Opioids interfere with cancer immunotherapy but these drugs could help

Opioids are often first-line treatments for cancer-related pain, but they can suppress the immune system and reduce the effectiveness of immunotherapy. New research from the University of Pittsburgh and UPMC Hillman Cancer Center found that a type of drug called peripherally restricted OPRM1 antagonists (PAMORAs) blocked opioid-induced immunosuppression and improved response rates to immune checkpoint inhibitor therapy in a mouse model of head and neck cancer.

The findings, published in the Journal for ImmunoTherapy of Cancer, suggest that PAMORAs could be given alongside immunotherapy and opioids to limit the negative effects of opioids on cancer treatment while maintaining pain relief.

“It is imperative — especially in head and neck cancer, which is one of the most painful cancers — that patients are comfortable during treatment,” said senior author Nicole Scheff, Ph.D., assistant professor in the Department of Neurobiology at the Pitt School of Medicine and UPMC Hillman. “Opioids, such as morphine, are the primary and most dependable strategy for cancer pain management, but our research shows that they limit the ability of immune checkpoint inhibitors to reactivate the tumor-associated immune response.”

In the new study, Scheff and her team found that morphine suppressed response to anti-PD1 immune checkpoint therapy in a mouse model of oral cancer. Animals that received morphine had fewer cancer-killing CD8 T cells in their tumors, larger tumors and worse survival.

By analyzing samples from both mice and patients with head and neck cancer, the researchers found that morphine binds to an opioid receptor called OPRM1 on CD8 T cells, suppressing their activity and canceling out the invigorating effects of anti-PD1 therapy.

According to Scheff, immune checkpoint therapies are becoming standard of care for recurrent and metastatic cancer, but response rates are less than 20% in head and neck cancer.

“The most exciting part of this research is that we were able to potentially identify why a subset of head and neck cancer patients who, on paper, should respond to immune checkpoint inhibitors, do not,” said Scheff. “To improve response rates, clinicians could limit opioid prescriptions prior to immunotherapy. In cases where that is not an option due to severe pain, our research suggests that PAMORAs can keep analgesia intact and allow the immune system to do its job.”

PAMORAs block the effects of opioids throughout the body but because they cannot cross the blood-brain barrier, they preserve pain-relieving properties of these drugs. Methylnaltrexone is approved by the U.S. Food and Drug Administration for relieving opioid-induced constipation, while axelopran is a new drug in development.

When given alongside morphine, methylnaltrexone and axelopran almost completely blocked opioid-induced immunosuppression in mice, allowing anti-PD1 to be effective.

Now, the researchers are investigating how other opioid derivatives that act on the OPRM1 receptor, such as buprenorphine, affect the immune system.

Other authors in the study are listed in the manuscript.

This work was supported by the National Institutes of Health (R01DE033473).