In a new review study entitled “Molecular Pathways: At the Crossroads of Cancer Epigenetics and Immunotherapy” a team of researchers suggests that epigenetic therapies, when combined with immunotherapy drugs, benefit the clinical outcome of cancer patients. The study was published in the journal Clinical Cancer Research.
Epigenetic modifications are site-specific chemical alterations in DNA that regulate gene expression without altering the DNA sequence itself. Cancer cells have been shown to use epigenetic modifications to avoid recognition by the immune system, a key step in tumor progression, thereby rendering epigenetics a particular important role in clinical outcomes.
Accordingly, the team of scientists led by Michele Maio, MD, PhD, chair of medical oncology and immunotherapy, Ospedale Santa Maria alle Scotte, Istituto Toscano Tumori, in Siena, Italy recently reported that the expression of cell-surface molecules that alert the immune system is “turned-off” via epigenetic changes, allowing cancer cells to remain undetected to the immune system. As such, Maio highlighted that “based on experimental evidence from our studies, we expect that epigenetic drugs could be efficiently utilized to restore the expression of these molecules, thus rendering cancer cells again ‘visible’ to the immune system to effectively eliminate them.”
In this review, the team revised a series of preclinical and clinical studies that support their hypothesis for the potential anti-cancer action of epigenetic drugs, when combined with immunotherapies, such as interleukin-2 therapy, adoptive T-cell transfer, and immune checkpoint inhibitors (immunotherapies is a type of treatment that uses our body own immune system to help fight cancer). Current clinical trials are testing the potential of epigenetic drugs combined with immunotherapies in multiple cancer types, including leukemias, metastatic melanoma, metastatic kidney cancer, peripheral neuroectodermal tumors, non-small cell lung cancer, and metastatic colorectal cancer.
Maio explained that “The data we generated in a mouse model demonstrated that combining epigenetic drugs, such as the DNA methyltransferase inhibitors (DNMTi) 5-aza-2?-deoxycytidine and guadecitabine, with immunomodulating antibodies that target CTLA-4 or the PD-1/PDL-1 immune checkpoint improves the therapeutic efficacy of each drug utilized alone. Based on this experimental evidence, we have now designed a phase Ib clinical trial in which guadecitabine and the anti-CTLA-4 immunomodulating monoclonal antibody ipilimumab will be given in sequence as first-line or second-line therapy to metastatic melanoma patients; this study is sponsored by the NIBIT Foundation and partially supported by Astex Pharmaceuticals.”
He cautioned, however, for potential side effects, particularly myelotoxicity (also known as bone marrow suppression: the decrease in production of key cells of the immune system and erythrocytes), “The major and well-known side effect of DNMTi is myelotoxicity, which poses limits to their dosage and length of administration, and needs to be carefully monitored in the course of treatment,” Maio cautioned. “Along this line, combination regimens with these epigenetic drugs have to be carefully reasoned and evaluated for potential additive myelotoxicity.”
“Like the tango, which takes two and in perfect syntony, the most successful results with cancer immunotherapies will require a perfect interaction between patients’ immune systems and their cancer cells. In light of their powerful immunomodulating potential, epigenetic drugs are seemingly the best ‘partner drugs’ to emerging immunotherapies to achieve this perfect interaction, and will most likely provide additional clinical benefit to cancer patients treated with state-of-the-art immunotherapeutic drugs,” Maio concluded.