Will Epigenetic Drugs Improve Immunotherapy Outcomes?

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Researchers are heartened by evidence that demethylating agents may strip tumors of their epigenetic resistance, opening up the door for treatment with immunotherapies.
Researchers are heartened by evidence that demethylating agents may strip tumors of their epigenetic resistance, opening up the door for treatment with immunotherapies.

Epigenetic alterations can reduce or prevent expression of tumor cell-surface proteins, rendering cancer “invisible” to the immune system. In the lab, demethylating agents strip tumors of their epigenetic cloaks, exposing them to immunotherapies like immune checkpoint inhibition, creating optimism about the potential for improved patient outcomes.

Researchers are also identifying other ways epigenetic agents improve antitumor immune responses. Now comes the hard part: clinical validation and figuring out the right agents, dosing, and sequencing.

Tumors impede immune attack with complex molecular arsenals, from robbing lymphocytes of glucose energy to donning molecular gene-silencing “invisibility cloaks” to evade attacking immune cells.1,2

Anticancer immunotherapies seek to bolster patients' antitumor immune responses, but a barrier to successful immunotherapy has been the tumor's ability to keep the immune system from functioning against the cancer, according to Stephen Baylin, MD, Virginia and D.K. Ludwig Professor for Cancer Research and chief of the Cancer Biology Division at the Sidney Kimmel Comprehensive Cancer Center at the Johns Hopkins University in Baltimore, MD.

“The immune cells are there, but like an unarmed army, they hang around and do nothing,” he explained.

A central challenge for immunotherapy has been the acquisition of epigenetic alterations in tumor genomes—cellular changes like methylation in gene expression that can be transmitted to daughter cells during mitosis.

“Epigenetic modifications do not involve structural alterations of the DNA sequence, as in the case of genetic mutations,” explained Michele Maio, MD, PhD, chair of medical oncology and immunotherapy at the Institute Toscano Tumori in Italy in a press release.

“Instead, they are chemical modifications of the DNA structure at specific sites that lead to the ‘hypermethylation' or ‘hypomethylation' of specific DNA elements that regulate gene expression,” he said.

Among the gene products that can be down regulated by these methylation “epimutations” are the tumor cell-surface proteins that allow immune cells to recognize cancers, Dr. Maio noted.

It stands to reason that drugs that reverse epimutations should bolster the benefits of immunotherapies. And now, a growing body of preclinical evidence suggests that might well be the case.2-5

However, it is still early days in translating preclinical findings into clinical evidence of efficacy and no data have been validated in a clinical trial.6

“It's a rational hypothesis, and it needs validity and efficacy,” Dr, Baylin told Cancer Therapy Advisor. But so far, clinical trials are “early and few in number.”

“We expect that epigenetic drugs could be efficiently utilized to restore the expression of these [cell-surface] molecules, thus rendering cancer cells again ‘visible' to the immune system to effectively eliminate them,” Dr. Maio said.

Dr. Maio and his team used a mouse model to demonstrate that combining epigenetic drugs like 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, improved the therapeutic efficacy of each drug.2

RELATED: Immunotherapy Combinations for Renal Cell Carcinoma Offer Promise, Challenges

“Based on this experimental evidence, we have now designed a phase 1b 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 patients with metastatic melanoma,” he added.

That's not the only way epigenetic agents might bolster immune attacks on cancer. They might also have a direct effect on immune cells, noted Jean-Pierre Issa, MD, a professor of medicine and director at the Fels Institute for Cancer Research and Molecular Biology at Temple University School of Medicine in Philadelphia, PA.

“Epigenetic priming may not be limited to changing cell-surface antigens—the epigenetic drugs could have a direct effect on immune cells themselves, making lymphocytes even more immunogenic,” Dr. Issa explained.

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