Biomarkers May Predict Adverse Reaction to Immunotherapy

Newly identified biomarkers may predict the likelihood that checkpoint inhibitors meant to boost immune response to melanoma will instead backfire, driving hyper-progression of cancerous cells instead. The findings in mice and human tissue also point to a strategy for inhibiting this adverse reaction, to the benefit of the estimated 10% of cancer patients who experience this complication to a treatment that is otherwise often successful.

“There is a continuum between resistance to immunotherapy and the development of a hyper-progressive state,” says Brent Hanks, M.D., Ph.D., associate professor in the Department of Medicine at Duke University School of Medicine and senior author of the study. “While hyper-progression occurs in a small percentage of cancer patients receiving checkpoint inhibitors, identifying the likelihood of this phenomenon has the potential to alter the clinical approach and avoid this complication.”

Hanks and colleagues investigated the underlying mechanism for hyper-progression in melanoma and identified NLRP3 inflammasome, a protein complex rooted in cancer tumors, as a potential source. Inflammasomes are danger sensors that typically help the immune system recognize foreign invaders. In certain cases, however, the researchers found that the NLRP3 inflammasome in tumors reacts to activated T-cell responses and triggers a cascade of events that results in resistance to the checkpoint inhibitors. The inflammasome process then goes into full-out protective mode where it builds an environment that helps cancer cells spread.

Once the process and key actors were identified, the researchers sought a way to determine which patients were at risk for developing hyper-progression prior to initiating checkpoint inhibitor immunotherapy. Using tumor tissue samples from stage IV melanoma patients at Duke, the researchers found that high baseline concentrations of the molecules involved in the inflammasome process were associated with the development of disease hyper-progression and inferior outcomes.

“This work has led to the discovery of predictive biomarkers for checkpoint inhibitor immunotherapy resistance, including a blood-based biomarker and tumor tissue-based biomarker,” Hanks says. “We will be testing these biomarkers for their ability to predict both disease resistance and disease hyper-progression in response to checkpoint inhibitor immunotherapy in a larger cohort of melanoma patients.”

Prior studies have shown that cancer patients who develop hyper-progression while on checkpoint inhibitors have a median overall survival of 4.6 months compared to 7.6 months in patients without the complication. The phenomenon has been shown to occur in multiple tumor types, not only melanoma, but also head and neck, lung, and breast cancers.

Hanks’ lab is also working with Duke colleagues on a clinical trial using a therapy that inhibits the NLRP3 inflammasome among patients whose tumors have developed resistance to checkpoint inhibitor immunotherapies.

The findings were published recently in Science Translational Medicine.