Triggering Body's 'Virus Alert' Could Help Response to Cancer Treatment

Findings could boost the efficacy of immunotherapy drugs.

Researchers at the Johns Hopkins Kimmel Center and elsewhere have developed a way to trigger a “virus alert” within the body that, in theory, should help the response of patients with cancer to immunotherapy drugs.

An increasingly promising focus of cancer research, the drugs are designed to disarm cancer cells’ ability to avoid detection and destruction by the immune system.

The Johns Hopkins research team said it has found a core group of genes related to both a viral defense warning system and susceptibility to a demethylating drug called 5-azacytidine that chemically alters their ability to operate through a process called demethylation.

Tumors adopt cellular gene-silencing systems that add small chemicals called methyl groups to areas of genes, which in effect turn of the affected gene function. This process occurs in many genes, including ones that contain DNA leftover from previous exposures to viruses. When the process is removed, the virus-laden gene sequences are activated and trigger a body-wide alert that a virus has invaded the system.

“A main barrier to immune therapy success has been the tumor’s ability to keep the immune system from functioning against the cancer,” said study leader Stephen Baylin, MD, the Virginia and Daniel K. Ludwig Professor of Cancer Research at the Kimmel Cancer Center. “The immune cells are there, but like an unarmed army, they hang around and do nothing. However, certain epigenetic processes that silence such viral defense genes can be reversed in tumor cells with a demethylating drug, making immunotherapies work more effectively to kill cancer cells.”

The new study evaluated cell lines from human ovarian, colon, and skin cancer. In the cancer cell lines, researchers found that the viral defense pathway can be turned on when the cells were exposed to 5-azacytidine. Once the pathway is activated, the tumor cells release signaling proteins called interferons that activate other cancer-fighting cells in the immune system.

The Johns Hopkins team of researchers created a gene signature of the viral defense pathway. Scientists used the gene signature to distinguish between tumor samples with high expression of the pathway from those with low expression. The determined that high expression may response to immunotherapy drugs without the aid of 5-azacytidine, but those with low-expression may need 5-azacytidine to boost response to immunotherapy, according to Baylin.

Scientists also observed that in a melanoma mouse model, ipilimumab, an immune therapy drug, was found to be effective treatment. However, the addition of 5-azacytidine to ipilimumab triggered a better tumor response.

“Our findings further decipher the mechanisms that lead to this tumor cell immune reaction and offer a way to potentially boost the success of immune therapies in patients with cancer,” said Baylin.

Baylin and colleagues attest that if their findings are confirmed and extended in clinical trials, the 5-azacytidine treatment could be followed by ipilimumab or other types of immunotherapy called checkpoint blockade, which lower cancer cells’ defenses and allow immune system cells to see and destroy them.

“Treatment with 5-azacytidine activates interferon signaling in tumor cells and, when followed by checkpoint blockade immune therapy, the immune cells could go into increased action against the cancer,” said Johns Hopkins research fellow and lead author Katherine Chiappinelli, PhD.

Further research needs to be done in order to evaluate the effectiveness of the strategy of alerting the viral defense pathway, but scientists remain hopeful that the method will yield positive results in clinical trials, allowing scientists to develop targeted medicines for the fight against cancer and other infectious diseases.