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Immune Checkpoint Inhibitors May Work in Brain Cancers

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Key Points

  • Patients with glioblastoma had fewer T-cells, and therefore less activation of the immune system, than patients with brain metastases.
  • PD-L1 was common in both glioblastoma and brain metastases, with glioblastoma showing particularly high PD-L1 positivity.
  • The findings demonstrate that the immune system interacts with glioblastoma and brain metastases, which is evidence that immune checkpoint inhibitors may work in these patients.

New evidence that immune checkpoint inhibitors may work in glioblastoma and brain metastases was presented today at the ESMO Symposium on Immuno-Oncology 2014 in Geneva (Abstract 1O). The novel research shows that brain metastases of tumor infiltrating lymphocytes, providing an immunoactive environment. Moreover, both primary and secondary brain cancers often exhibit high expression of PD-L1, which can be inhibited by new treatments that activate the immune system.

Immune checkpoint inhibitors are a new group of cancer treatments that work by boosting the patient’s immune response to the tumor. The immune system operates differently in the brain in comparison to other organs. “Patients with glioblastoma and brain metastases have very few treatment options and usually die within a short period of time,” said Anna Sophie Berghoff, MD, of the Medical University of Vienna, who presented the findings. “Our study was designed to find out whether the immune system is activated and working in brain tumors, which would provide the foundation for immune checkpoint inhibitors to work.”

Study Details

The study included 117 patients with glioblastoma and 116 patients with brain metastases. Using immunohistochemistry the researchers looked for the presence of T-cells—also called tumor infiltrating lymphocytes—in the tumors and whether they were accentuated in different areas of the tumor. They also looked for PD-L1, an immunosuppressive protein that influences responses to immune checkpoint inhibitors.

The researchers found that patients with glioblastoma had fewer T cells, and therefore less activation of the immune system, than patients with brain metastases who had high concentrations of T cells. They also found that PD-L1 was common in both glioblastoma and brain metastases, with glioblastoma showing particularly high PD-L1 positivity.

“We saw that these brain tumor types have a different interaction with the immune system. The glioblastoma actively suppresses the immune system, and there is little immune response. In contrast the brain metastases do a little less suppression of the immune system, and there are a lot more tumor-infiltrating lymphocytes,” Dr Berghoff said.

Dr. Berghoff said the findings demonstrate that the immune system interacts with glioblastoma and brain metastases, which is evidence that immune checkpoint inhibitors may work. “We have arguments for conducting clinical studies with immune checkpoint inhibitors in patients with glioblastoma and brain metastases,” she said. “In both tumor types we commonly see high expression of PD-L1…. By inhibiting the suppression you can activate the immune system which in theory would work in brain cancers.”

She continued, “We know that immune checkpoint inhibitors are more effective in immunoactive microenvironments. In brain metastases we see dense infiltration with T-cells which provides a good background for immune checkpoint inhibitors.”

Potential for Treatment

Small preliminary studies have shown efficacy of immune checkpoint inhibitors in melanoma brain metastases. However, melanoma is only the third most common brain metastases, the most common being non–small cell lung cancer. Immune checkpoint inhibitors are active in lung cancer with extracranial metastases but it is unknown whether this holds true for patients with brain metastases. Data on immune checkpoint inhibitors in glioblastoma exists only in mice.

“Our study shows that T-cells and PD-L1 expression are present in glioblastoma and brain metastases. This means that the targets for novel drugs that activate the immune system against cancer cells are present and brain tumors may be effectively treatable with such drugs,” Dr. Berghoff said.

She concluded, “Our data strongly support the launch of clinical trials with immune checkpoint inhibitors, especially the ones targeting the PD-1/PD-L1 axis, in patients with glioblastoma and brain metastases. Indeed, some early studies are being designed and started at the moment. In addition, profiling of other immune checkpoint molecules and modes of immune escape in brain tumors need to be identified to prepare for the development of next generation immunomodulators.”

Study Implications

Commenting on the implications of the findings for patients with glioblastoma and brain metastases, Martin J. van den Bent, MD, of Erasmus Medical Center, Rotterdam, the Netherlands, said, “The investigators found different immune reactions to the malignant process in the brain that were related to the type of cancer. It is quite interesting that the immune system does play a role in brain metastases as well. The findings indicate that therapeutic interventions for brain cancers that use the immune system should be explored.”

Dr. van den Bent commented that brain metastases are not a homogenous group but vary depending on the primary tumor. He posited that the type of immune reaction to brain metastases would differ between the various tumor types, noting that “the mechanism with which metastases arise can be completely different between the various diseases.”

“The debate on the penetration through the intact blood brain barrier and how significant that is for treatment effectiveness is still on the table,” Dr. van den Bent continued. “But the general understanding is that any therapy that works for a specific type of cancer will also work if it has metastasized to the brain provided the access is good.”

The study authors reported no potential conflicts of interest.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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