CNIO researchers propose new treatment for patients with brain metastases who do not respond to immunotherapy

Immunotherapy against brain metastases (secondary tumors, those that start in another organ and then spread to the brain) has shown clinical benefit when given to asymptomatic patients, but is largely ineffective in symptomatic cases for unknown reasons.

Now a team of researchers from the National Center for Cancer Research (CNIO) has discovered that cancer twists certain brain cells, astrocytes, and causes them to produce a protein that acts in favor of the tumor.

Well, these scientists are proposing a new treatment for brain metastases based on combining a drug with immunotherapy, and providing a biomarker to predict when it should be used.

Specifically, the authors of a study published today in the American Association for Cancer Research journal Cancer Discovery suggest that antibody combination Immune checkpoint blockers with inhibition of local mediated immunosuppression astrocytes may benefit patients with symptomatic brain metastases.

But let’s take it piece by piece. The immune system has a mechanism to destroy viruses, bacteria or cancer cells that attack the body. Cancer grows when tumor cells trick this system into not attacking them.

Cancer immunotherapy uses drugs that prevent cancer cells from blocking the immune system. But immunotherapy doesn’t always work.

“Clinical trials of immunotherapy in patients with brain metastases show variable response rates ranging from 0 to 60%, but benefits are primarily seen in patients with asymptomatic metastases, and response is significantly reduced in patients with symptoms,” he explains. , first author of the study and CNIO researcher. And they are the object of this study.

The reason why this happens is unknown. One hypothesis is the presence of a blood-brain barrier, a type of permeable membrane that filters blood entering the brain and protects it from toxins. But this barrier also stops the entry of antibodies used in immunotherapy. And without antibodies, immunotherapy does not work.

So, CNIO researchers have discovered that certain brain cells called astrocytes interact with the brain’s immune system, and in the case of brain metastasis, they abuse this function to the extent that they interfere with the functioning of the protective cells and damage them. They prevent murder. tumor cells.

“These star-shaped cells that help the brain in normal situations are not a homogeneous population, but rather have great heterogeneity, so we can and want to develop treatments that help fight the tumor without attacking other cells.” healthy tissue,” explains Priego.

And they discovered that some astrocytes produce TIMP1, a protein involved in the deactivation of protective cells that are supposed to destroy cancer cells.

Having demonstrated that TIMP1 acts on cells of the immune system and makes them less effective, CNIO researchers propose using it as a biomarker to detect brain metastases.

“It is an excellent biomarker for patient stratification because it is secreted in higher quantities in patients suffering from brain metastases. In people without metastases, it increases three and four times,” Priego says.

The research goes further. The team led by Manuel Valiente, head of the CNIO group on brain metastases and director of the study, proposes a therapeutic alternative targeting astrocytes: a combination of immunotherapy with inhibitors that prevent the production of the TIMP1 molecule.

In particular, about the drug silibinin, which inhibits this protein and can be used to treat brain metastases using immunotherapy.