

Epigenetic Agents Can Induce Re-Expression of Tumor-Associated Antigens to Overcome Immune Evasion

Studies have demonstrated that epigenetic agents which function to inhibit either DNMT or HDAC can induce protein expression of Tumor-Associated Antigens (e.g. MAGE, NY-ESO-1, etc).

In addition, these agents upregulate human leukocyte antigen (HLA) class I antigens and an array of co-stimulatory molecules important for T cell function. As a result, tumor specific antigens that were silenced by the cancer cell to evade immune detection get switched back on.

Moreover, HDAC and DNMT inhibitors have been shown to eradicate myeloid derived suppressor cells in syngeneic mouse tumor models (4).

Ideal Combination Therapy with Checkpoint Inhibitors

With the growing evidence on the mechanisms of tumor antigen re-expression by epigenetic inhibitors, these agents are therefore ideal for combination with checkpoint inhibitors, especially in tumors that are phenotypically less immunogenic.

References and Further Reading on Epigenetic Agents

  1. Li Y and Tollefsbol TO. Impact on DNA methylation in cancer prevention and therapy by bioactive dietary components. Curr Med Chem. 2010; 17(20): 2141–2151.
  2. Gui CY, Ngo L, Xu WS, et al. Histone deacetylase (HDAC) inhibitor activation of p21WAF1 involves changes in promoter-associated proteins, including HDAC1. Proc Natl Acad Sci U S A. 2004 Feb 3;101(5):1241-6.
  3. Jones PA, Issa JP, Baylin S. Targeting the cancer epigenome for therapy. Nat Rev Genet. 2016 Sep 15;17(10):630-41.
  4. Kim K, Skora AD, Li Z et al. Eradication of metastatic mouse cancers resistant to immune checkpoint blockade by suppression of myeloid-derived cells. Proc Natl Acad Sci U S A. 2014 Aug 12;111(32):11774-9.

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