Epigenetic treatment turns on a number of silenced genes. Some of them encode molecules in the immune system that turn on immune responses and some turn them off and lead to immune evasion. Immune-inhibiting genes turned on by epigenetic therapy include PD-1, part of the intricate checkpoint system hardwired into the immune system, and its partner PD-L1. Normal human cells need the ability to communicate with immune cells that they are the good guys and should be left alone. Unfortunately, cancer cells exploit the same process to avoid an immune attack.
Drs. Stephen Baylin and Cynthia Zahnow sought out the help of one of the world’s leading cancer immunology experts and their Johns Hopkins Kimmel Cancer Center colleague Drew Pardoll. In some patients with advanced lung, breast and colon cancers being studied, the PD-L1 gene was already active, and laboratory studies indicated that its expression by lung cancer cells might be enhanced by epigenetic therapy. Dr. Pardoll believed that using a drug to block PD-L1 or PD-1 in conjunction with epigenetic therapy could alter the balance of immune effects of the treatment toward an activated immune response right within the tumor. It was worth a try.
For that, Dr. Pardoll recruited the help of his wife and cancer immunology colleague at the Kimmel Cancer Center, Suzanne Topalian, and lung cancer expert Julie Brahmer.
It has been well established that cancer has an immune evasion signal. To survive, cancer cells need to at least partially adapt to their environment. They send out a “don’t look at me” signal to immune cells. Treated with epigenetic drugs however, the ability to evade the immune system is broken and cancer cells send new signals—on one hand, they beckon the immune cells to come and get them, and on the other, they shield against immune attack by expressing PD-L1.
Drs. Baylin, Zahnow, and colleague John Wrangle went back to the laboratory to decipher the immune evasion signature for lung, breast, colon, and ovarian cancers. To do this they looked at all of the genes that get turned on in cancer cells with demethylating drugs.
Lots of genes, they found, get reactivated, but about 20 percent of them are related to immune regulation.
“This is a much bigger component then we thought,” says Dr. Ahuja. “A significant part of what the epigenome does is regulate the immune system.”
Their research revealed a set of genes that are epigenetically programmed to evade detection by the immune system. Using a drug to reverse this programming may force the cancer cells out of hiding and make them more vulnerable to treatment, or even better, allow the immune system to see the cancer and kill it.
“Imagine if we could get the immune system itself to fight the tumors and keep the cancer in check. Then we might have a permanent cure,” says Dr. Zahnow.
They are now working to verify their laboratory findings by studying tumor samples from patients in the most recent Stand Up 2 Cancer lung cancer patient study who are receiving the epigenetic combined therapy of a demethylating agent, histone-blocking HDAC inhibitor and anti-PD-1 treatment.
Dr. Ahuja explains the imagery on the gene expression analysis array. Immune genes that are turned on appear red and those that are suppressed are labeled green. If the epigenetic therapy is working, they should start to turn “green” tumors into “red” tumors.
“The promise is immense,” says Dr. Baylin. “It’s a beautiful concept, and it represents translational science at its best. We hope it is as beautiful in patients. That’s what this trial will show us.”
Chris Gamper with colleague
At the same time, researchers like pediatric oncologist and cancer immunology expert Christopher Gamper are interested in deciphering what epigenetic therapy does to normal immune cells.
His hope is that these drugs may be used to augment the effectiveness of other immune treatments, such as cancer vaccines. Rather than reprogramming cancer cells to make them more susceptible to immune attack, Dr. Gamper would like to reprogram immune soldiers called T-cells that patrol the body looking for danger to make them better at killing cancer cells. Like PD-L1, the researchers are finding that other immune genes also are controlled epigenetically.
The Viral Defense Pathway
Baylin continued his research of epigenetic controls of immune response, collaborating with another epigenetics research giant, Peter Jones, director of research at the Van Andel Institute. Working together as co-leaders of the Stand Up To Cancer Epigenetics Dream Team, they uncovered a viral defense mechanism in tumors that mimics a viral infection. Epigenetic drugs cause it to simulate an infection and summon immune cells to tumors.
“Epigenetic drugs upregulate the viral defense pathway, activating interferon signaling, and this brings in immune cells,” says post-doctoral fellow Kate Chiappinelli. “When epigenetic therapy is followed by anti-PD-1 checkpoint blockade immune therapy, the immune cells go into action against the cancer.”
The viral defense pathway is an ancient human biological mechanism that allows cells to recognize when they have been infected by a virus and helps activate an immune response to the viral invader. Our DNA retains a record of our viral exposure, creating a history that becomes integrated into the genome. This viral record is rendered dormant through epigenetic signaling, but as Baylin and Chiappinelli found, it can be reactivated when epigenetic-targeted therapies are given. Since it is reactivating only a memory of viruses, it only mimics an infection in tumor cells. The fake infection is enough to generate an immune response.
When they examined the DNA of a variety of cancer types, including ovarian cancer, colon cancer, and melanoma, they found that tumors with high expression of the viral defense pathway were more likely to respond to immune therapy with anti-PD-1. Tumors with low viral defense expression could be coaxed into response if epigenetic-targeted drugs were given before immune therapy. The FDA-approved epigenetic drug 5-azacityidine (Aza) converted low viral defense expression to high expression.
“Our research findings are consistent with the previous notion that silencing viral sequences in the human genome is a major function controlled epigenetically,” says Baylin.
Using drugs like Aza to remove the epigenetic controls that silence the noninfectious viral memory locked away within tumor cells activates interferon, a signal to the immune system released by cells when they are invaded by bacteria or viruses. In essence, Aza makes tumor cells think they are infected with a virus and causes them to sound the alarm to alert the immune system. In laboratory experiments when Baylin and Chiapinnelli blocked interferon in tumor cells, the Aza-induced immune response stopped.
To further test their theory, the two collaborated with experts at Memorial Sloan Kettering Cancer Center in New York to examine cancer cells from melanoma patients treated with anti-CTLA-4, another checkpoint blockade immune therapy similar to anti-PD-1. They determined the viral defense pathway expression for each tumor and matched it back to the patients. High viral defense expression matched with all of the patients who responded to immune therapy and low expression matched with those who did not respond.
In a mouse model of melanoma, adding an epigenetic drug to cancers that were not responding to immune checkpoint blockade triggered an immune response. Baylin says the true test will come from clinical studies, but he is energized by these laboratory results.
“This is the most exciting time of my entire career,” he says. “Kimmel Cancer Center scientists have made seminal contributions to the basic science, and now what is happening is almost magical as we make unbelievable transformation to harness the immune system to attack tumors. Our latest findings further decipher the mechanisms that lead to this immune reaction and offer a novel way to potentially boost the success of immune therapies in cancer patients.”
Baylin, like all of the Kimmel Cancer Center researchers and clinicians who held firm to their belief in immune therapy, is most excited by the safe and durable responses it delivers.
“Many people still view cancer as a terminal disease, particularly advanced cancers, and look what we have to put patients through to treat them,” says Baylin. “Immunotherapy promises to change that. It’s already made a huge difference. We have patients now who, against all odds, are alive and living well even when we have not completely eliminated their cancer. I can only imagine what the next 10 years will bring.”
Read apress release from the team’s 2015 publication in Cell, demonstrating a way to trigger a type of immune system “virus alert” that may one day boost cancer patients’ response to immunotherapy drugs.