Biomarkers predict melanoma resistance to immunotherapy

Researchers at Duke Cancer Institute have identified potential biomarkers that predict the likelihood that checkpoint inhibitor drugs will backfire, driving hyperprogression in melanoma cells rather than releasing the immune system to fight them
.

Previous studies have shown that the median overall survival was 4.
6 months for patients with hyperprogression of cancer while taking checkpoint inhibitors, compared with 7.
6 months
for patients without complications.
This phenomenon has been shown to occur in many types of tumors, not only melanoma, but also head and neck, lung, and breast cancer
.

The new study in mice and human tissues points to a strategy to inhibit hyperprogression, with an estimated 10 percent of cancer patients likely to benefit
from checkpoint inhibitor immunotherapy.

The study was published Nov.
23 in
the journal Science Translational Medicine.

Brent Hanks, MD, Ph.
D.
, associate professor of medicine at Duke University School of Medicine and senior author of the study, said: "There is a continuous relationship
between resistance to immunotherapy and the development of hyper-progressive states.
"

"While hyperprogression occurs in a small percentage of cancer patients who receive checkpoint inhibitors, the possibility of identifying this phenomenon has the potential to change clinical approaches and avoid this complication
," Hanks said.

Checkpoint inhibitors are a successful cancer case, but hyperprogression has been a troubling side effect
in some patients.
Hanks and his colleagues studied the underlying mechanisms of this process in melanoma, discovering a protein complex rooted in the cancer tumor, called NLRP3 inflammasomes
.

Inflammatorysomes are dangerous sensors that normally help the immune system recognize foreign invaders
.
In some cases, however, the researchers found that NLRP3 inflammasomes in tumors responded to activated T cell responses and triggered cascading events that led to resistance to checkpoint inhibitors
.
The inflammasome process then goes into full-fledged protective mode, which establishes an environment
that helps cancer cells spread.

Once the process and key roles have been identified, the researchers sought a way to determine which patients were at risk
of developing hyperprogression before initiating checkpoint inhibitor immunotherapy.

Using tumor tissue samples from Duke University patients with stage IV melanoma, the researchers found that high baseline concentrations of molecules involved in the inflammasome process were associated with
the development of disease hyperprogression and low survival.

"This work has led to the discovery of predictive biomarkers of checkpoint inhibitor immunotherapy resistance, both blood-based and tumor tissue-based
," Hanks said.
"We will test the ability of these biomarkers in a larger cohort of melanoma patients to predict resistance and disease hyperprogression
to checkpoint inhibitor immunotherapy.
"

Hanks said his team is working with colleagues at Duke University, including April Salama, M.
D.
, on a clinical trial to use a therapy
that inhibits the NLRP3 inflammasome in tumor patients who have developed resistance to checkpoint inhibitor immunotherapy.

The study was supported in part by funding from the National Institutes of Health (R37CA249085, R37CA249085- 02s1, F32CA247067).