Inside Precision Medicine recently featured an article focusing on biomarkers that suggest the likelihood of drugs called checkpoint inhibitors to “backfire” during melanoma treatment. Checkpoint inhibitors are one of the best-known and most successful drug classes discovered thus far including Merck’s Keytruda and Bristol Myers Squibb’s Opdivo.
About Immune Checkpoints
Immune checkpoints are a natural part of our immune system. They prevent an immune response from destroying healthy cells.
But when immune checkpoint proteins and others bind together, they transmit an “off” signal to the T cells thus interfering with the immune system’s ability to destroy cancer.
The Way Forward
Researchers at Duke University discovered why a certain number of patients experience this side effect.
The researchers created a model of a mouse with melanoma and identified NLRP3 inflammasomes which are immune system sensors and receptors that have been associated with various inflammatory disorders.
The team then determined that the inflammasome is responsible for the spread of premetastatic cancer of the lungs. It is also furthered by PD-1. The findings correlated with that of melanoma patients.
Genetic ablation, which is another term for gene silencing, suppressed metastasis in the mouse model. This was an indication to the researchers that they may have found a possible clinical target.
An estimated thirty percent of patients with cancer may be affected by hyper-progression during treatment with checkpoint inhibitors. The median survival while receiving treatment with checkpoint inhibitors is reduced by about two months. The progression may appear in melanoma, head, neck, breast, and lung cancers.
Professor Brent Hanks, the senior author, pointed out the correlation between immunotherapy resistance and a state of hyper-progression.
Science Translational Medicine featured the study on November 23rd in its online edition.
About Hyper-progression
Admittedly, hyper-progression only occurs in a small percentage of patients with cancer who receive checkpoint inhibitors. Yet Professor Hanks looked forward to seeing the potential of altering the current clinical approach to avoid hyper-progression.
The team continued to assess patients they saw as being candidates for hyper-progression before they initiated checkpoint inhibitors. The researchers used samples of tumor tissue considered to be stage IV and discovered high levels of molecules from inflammasome procedures were connected to the inflammasome process. This was associated with hyper-progression of disease and shortened length of survival.
Professor Hanks announced that the team will continue to test the ability of biomarkers to identify disease hyper-progression versus disease resistance as a response to checkpoint inhibitors but in a substantially larger number of patients.
