Will Epigenetic Drugs Improve Immunotherapy Outcomes?

Demethylating drugs may also enhance immunotherapy by lowering or eliminating myeloid-derived suppressor cells, which are believed to be involved in hastened tumor growth, Dr. Maio noted.

“I am very optimistic about this approach,” noted Amir A. Toor, MD, associate professor of medicine at the Massey Cancer Center at Virginia Commonwealth University in Richmond, VA. “Epigenetic modification is very likely to augment immunotherapy trials, as we demonstrated some years ago.”

Dr. Toor’s team reported evidence in 2012 that epigenetic induction of adaptive immune response in multiple myeloma might be possible using sequential therapy with the demethylating agent 5-azacitidine and lenalidomide.⁷

“There are epigenetic drugs that offer a real opportunity to sensitize patients to immunotherapy—it’s an ongoing and very important discussion,” says Dr. Baylin.

Dr. Baylin’s team authored one of two papers recently published in the journal Cell, showing that in human cancer cell lines and mice, epigenetic demethylating agents increase immune system antitumor vigilance by reversing tumors’ silencing of immune antiviral genes.^4,5 By reversing tumors’ epigenetic silencing of these genes with 5-azacytidine, a “virus alert” pathway is activated, and tumor cells release interferons, mobilizing an antitumor immune response, Dr. Baylin and his colleagues reported. The response involves transcriptional activation of endogenous retroviral sequences—bits of viral DNA that have been incorporated into the human genome over millions of years.^4,5

In a mouse melanoma model, 5-azacytidine was associated with improved ipilimumab tumor responses, they found. 

It comes down to “making the cell act like it’s seen a virus, triggering an ancient viral defense pathway,” Dr. Baylin explained. “This is a core mechanism that might be central to everything we’re talking about.”

Toxicity is a concern, and DNMTi is well-known to induce myelotoxicity, Dr. Maio acknowledged. “Combination regimens with these epigenetic drugs have to be carefully reasoned and evaluated for potential additive myelotoxicity,” he said.

CTLA4 checkpoint inhibitors seem to be “quite a bit more toxic” than PD-1 agents, noted Dr. Issa.

But there’s relatively little overlap in the toxicity profiles of epigenetic drugs and immunotherapies, others note–and so far, at least, no evidence of toxic synergies between these classes of drugs.

Given their “powerful immunomodulating potential,” Dr. Maio believes epigenetic agents will “most likely provide additional clinical benefit to patients with cancer treated with state-of-the-art immunotherapeutic drugs.”

“The paradigm could be right, but you have to figure out how to do dose and timing,” cautioned Dr. Baylin. “I’m excited about the potential here, but it’s potential at this point—we really need to show how far this can go in the clinic, how powerful it will be.”

“Will some patients get worse before they get a chance to benefit from the drugs?” added Dr. Issa. “One strategy is 2 months of methylation inhibitor followed by an immune checkpoint inhibitor—that looks quite reasonable. But the concern is that patients might progress during those 2 months. Another strategy is to give 1 drug for the first week and then come in at week 2 with a checkpoint inhibitor. That’s being tested in the clinic now.”

Ultimately, the only way to prove the benefit of epigenetic priming for anticancer immunotherapy is randomized clinical trials.

RELATED: T-VEC Immunotherapy Demonstrates Activity Against Locally Advanced Melanoma

A randomized phase 2 clinical trial is now accruing study participants at Johns Hopkins, to test the value of epigenetic priming for PD-1 immune checkpoint inhibition against non-small-cell lung cancer (NSCLC).⁸ Patients in the investigational arm will be administered 5-azacitidine and entinostat, followed by nivolumab.

“The excitement is that, should a strategy like this work, it might actually increase cure rates—might lead to not just shrinking tumors but some cures,” Dr. Issa said. “The potential payoff is very large.”

References

1. Sukumar M, Roychoudhuri R, Restifo NP. Nutrient competition: a new axis of tumor immunosuppression. Cell. 2015;162(6):1206-1208.
2. Maio M, Covre A, Fratta E, et al. Molecular pathways: at the crossroads of cancer epigenetics and immunotherapy. Clin Cancer Res. 2015;21(18):4040-4047.
3. Licht JD. DNA methylation inhibitors in cancer therapy: the immunity dimension. Cell. 2015;162(5):938-939.
4. Roulois D, Yau HL, Singhania R, et al. DNA-demethylating agents target colorectal cancer cells by inducing viral mimicry by endogenous transcripts. Cell. 2015;162(5):961-973.
5. Chiappinelli KB, Strissel PL, Desrichard A, et al. Inhibiting DNA methylation causes an interferon response in cancer via dsRNA including endogenous retroviruses. Cell. 2015;162(5):975-986.
6. Jones PA, Baylin SB. The epigenomics of cancer. Cell. 2007;128(4):683-692.
7. Toor AA, Payne KK, Chung HM, et al. Epigenetic induction of adaptive immune response in multiple myeloma: sequential azacitidine and lenalidomide generate cancer testis antigen-specific cellular immunity. Br J Haematol. 2012;158(6):700-711.
8. ClinicalTrials.gov. Phase II anti-PD1 epigenetic priming study in NSCLC. (NA_00084192). https://www.clinicaltrials.gov/ct2/show/NCT01928576?term=NCT+01928576&rank=1. Updated March 17, 2015. Accessed September 29, 2015.