Researchers at the Duke Cancer Institute (USA) have identified potential biomarkers that predict the probability that drugs checkpoint inhibitors are counterproductivedriving the hyperprogression of melanoma cells instead of triggering the immune system to fight them.
Previous studies have shown that cancer patients who develop a hyperprogression while receiving checkpoint inhibitor drugs have a median overall survival of 4.6 months, compared with 7.6 months for patients without this complication. The phenomenon has been shown to occur in multiple types of tumors, not only melanoma, but also those of the head and neck, lungs, and breast.
The new work in mice and in human tissue points to a strategy for inhibit hyperprogressionwhich could benefit 10% of cancer patients suffering from this devastating complication of checkpoint inhibitor immunotherapies.
The study is published in the journal “Science Translational Medicine”.
“There is a continuum between resistance to immunotherapy and the development of a hyperprogressive state,” explains Dr. Brent Hankslead author of the study.
“Although hyperprogression occurs in a small percentage of cancer patients receiving checkpoint inhibitors, identifying the likelihood of this phenomenon has the potential to alter clinical approach and avoid this complication,” Hanks says.
Checkpoint inhibitors have been successful in the fight against cancer, but the hyperregression it has been a worrisome side effect in some patients. Hanks and his colleague investigated the underlying mechanism of this process in melanoma, identifying a protein complex embedded in cancerous tumors called the NLRP3 inflammasome.
Inflammasomes are danger sensors that often help the immune system recognize foreign invaders. However, in certain cases, the researchers found that the NLRP3 inflammasome in tumors reacts to activated T cell responses, triggering a cascade of events that leads to resistance to checkpoint inhibitors. The inflammasome process then goes into a full protective mode where it builds an environment that helps cancer cells spread.
Having identified the process and key players, the researchers sought a way to identify which patients were at risk of developing hyperprogression before initiating checkpoint inhibitor immunotherapy.
The phenomenon has been shown to occur in multiple types of tumors, not only in melanoma, but also in head and neck, lung, and breast tumors.
Using samples of tumor tissue from patients with melanoma in stage IV at Duke, researchers found that high basal concentrations of molecules involved in the inflammasome process were associated with the development of hyperprogressive disease and decreased survival.
This work has led to the discovery of predictive biomarkers of resistance to checkpoint inhibitor immunotherapy, including a blood-based biomarker and a tumor tissue-based biomarker,” says Hanks. “We will test the ability of these biomarkers to predict both resistance and hyperprogression of disease in response to checkpoint inhibitor immunotherapy in a larger cohort of melanoma patients.”
His team is simultaneously working on a clinical trial using a therapy that inhibits the NLRP3 inflammasome among patients whose tumors have developed resistance to checkpoint inhibitor immunotherapies.